Current Clinical Strategies of Pancreatic Cancer Treatment and Open Molecular Questions - Brunner, Maximilian; Wu, Zhiyuan; Krautz, Christian; Pilarsky, Christian; Grützmann, Robert; Weber, Georg (International Journal of Molecular Sciences, 2019)
Pancreatic cancer is one of the most lethal malignancies and is associated with a poor prognosis. Surgery is considered the only potential curative treatment for pancreatic cancer, followed by adjuvant chemotherapy, but surgery is reserved for the minority of patients with non-metastatic resectable tumors. In the future, neoadjuvant treatment strategies based on molecular testing of tumor biopsies may increase the amount of patients becoming eligible for surgery. In the context of non-metastatic disease, patients with resectable or borderline resectable pancreatic carcinoma might benefit from neoadjuvant chemo- or chemoradiotherapy followed by surgeryPatients with locally advanced or (oligo-/poly-)metastatic tumors presenting significant response to (neoadjuvant) chemotherapy should undergo surgery if R0 resection seems to be achievable. New immunotherapeutic strategies to induce potent immune response to the tumors and investigation in molecular mechanisms driving tumorigenesis of pancreatic cancer may provide novel therapeutic opportunities in patients with pancreatic carcinoma and help patient selection for optimal treatment.
CRIS-Team Scopus Importer:2019-10-01
Keywords: chemoradiation; chemotherapy; immunotherapy; molecular mechanism; pancreatic cancer; surgery; therapeutic targets; treatment options

Curriculum kardiale Computertomographie - Schmermund, A.; Achenbach, Susanne; Leber, A.; Strasser, R. H.; Korosoglou, G.; Hausleiter, J.; Voigtländer, T.; Katus, H. A. (Der Kardiologe, 2015)
The curriculum presented describes a structured process of further education allowing cardiologists to obtain an additional qualification in cardiac computed tomography (CT). The additional qualification is defined by the German Cardiac Society and certified according to uniform criteria. Three levels of education are associated with increasing degrees of qualification. Level 1 mainly pertains to CT indications, diagnostic value and comparisons with alternative diagnostic methods, level 2 adds further competence in cardiac CT, enabling independent performance of cardiac CT examinations and level 3 allows cardiologists to operate a cardiac CT imaging unit in their own right, under the premise of radiation safety rules being observed and to oversee the education of candidates for additional cardiac CT qualifications. Apart from individual education the process of certifying training centres is also described and examination of the candidates for additional CT qualifications. The current curriculum takes the curriculum for further cardiological education of the German Cardiac Society into consideration as well as national and European consensus recommendations on cardiovascular imaging.
CRIS-Team Scopus Importer:2023-03-08
Keywords: Advanced training; Certification; Coronary angiography; Tomographic imaging; Training

Cylindric Abdominoperineal Rectum Exstirpation with Partial Vulvar and Vaginal Resection as well as Perineal and Vaginal Defect Reconstruction by a Vertical Rectus Abdominis Myocutaneous (VRAM) Flap - Krautz, Christian; Weber, Klaus; Croner, Roland; Denz, Axel; Maak, Matthias; Horch, Raymund E.; Grützmann, Robert (Zentralblatt für Chirurgie, 2017)
Introduction Patients with low rectal cancer or anal cancer undergoing abdominoperineal excision (APE) benefit from extended surgery and the subsequent avoidance of surgical "waisting" at the level of the puborectalis muscle. The method of cylindrical APE was introduced by T. Holm and led to a reduction of intraoperative perforations and involvement of circumferential resection margins, and subsequently reduced the risk of local recurrence. The use of myocutaneous flaps reduces perineal wound complications, which occur in up to 60% of patients with primary closure of perineal defects, especially following neoadjuvant radiochemotherapy. Flaps obliterate pelvic dead space, recruit well-vascularised tissue into irradiated regions, facilitate wound closure and allow for vaginal and perineal reconstructions. This video shows the technique of extended cylindrical APE with partial vulvar and vaginal resection and subsequent reconstruction of the posterior vaginal wall and the pelvic floor defect by a vertical rectus abdominis myocutaneous (VRAM) flap. Indication Locally advanced anal cancer with infiltration and fistula to the posterior vaginal wall without metastatic spread following neoadjuvant radiochemotherapy. Procedure Extended cylindric APE with partial vulvar and vaginal resection, construction of a descending colostomy with parastomal intraperitoneal onlay mesh augmentation, pelvic reconstruction with a VRAM flap and inlay mesh augmentation of the anterior rectus sheath. Conclusion From the oncological point of view, extralevator APE is superior to standard surgery. The use of myocutaneous flaps improves postoperative wound healing and quality of life.
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Cytochemical and molecular properties of simian virus 40 transformed Kaposi's sarcoma-derived cells: evidence for the secretion of a member of the fibroblast growth factor family. - Werner, Sabine; Hofschneider, Peter Hans; Stürzl, Michael; Dick, Irene; Roth, Willi Kurt (Journal of Cellular Physiology, 1989)
Contact-inhibited Kaposi's sarcoma-derived cells (KS cells) were transfected with Simian Virus 40 (SV40) DNA. Transformed cells (SV-KSC) were selected for their capacity to form foci on monolayers of the low-malignant KS cells. Isolated SV-KSC foci were found to contain integrated SV40 DNA sequences and to express SV40 large T-antigen. Several differentiation properties of KS cells are retained in the SV40 transformants, e.g., expression of vimentin and the endothelial cell marker BMA 120. In contrast to the maternal KS cells, SV-KSC are capable of growing in platelet-derived growth factor (PDGF)-depleted platelet-poor-plasma serum (PPPS) and in soft agar. However, they are not tumorigenic in nude mice. Expression of the oncogenes c-myc, c-N-ras, c-Ha-ras, and p53 is significantly elevated in SV-KSC, whereas c-fos and c-erb B expression is comparable to that of KS cells and fibroblasts. Conditioned medium from SV-KSC can substitute for PDGF when PDGF-dependent, nontransformed KS cells are grown in PPPS. Biochemical analysis of the SV-KSC supernatant and PDGF A and B mRNA expression analysis provide evidence that the mitogenic activity is not due to a PDGF-like growth factor. On the other hand, there is evidence to indicate that the SV-KSC mitogen is a member of the fibroblast growth factor family. SV-KSC represent an interesting model system for the study of different degrees of malignancy of cultured mesenchymal cells and especially provide an important source for the isolation of a potent growth factor for KS cells and other mesenchymal cells in vitro.

Cytokine-induced guanylate binding protein 1 (GBP1) release from human ovarian cancer cells - Carbotti, Grazia; Petretto, Andrea; Naschberger, Elisabeth; Stürzl, Michael; Martini, Stefania; Mingari, Maria Cristina; Filaci, Gilberto; Ferrini, Silvano; Fabbi, Marina (Cancers, 2020)
We showed that IL-27 shares several effects with IFN-γ in human cancer cells. To identify novel extracellular mediators, potentially involved in epithelial ovarian cancer (EOC) biology, we analyzed the effect of IL-27 or IFN-γ on the secretome of cultured EOC cells by mass-spectrometry (nano-UHPLC-MS/MS). IL-27 and IFN-γ modulate the release of a limited fraction of proteins among those induced in the whole cell. We focused our attention on GBP1, a guanylate-binding protein and GTPase, which mediates several biological activities of IFNs. Cytokine treatment induced GBP1, 2, and 5 expressions in EOC cells, but only GBP1 was secreted. ELISA and immunoblotting showed that cytokine-stimulated EOC cells release full-length GBP1 in vitro, through non-classical pathways, not involving microvesicles. Importantly, full-length GBP1 accumulates in the ascites of most EOC patients and ex-vivo EOC cells show constitutive tyrosine-phosphorylated STAT1/3 proteins and GBP1 expression, supporting a role for Signal Transducer And Activator Of Transcription (STAT)-activating cytokines in vivo. High GBP1 gene expression correlates with better overall survival in the TCGA (The Cancer Genome Atlas) dataset of EOC. In addition, GBP1 transfection partially reduced EOC cell viability in an MTT assay. Our data show for the first time that cytokine-stimulated tumor cells release soluble GBP1 in vitro and in vivo and suggest that GBP1 may have anti-tumor effects in EOC.
CRIS-Team Scopus Importer:2020-02-28
Keywords: Guanylate binding protein 1; Interferon-γ; Interleukin-27; Microenvironment; Ovarian cancer; Secretome

Cytokine-mediated growth promotion of Kaposi's sarcoma and primary effusion lymphoma. - Ensoli, Barbara; Stürzl, Michael; Monini, Paolo (Seminars in Cancer Biology, 2000)
Kaposi's sarcoma (KS) is an angioproliferative disease particularly frequent and aggressive in patients with AIDS but occurring also in post-transplant patients or in immunocompetent individuals of certain geographic areas. At least in its early stages, KS behaves as a reactive hyperplastic process mediated by inflammatory cytokines and angiogenic factors triggered or exacerbated by human herpesvirus-8 (HHV-8) infection. The HIV Tat protein appears to be responsible for the highly aggressive nature of AIDS-KS. Over time, however, KS may evolve into a true sarcoma in association with the expression of oncogenes and/or HHV-8 latency genes endowed with growth and anti-apoptotic properties. HHV-8 infection is also associated with primary effusion lymphoma (PEL), a rare tumor that similarly develops more frequently in the setting of HIV infection. HHV-8 latency genes are likely to contribute to the neoplastic phenotype of PEL cells, whose growth in vivo may require cytokines and factors from the host, or encoded by the virus.

Cytokine profile of HIV-positive Kaposi's sarcoma derived cells in vitro. - Brockmeyer, Norbert H.; Willers, C P; Anders, S; Mertins, L; Rockstroh, Jürgen; Stürzl, Michael (European Journal of Medical Research, 1999)
Kaposi's sarcoma (KS) is the most frequent neoplastic complication observed in HIV-infected patients. Cutaneous KS is the most common manifestation but visceral and lymph node involvement may occur. HIV-infection does not only lead to a decrease of certain cell types (CD4 T-lymphocytes), but also modifies the function of non-infected cells such as B-lymphocytes and NK-cells by upregulating cytokine release of IL-1, IL-6, GM-CSF, IFN-gamma and TNF-alpha. These multifunctional mediators show both autocrine and paracrine proliferative effects on normal endothelial cells and AIDS-related KS-cells. Using ELISA-, RIA- and IRMA-techniques we analysed the influence of seven cytokines (IL-1beta, IL-6, TNF-alpha, GM-CSF, IFN-alpha, IFN-beta, IFN-gamma) and the soluble IL-2 receptor (sIL-2R) on the growth of eight different KS-derived cell lines compared with eight fibroblast cell lines, established from skin biopsies of HIV-positive individuals. Furthermore, we analysed the dose-dependent effect of the above mentioned cytokines on KS-derived cells in vitro. The KS-derived cell culture medium demonstrated significantly higher concentrations than the fibroblast cell lines in view of the following cytokines: sIL-2R, IL-1beta, IL-6, TNF-alpha, GM-CSF, IFN-gamma (p<0.05). The most pronounced differences between KS-cells and fibroblasts were observed for IL-1beta and IFN-gamma. The antiproliferative effect of IFN-beta and IFN-gamma began at a concentration of 20 and 50 IU/ml, respectively, whereas for IFN-alpha an antiproliferative effect was observed at a concentration of 100 U/ml. Furthermore we observed a proliferative effect in low concentrations (2-5 IU/ml) of IFN-gamma in our in vitro model

Cytokine storm and sepsis disease pathogenesis - Chousterman, Benjamin G.; Swirski, Filip K.; Weber, Georg (Seminars in Immunopathology, 2017)
Infectious diseases are a leading cause of death worldwide. Sepsis is a severe clinical syndrome related to the host response to infection. The severity of infections is due to an activation cascade that will lead to an autoamplifying cytokine production: the cytokine storm. Cytokines are a broad category of relatively small proteins (<40 kDa) that are produced and released with the aim of cell signaling. Our understanding of the processes that trigger this tremendous amount of cytokine production has made dramatic progress over the last decades, but unfortunately, these findings could not translate yet into effective treatments; so far, all clinical trials targeting cytokine production or effects failed. This review aims to summarize the pathophysiology of the cytokine storm; to describe the type, effects, and kinetics of cytokine production; and to discuss the therapeutic challenges of targeting cytokines. New promising therapeutic strategies focusing on the endothelium, as a source and a target of cytokines, are described.
EVALuna2:15318

Cytosolic 5 '-nucleotidase 1A is overexpressed in pancreatic cancer and mediates gemcitabine resistance by reducing intracellular gemcitabine metabolites - Patzak, Melanie S.; Kari, Vijayalakshmi; Patil, Shilpa; Hamdan, Feda H.; Goetze, Robert G.; Brunner, Marius; Gaedcke, Jochen; Kitz, Julia; Jodrell, Duncan; Richards, Frances M.; Pilarsky, Christian; Grützmann, Robert; et al. (EBioMedicine, 2019)
Background: Cytosolic 5'-nucleotidase 1A (NT5C1A) dephosphorylates non-cyclic nucleoside monophosphates to produce nucleosides and inorganic phosphates. Here, we investigate NT5C1A expression in pancreatic ductal adenocarcinoma (PDAC) and its impact on gemcitabine metabolism and therapeutic efficacy.
CRIS-Team WoS Importer:2019-03-22

Cytotoxic effect of Efavirenz in BxPC-3 pancreatic cancer cells is based on oxidative stress and is synergistic with ionizing radiation - Hecht, Markus; Harrer, Thomas; Koeber, Verena; Sarpong, Eric Opoku; Moser, Fabian; Fiebig, Nora; Schwegler, Manuela; Stürzl, Michael; Fietkau, Rainer; Distel, Luitpold (Oncology Letters, 2018)
The non-nucleoside reverse transcriptase inhibitor (NNRTI) Efavirenz is frequently used in human immunodeficiency virus treatment, but also efficient against cancer in mouse models. Its radiosensitizing effect makes it a promising drug for combination with radiotherapy. The efficacy of Efavirenz combined with irradiation was assessed with immunostaining of DNA-damage markers and colony formation assays in BxPC-3 pancreatic cancer cells. Gene expression and protein phosphorylation of the Efavirenz-sensitive BxPC-3 cells was compared to the resistant primary fibroblasts SBL-5. Oxidative stress, mitochondrial damage and cell death were studied with live-cell microscopy and flow cytometry. Combined Efavirenz and radiation significantly increased the number of γH2AX and phospho-ataxia telangiectasia mutated foci. Efavirenz and ionizing radiation had a synergistic effect using the clonogenic survival assay. Efavirenz selectively induced cell death in the BxPC-3 cells. The differing gene expression of cell cycle and apoptotic regulator genes in both cell cultures after Efavirenz treatment match with this selective effect against cancer cells. In the phosphoprotein array, an early phosphorylation of extracellular signal-related kinase 1/2 and p38 mitogen-activated protein kinase was notably detected in the cancer cells. The phosphorylation of AKT decreased in the cancer cells whereas it increased in the fibroblasts. Oxidative stress and mitochondrial membrane depolarization appeared in the cancer cells immediately after Efavirenz treatment, but not in the fibroblasts. Efavirenz has an anti-cancer effect against pancreatic cancer mainly by the induction of oxidative stress. The antitumor potential of Efavirenz and radiotherapy are additive.
EVALuna2:36443

Dabigatran Plasma Levels in Acute Cerebrovascular Events - Volbers, Bastian; Köhrmann, Martin; Kallmünzer, Bernd; Kurka, Natalia; Breuer, Lorenz; Ringwald, Juergen; Schwab, Stefan (Journal of Stroke and Cerebrovascular Diseases, 2016)
Oral anticoagulation with dabigatran was shown to be effective for stroke prevention in patients with nonvalvular atrial fibrillation without the need for laboratory monitoring. However, a recent publication based on data of the Randomized Evaluation of Long-Term Anticoagulation Therapy study reported that ischemic stroke and bleeding outcomes are correlated with dabigatran plasma concentration (DPC). DPC was determined at a prespecified time point and correlated with cardiovascular events at any time during follow-up. Because of the known variability of DPC, among others depending on renal function, this approach might compromise data evaluation. We report on dabigatran plasma levels in acute cerebrovascular events.Consecutive patients with acute ischemic stroke (AIS) or intracerebral hemorrhage (ICH) while taking dabigatran were retrospectively identified if admission DPC was available. DPC was determined using the diluted thrombin time (Hemoclot (HYPHEN BioMed, Neuville sur Oise, France)). Creatinine clearance (CrCl) was determined by measuring creatinine in plasma and 24-hour urine.Fifteen AIS and 4 ICH patients were included. Median DPC on admission was significantly higher in ICH patients than in AIS patients (135 ng/mL [interquartile range IQR 79-218] and 69.1 ng/mL [IQR 20.6-85.0], respectively; P = .035). Increased CrCl (values above published normal range) was correlated with lower median DPC (60 ng/mL [IQR 10-69] versus 100 ng/mL [IQR 79-157] in patients with normal CrCl, P = .01).Higher DPC was found in ICH patients than in AIS patients in temporal proximity to the event. Both decreased and increased renal functions seem to have an important influence on DPC.
EVALuna2:15996

Das Bauchaortenaneurysma: Faktencheck zu Mindestmengen und Qualitätsindikatoren - Behrendt, Christian Alexander; Gombert, Alexander; Busch, Albert; Trenner, Matthias; Bischoff, Moritz S.; Rother, Ulrich (Gefässchirurgie, 2023)
Decreasing prevalences have been reported for abdominal aortic aneurysms for many years, whereby the median case number especially for open surgical treatment of aneurysms in decentralized healthcare systems was recently still only approximately 7 per year. Against the background of the dynamic developments over more than two decades with respect to treatment procedures and medical products, the impact of the annual case volume on treatment outcomes was repeatedly controversially discussed. So far, the short-term perioperative overall mortality was predominantly available as a suitable outcome quality parameter, while many studies stem from an era where hospital mortality rates after endovascular treatment were 3 % higher than today. The current data suggest an association between case volume and outcome, particularly for open surgical procedures, while no robust effects were found for endovascular treatment with stent grafts. The heterogeneous data situation is also reflected in the current guidelines. While the North American guidelines of the Society for Vascular Surgery (SVS) recommend a procedure-specific minimum threshold of 10 procedures per year for each procedure, the European guidelines of the European Society for Vascular Surgery (ESVS) recommend a mixed minimum threshold of 20 for both procedures.
CRIS-Team Scopus Importer:2023-12-29
Keywords: Case volume; Centralization; Health services research; Outcomes; Quality

Das große Verbesserungspotenzial in der multimodalen Basisbehandlung der peripheren arteriellen Verschlusskrankheit (pAVK): ein Aufruf zum flächendeckenden Ausbau der pAVK-Gehtrainingsgruppen in Deutschland - Dovzhanskiy, Dmitriy; Behrendt, Christian Alexander; Görtz, Hartmut; Uhl, Christian; Classen, Simon; Marchiori, Elena; Neufang, Achim; Rümenapf, Gerhard; Stavroulakis, Konstantinos; Rother, Ulrich; Jaron, Vera; Kunert, Katrin (Gefässchirurgie, 2023)
Walking exercise is one of the most important pillars of the treatment of peripheral arterial disease (PAD). Walking exercise in groups under supervision is especially effective. In Germany, a nationwide offer of walking exercise groups is not available. Thus, the German Society for Vascular Surgery and Vascular Medicine (DGG e. V.), represented by the Committee “PAD and the diabetic foot”, launched a nationwide campaign to promote the establishment of local walking exercise groups. This article appeals to vascular physicians to establish and shape local walking exercise groups. Ways of creating such groups are described.
CRIS-Team Scopus Importer:2023-01-13
Keywords: Basic therapy; Claudicatio intermittens; Peripheral arterial disease; Rehabilitation sports; Vascular Surgery and Vascular Medicine; Walking exercise

Das Revival der Serumtherapie Antikörper von Rekonvaleszenten sollen schwer COVID-19-Erkrankten helfen - Hackstein, Holger (Deutsche Apotheker Zeitung, 2020)
CRIS-Team Scopus Importer:2021-04-19

Decreased Thymic Output Contributes to Immune Defects in Septic Patients - Sommer, Natascha; Noack, Steffen; Hecker, Andreas; Hackstein, Holger; Bein, Gregor; Weissmann, Norbert; Seeger, Werner; Mayer, Konstantin; Hecker, Matthias (Journal of Clinical Medicine, 2020)
Background: Prolonged immunosuppression and hypoinflammation, termed compensatory anti-inflammatory response syndrome (CARS), contribute to high morbidity and mortality in the late phase of sepsis. Although apoptosis is a well-known cause of lymphopenia in sepsis, the contribution of thymic output to immune alterations in sepsis and potential compensatory mechanisms are largely unknown. Methods: We investigate the release of CD4+ T cells from the thymus and their peripheral proliferation by evaluating T-cell receptor excision circles (TREC) and the expression of CD31 as markers for recent thymic emigrants (RTE) and their proliferative offspring in septic patients with relevant lymphopenia in the CARS phase. Moreover, we determine the aging of T cells by measuring telomere characteristics. Results: In septic patients, we found decreased CD4+ T-helper cell numbers, while CD8+ T cell numbers were unchanged. As a possible cause, we detected increased apoptosis of CD4+ T-helper cells and decreased levels of IL-7, which promotes the maturation of T cells in the thymus. Accordingly, the relative number of mature CD4+ T cells, TREC-containing CD4+ T cells, and CD31+ RTEs (characteristic of thymic output) was decreased, while the relative number of CD31-T cells (peripherally expanded naive T cells) was increased. Furthermore, the telomere length decreased, although telomerase activity and markers for the shelterin complex were increased specifically in CD4+ but not in CD8+ T cells. Conclusion: We thus conclude that, in addition to T-cell apoptosis, decreased thymic output and increased aging of CD4+ T cells may contribute to lymphopenia and immunosuppression in sepsis. Increased proliferation of peripheral T cells cannot compensate for these effects.
CRIS-Team WoS Importer:2020-11-06

DECREASING GPLD 1-LEVELS IN PATIENTS AFTER ST-ELEVATED MYOCARDIAL INFARCTION - Kruse, A.; Bischof, Erik; Raaz-Schrauder, D.; Achenbach, Susanne; Dietel, B.; Tauchi, Miyuki; Urschel, K. (ATHEROSCLEROSIS, 2022)
CRIS-Team WoS Importer:2022-10-14

Deep characterization of human γδ T cell subsets defines shared and lineage-specific traits. - Sanz, Marta; Mann, Brendan T.; Ryan, Paul L.; Bosque, Alberto; Pennington, Daniel J.; Hackstein, Holger; Soriano-Sarabia, Natalia (Frontiers in Immunology, 2023)
Under non-pathological conditions, human γδ T cells represent a small fraction of CD3+ T cells in peripheral blood (1-10%). They constitute a unique subset of T lymphocytes that recognize stress ligands or non-peptide antigens through MHC-independent presentation. Major human γδ T cell subsets, Vδ1 and Vδ2, expand in response to microbial infection or malignancy, but possess distinct tissue localization, antigen recognition, and effector responses. We hypothesized that differences at the gene, phenotypic, and functional level would provide evidence that γδ T cell subpopulations belong to distinct lineages. Comparisons between each subset and the identification of the molecular determinants that underpin their differences has been hampered by experimental challenges in obtaining sufficient numbers of purified cells. By utilizing a stringent FACS-based isolation method, we compared highly purified human Vδ1 and Vδ2 cells in terms of phenotype, gene expression profile, and functional responses. We found distinct genetic and phenotypic signatures that define functional differences in γδ T cell populations. Differences in TCR components, repertoire, and responses to calcium-dependent pathways suggest that Vδ1 and Vδ2 T cells are different lineages. These findings will facilitate further investigation into the ligand specificity and unique role of Vδ1 and Vδ2 cells in early immune responses.
EVALuna2:534012

Deep learning-based plaque quantification from coronary computed tomography angiography: external validation and comparison with intravascular ultrasound - Lin, A.; Manral, N.; Mcelhinney, P.; Killekar, A.; Matsumoto, H.; Cadet, S.; Achenbach, Susanne; Nicholls, S. J.; Wong, D. T.; Berman, D.; Dweck, M.; Newby, D. E.; et al. (EUROPEAN HEART JOURNAL, 2021)
CRIS-Team WoS Importer:2021-12-10

Deep learning improves pancreatic cancer diagnosis using rna-based variants - Al-Fatlawi, Ali; Malekian, Negin; García, Sebastián; Henschel, Andreas; Kim, Ilwook; Dahl, Andreas; Jahnke, Beatrix; Bailey, Peter; Bolz, Sarah Naomi; Poetsch, Anna R.; Mahler, Sandra; Grützmann, Robert; et al. (Cancers, 2021)
For optimal pancreatic cancer treatment, early and accurate diagnosis is vital. Blood-derived biomarkers and genetic predispositions can contribute to early diagnosis, but they often have limited accuracy or applicability. Here, we seek to exploit the synergy between them by combining the biomarker CA19-9 with RNA-based variants. We use deep sequencing and deep learning to improve differentiating pancreatic cancer and chronic pancreatitis. We obtained samples of nucleated cells found in peripheral blood from 268 patients suffering from resectable, non-resectable pancreatic cancer, and chronic pancreatitis. We sequenced RNA with high coverage and obtained millions of variants. The high-quality variants served as input together with CA19-9 values to deep learning models. Our model achieved an area under the curve (AUC) of 96% in differentiating resectable cancer from pancreatitis using a test cohort. Moreover, we identified variants to estimate survival in resectable cancer. We show that the blood transcriptome harbours variants, which can substantially improve noninvasive clinical diagnosis.
CRIS-Team Scopus Importer:2021-06-11
Keywords: Chronic pancreatitis; Deep learning; Pancreatic cancer; Transcriptome-wide association study

Defining early recurrence in patients with resected primary colorectal carcinoma and its respective risk factors - Wiesmüller, Felix; Schuetz, Rolf; Langheinrich, Melanie; Brunner, Maximilian; Grützmann, Robert; Merkel, Susanne; Krautz, Christian; Weber, Georg (International Journal of Colorectal Disease, 2021)
Purpose: There is no evidence-based definition of early recurrence following resection of colorectal cancer. The purpose of this study is to define a point that discriminates between early and late recurrence in patients who have undergone colorectal cancer resection with curative intent and to analyze associated risk factors. Methods: A retrospective single-center cohort study was performed at a university hospital recognized as a comprehensive cancer center, specializing in colorectal cancer surgery. Patient data were retrieved from a prospectively maintained institutional database. Included patients underwent resection for primary, non-metastatic colorectal carcinomas with curative intent between 1995 and 2010. Aims of the study were (1) to define the optimal cut-off point of recurrence-free survival based on overall survival using a minimum p value approach and (2) to identify patterns of initial recurrence and putative risk factors for early recurrence using regression models. Results: Recurrence was diagnosed in 412 of 1893 patients. Statistical analysis suggested that a recurrence-free survival of 16 months could be used to distinguish between early and late recurrence based on overall survival (p < 0.001). Independent risk factors for early recurrence included advanced pT categories (pT3,4/ypT3,4) and positive lymph node status (pN+/ypN+). Early recurrence was independent of site of recurrence and was associated with worse prognosis. Conclusions: Recurrence of colorectal carcinoma within 16 months after primary treatment should be labeled as “early.” Tumor categories pT3,4/ypT3,4 and positive lymph node status pN+/ypN+ are predictive of early recurrence.
CRIS-Team Scopus Importer:2021-02-05
Keywords: Cancer recurrence; Colorectal cancer; Colorectal carcinoma; Follow-up; Hemicolectomy; Low anterior resection; Recurrence group

Deletion of Kaposi's sarcoma-associated herpesvirus FLICE inhibitory protein, vFLIP, from the viral genome compromises the activation of STAT1-responsive cellular genes and spindle cell formation in endothelial cells. - Stürzl, Michael; et al. (Journal of Virology, 2011)
Kaposi's sarcoma herpesvirus (KSHV) Fas-associated death domain (FADD)-like interleukin-1 beta-converting enzyme (FLICE)-inhibitory protein, vFLIP, has antiapoptotic properties, is a potent activator of the NF-κB pathway, and induces the formation of endothelial spindle cells, the hallmark of Kaposi's sarcoma, when overexpressed in primary endothelial cells. We used a reverse genetics approach to study several functions of KSHV vFLIP in the context of the whole viral genome. Deletion of the gene encoding vFLIP from a KSHV genome cloned in a bacterial artificial chromosome (BAC) reduced the ability of the virus to persist and induce spindle cell formation in primary human umbilical vein endothelial cells (HUVECs). Only a few, mainly interferon (IFN)-responsive, genes were expressed in wild-type KSHV (KSHV-wt)-infected endothelial cells at levels higher than those in KSHV-ΔFLIP-infected endothelial cells, in contrast to the plethora of cellular genes induced by overexpressed vFLIP. In keeping with this observation, vFLIP induces the phosphorylation of STAT1 and STAT2 in an NF-κB-dependent manner in endothelial cells. vFLIP-dependent phosphorylation of STAT1 and STAT2 could be demonstrated after endothelial cells were infected with KSHV-wt, KSHV-ΔFLIP, and a KSHV-vFLIP revertant virus. These findings document the impact of KSHV vFLIP on the transcriptome of primary endothelial cells during viral persistence and highlight the role of vFLIP in the activation of STAT1/STAT2 and STAT-responsive cellular genes by KSHV.

Der „critical view of safety“ zur Vermeidung von Gallengangskomplikationen bei der laparoskopischen Cholezystektomie - Grass, Katharina; Oeckl, Karin; Kersting, Stephan (Zentralblatt für Chirurgie, 2020)
Laparoscopic cholecystectomy is one of the most frequently performed procedures worldwide. Therefore, iatrogenic injury to the choledochal duct, although rare, remains a surgical risk that should not be underestimated. Over the years, various methods have been described to avoid this serious complication, with its high morbidity and even mortality. One of the safest methods to avoid bile duct lesions is to establish the so called "critical view of safety" before cutting any structures. This method shall be demonstrated in this instructional video.
CRIS-Team Scopus Importer:2020-09-04

Dermatofibrosarcoma protuberans: Surgical management of a challenging mesenchymal tumor - Wiesmüller, Felix; Agaimy, Abbas; Perrakis, Aristotelis; Arkudas, Andreas; Horch, Raymund E.; Grützmann, Robert; Vassos, Nikolaos (World Journal of Surgical Oncology, 2019)
Introduction: Dermatofibrosarcoma protuberans (DFSP) is a rare, low-grade malignant mesenchymal tumor of the soft tissue, characterized by slow infiltrative growth and common local recurrence, with rare distant metastases. Patients and methods: We present a retrospective study of nineteen patients who were diagnosed with DFSP and operated at our institution in > 10-year period. We examined the clinicopathological parameters with special emphasis on the margin status regarding the clinical outcome and the follow-up. Results: A total of eight cases underwent re-excision at our institution following primary excision or incisional biopsy performed at a different institution. Seven cases received excision after incisional biopsy at our institution. Four patients developed recurrent disease following primary excision with histological R0 margins at other institutions and received re-excision at our institution. All excisions at our institution resulted in R0 margins with no recurrence recorded at last follow-up (6 to 175; mean 84 months). The mean margin for those who received resection at our institution was 1.67 cm. Negative margins upon primary excision were achieved using a mean margin width of 2.04 cm. Most common tumor localization was the trunk (10 cases). Conclusion: Awareness of this rare entity is important for a prompt diagnosis and a proper management of the disease. The greatest clinical challenge in the management of DFSP is achieving local control. Complete excision of the tumor with surgical margin widths of at least 2 cm is recommended.
CRIS-Team Scopus Importer:2019-06-18
Keywords: Cutaneous lesions; Dermatofibrosarcoma protuberans; DFSP; Mesenchymal tumor; Wallace rule of 9s

Detection of COPB2 as a KRAS synthetic lethal partner through integration of functional genomics screens - Christodoulou, Eleni G.; Yang, Hai; Lademann, Franziska; Pilarsky, Christian; Beyer, Andreas; Schroeder, Michael (Oncotarget, 2017)
Mutated KRAS plays an important role in many cancers. Although targeting KRAS directly is difficult, indirect inactivation via synthetic lethal partners (SLPs) is promising. Yet to date, there are no SLPs from high-throughput RNAi screening, which are supported by multiple screens. Here, we address this problem by aggregating and ranking data over three independent high-throughput screens. We integrate rankings by minimizing the displacement and by considering established methods such as RIGER and RSA.Our meta analysis reveals COPB2 as a potential SLP of KRAS with good support from all three screens. COPB2 is a coatomer subunit and its knock down has already been linked to disabled autophagy and reduced tumor growth. We confirm COPB2 as SLP in knock down experiments on pancreas and colorectal cancer cell lines.Overall, consistent integration of high throughput data can generate candidate synthetic lethal partners, which individual screens do not uncover. Concretely, we reveal and confirm that COPB2 is a synthetic lethal partner of KRAS and hence a promising cancer target. Ligands inhibiting COPB2 may, therefore, be promising new cancer drugs.
EVALuna2:15311

Detection of SARS-CoV-2-independent immunoregulatory activity of COVID-19 convalescent plasma - Brox, Regine; Achenbach, Susanne; Hackstein, Holger (Transfusion, 2021)
Background: Convalescent plasma has emerged as a potential specific treatment for coronavirus disease 2019 (COVID-19), since it contains severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies. Several studies are currently investigating the efficacy of convalescent plasma for treatment of COVID-19, with a focus on neutralizing antibodies. However, there is little information on whether convalescent plasma may contain additional immunoregulatory constituents produced by the blood donor during convalescence. Therefore, using a standardized whole blood assay employing synthetic toll-like receptor (TLR) ligands, we have investigated the immunoregulatory capacity of convalescent plasma in direct comparison to ABO-matched allogeneic control plasma. Study design and methods: Whole blood samples from healthy blood donors were collected, and autologous plasma was replaced by convalescent plasma or ABO-matched control plasma. Standardized innate immune triggering and monitoring was performed by adding different TLR ligands (Pam3CsK4 [TLR1/2], HKLM [TLR2], LPS [TLR4], flagellin [TLR5], ssRNA40 [TLR8], imiquimod [TLR7], and FSL-1 [TLR2/6]) and subsequent quantitative analysis of pro- and anti-inflammatory cytokines (IP-10, IL-1β, TNF-α, MCP-1, IL-6, IL-10, and IFN-γ) by cytometric bead array. Negative controls included unstimulated samples as well as samples spiked with autologous plasma. Results: COVID-19 convalescent plasma (CCP) significantly decreased pro-inflammatory cytokines production triggered by different TLR ligands in healthy donors as compared with healthy control plasma. IL-6, MCP-1, and IFN-γ represented the cytokines that are most frequently downregulated by convalescent plasma. Conclusion: Our experiments reveal a potential novel, SARS-CoV-2-independent immunomodulatory activity of CCP, which may be beneficial for COVID-19 patients.
CRIS-Team Scopus Importer:2021-10-22
Keywords: convalescent plasma; COVID-19

Development and Validation of a Multivariable Prediction Model Based on Blood Plasma and Serum Metabolomics for the Diagnosis of Chronic Pancreatitis - Beyer, G.; Adam, M. G.; Christiansen, N.; Kamlage, B.; Pilarsky, Christian; Distler, M.; Falbusch, T.; Chromik, A.; Klein, F.; Bahra, M.; Uhl, W.; Grützmann, Robert; et al. (PANCREAS, 2020)
CRIS-Team WoS Importer:2021-02-19

Development and validation of a prognostic model to predict the prognosis of patients who underwent chemotherapy and resection of pancreatic adenocarcinoma: a large international population-based cohort study - Huang, Lei; Balavarca, Yesilda; Van Der Geest, Lydia; Lemmens, Valery; Van Eycken, Liesbet; De Schutter, Harlinde; Johannesen, Tom B.; Zadnik, Vesna; Primic-Zakelj, Maja; Magi, Margit; Grützmann, Robert; Besselink, Marc G.; et al. (BMC Medicine, 2019)
BackgroundPancreatic cancer (PaC) remains extremely lethal worldwide even after resection. PaC resection rates are low, making prognostic studies in resected PaC difficult. This large international population-based study aimed at exploring factors associated with survival in patients with resected TNM stage I-II PaC receiving chemotherapy and at developing and internationally validating a survival-predicting model.MethodsData of stage I-II PaC patients resected and receiving chemotherapy in 2003-2014 were obtained from the national cancer registries of Belgium, the Netherlands, Slovenia, and Norway, and the US Surveillance, Epidemiology, and End Results (SEER)-18 Program. Multivariable Cox proportional hazards models were constructed to investigate the associations of patient and tumor characteristics with overall survival, and analysis was performed in each country respectively without pooling. Prognostic factors remaining after backward selection in SEER-18 were used to build a nomogram, which was subjected to bootstrap internal validation and external validation using the European datasets.ResultsA total of 11,837 resected PaC patients were analyzed, with median survival time of 18-23months and 3-year survival rates of 21-31%. In the main analysis, patient age, tumor T stage, N stage, and differentiation were associated with survival across most countries, with country-specific association patterns and strengths. However, tumor location was mostly not significantly associated with survival. Resection margin, hospital type, tumor size, positive and harvested lymph node number, lymph node ratio, and comorbidity number were associated with survival in certain countries where the information was available. A median survival time- and 1-, 2-, 3-, and 5-year survival probability-predictive nomogram incorporating the backward-selected variables in the main analysis was established. It fits each European national cohort similarly well. Calibration curves showed very good agreement between nomogram-prediction and actual observation. The concordance index of the nomogram (0.60) was significantly higher than that of the T and N stage-based model (0.56) for predicting survival.ConclusionsIn these large international population-based cohorts, patients with resected PaC receiving chemotherapy have distinct characteristics independently associated with survival, with country-specific patterns and strengths. A robust benchmark population-based survival-predicting model is established and internationally validated. Like previous models predicting survival in resected PaC, our nomogram performs modestly.
CRIS-Team WoS Importer:2019-04-04

Development of a Class Prediction Model to Discriminate Pancreatic Ductal Adenocarcinoma from Pancreatic Neuroendocrine Tumor by MALDI Mass Spectrometry Imaging - Casadonte, Rita; Kriegsmann, Mark; Perren, Aurel; Baretton, Gustavo; Deininger, Soeren-Oliver; Kriegsmann, Katharina; Welsch, Thilo; Pilarsky, Christian; Kriegsmann, Joerg (Proteomics Clinical Applications, 2019)
Purpose To define proteomic differences between pancreatic ductal adenocarcinoma (pDAC) and pancreatic neuroendocrine tumor (pNET) by matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI). Experimental design Ninety-three pDAC and 126 pNET individual tissues are assembled in tissue microarrays and analyzed by MALDI MSI. The cohort is separated in a training (52 pDAC and 83 pNET) and validation set (41 pDAC and 43 pNET). Subsequently, a linear discriminant analysis (LDA) model based on 46 peptide ions is performed on the training set and evaluated on the validation cohort. Additionally, two liver metastases and a whole slide of pDAC are analyzed by the same LDA algorithm. Results Classification of pDAC and pNET by the LDA model is correct in 95% (39/41) and 100% (43/43) of patients in the validation cohort, respectively. The two liver metastases and the whole slide of pDAC are also correctly classified in agreement with the histopathological diagnosis. Conclusion and clinical relevance: In the present study, a large dataset of pDAC and pNET by MALDI MSI is investigated, a class prediction model that allowed separation of both entities with high accuracy is developed, and differential peptide peaks with potential diagnostic, prognostic, and predictive values are highlighted.
CRIS-Team WoS Importer:2019-02-27

Diabetisches Fußsyndrom – Teil 1. Definition, Pathophysiologie, Diagnostik und Klassifikation - Rümenapf, G.; Morbach, S.; Rother, Ulrich; Uhl, C.; Görtz, H.; Böckler, D.; Behrendt, C. ‑.A.; Hochlenert, D.; Engels, G.; Sigl, M. (Chirurg, 2020)
There are ca. 8 million persons with diabetes mellitus living in Germany. A late sequelae of diabetes is the diabetic foot syndrome (DFS), the prevalence of which is greatly increasing. It comprises all alterations of the foot as a result of diabetic polyneuropathy as well as microvascular and macrovascular (peripheral arterial occlusive disease, PAOD) alterations. Many of the ca. 250,000 newly diagnosed diabetic foot ulcers per year become chronic wounds. Despite intensive efforts for prevention, early diagnosis and adequate wound care, ca. 13,000 persons with diabetes undergo major limb amputation in Germany every year. With consistent treatment in interdisciplinary centers and by exhausting all possible methods of wound treatment, pressure relief as well as arterial revascularization, the major amputation rate in patients with diabetic foot problems can be reduced by 80%. With a suitable strategy of prevention, the recurrence rate of foot ulcers would be reduced.
CRIS-Team Scopus Importer:2020-11-20
Keywords: Amputation; Diabetes mellitus; Diabetic foot syndrome; Diabetic polyneuropathy; Peripheral arterial occlusive disease

Diabetisches Fußsyndrom – Teil 2. Revaskularisation, Behandlungsalternativen, Versorgungsstrukturen, Rezidivprophylaxe - Rümenapf, G.; Morbach, S.; Rother, Ulrich; Uhl, C.; Görtz, H.; Böckler, D.; Behrendt, C. A.; Hochlenert, D.; Engels, G.; Hohneck, A.; Sigl, M. (Chirurg, 2020)
Diabetic foot syndrome (DFS) is the most frequent reason for major amputations in Germany. The majority of foot lesions are triggered by repetitive pressure in diabetic polyneuropathy. Peripheral arterial occlusive disease (PAOD) impairs wound healing and is the main risk factor for amputations. The treatment of wounds and infections as well as timely revascularization are decisive. The use of endovascular and vascular surgical methods depends on the distribution pattern and length of the occlusion processes. Both procedures are complementary. Bypass surgery is of great importance for neuroischemic DFS. Multidisciplinary centers that provide revascularization in DFS can achieve an improvement of arterial blood flow in 90% of the cases and reduce the amputation rate by up to 80%. Due to the high recurrence rate of diabetic foot lesions, measures for secondary prophylaxis are of exceptional importance (podological and orthopedic technical care, foot surgery).
CRIS-Team Scopus Importer:2020-12-04
Keywords: Foot surgery; Peripheral arterial occlusive disease; Secondary prophylaxis; Vascular surgery; Wound treatment

Diagnosis and Treatment of Endometriosis. Guideline of the DGGG, SGGG and OEGGG (S2k Level, AWMF Registry Number 015/045, August 2020) - Burghaus, Stefanie; Schäfer, Sebastian D.; Beckmann, Matthias; Brandes, Iris; Brünahl, Christian; Chvatal, Radek; Drahoå ovský, Jan; Dudek, Wojciech; Ebert, Andreas D.; Fahlbusch, Christine; Fehm, Tanja; Fehr, Peter Martin; et al. (Geburtshilfe und Frauenheilkunde, 2021)
Aims The aim of this official guideline published and coordinated by the German Society of Gynaecology and Obstetrics (DGGG) in cooperation with the Austrian Society for Gynaecology and Obstetrics (OEGGG) and the Swiss Society for Gynaecology and Obstetrics (SGGG) was to provide consensus-based recommendations for the diagnosis and treatment of endometriosis based on an evaluation of the relevant literature. Methods This S2k guideline represents the structured consensus of a representative panel of experts with different professional backgrounds commissioned by the Guideline Committee of the DGGG, OEGGG and SGGG. Recommendations Recommendations on the epidemiology, aetiology, classification, symptomatology, diagnosis and treatment of endometriosis are given and special situations are discussed.
CRIS-Team Scopus Importer:2021-04-23
Keywords: diagnosis; endometriosis; guideline; pelvic pain; treatment

Diagnostic criteria for Buerger's disease: International Consensus of VAS - European Independent Foundation in Angiology/Vascular Medicine - Fazeli, Bahare; Poredos, Pavel; Kozak, Matija; Pecsvarady, Zsolt; Catalano, Mariella; Al Salman, Mussaad M.; Altarazi, Louay; Ali, Abrar A.; Bashar, Abul H.; Bozkurt, Kursat; Cacione, Daniel; Chua, Benjamin; et al. (International Angiology, 2023)
Buerger's disease (BD) remains a debilitating condition and early diagnosis is paramount for its effective management. Despite many published diagnostic criteria for BD, selective criteria have been utilized in different vascular centers to manage patients with BD worldwide. A recent international Delphi Consensus Study on the diagnostic criteria of BD showed that none of these published diagnostic criteria have been universally accepted as a gold standard. Apart from the presence of smoking, these published diagnostic criteria have distinct differences between them, rendering the direct comparison of patient outcomes difficult. Hence, the expert committees from the Working Group of the VAS-European Independent Foundation in Angiology/Vascular Medicine critically reviewed the findings from the Delphi study and provided practical recommendations on the diagnostic criteria for BD, facilitating its universal use. We recommend that the 'definitive' diagnosis of BD must require the presence of three features (history of smoking, typical angiographic features and typical histopathological features) and the use of a combination of major and minor criteria for the 'suspected' diagnosis of BD. The major criterion is the history of active tobacco smoking. The five minor criteria are disease onset at age less than 45 years, ischemic involvement of the lower limbs, ischemic involvement of one or both of the upper limbs, thrombophlebitis migrans and red-blue shade of purple discoloration on edematous toes or fingers. We recommend that a 'suspected' diagnosis of BD is confirmed in the presence of a major criterion plus four or more minor criteria. In the absence of the major criterion or in cases of fewer than four minor criteria, imaging and laboratory data could facilitate the diagnosis. Validation studies on the use of these major and minor criteria are underway.
CRIS-Team Scopus Importer:2023-12-08

Diagnostic performance of four SARS-CoV-2 antibody assays in patients with COVID-19 or with bacterial and non-SARS-CoV-2 viral respiratory infections - Huber, Timo; Steininger, Philipp; Irrgang, Pascal; Korn, Klaus; Tenbusch, Matthias; Diesch, Katharina; Achenbach, Susanne; Kremer, Andreas; Werblow, Marissa; Vetter, Marcel; Bogdan, Christian; Held, Jürgen (European Journal of Clinical Microbiology & Infectious Diseases, 2021)
SARS-CoV-2 antibody assays are used for epidemiological studies and for the assessment of vaccine responses in highly vulnerable patients. So far, data on cross-reactivity of SARS-CoV-2 antibody assays is limited. Here, we compared four enzyme-linked immunosorbent assays (ELISAs; Vircell SARS-CoV-2 IgM/IgA and IgG, Euroimmun SARS-CoV-2 IgA and IgG) for detection of anti-SARS-CoV-2 antibodies in 207 patients with COVID-19, 178 patients with serological evidence of different bacterial infections, 107 patients with confirmed viral respiratory disease, and 80 controls from the pre-COVID-19 era. In COVID-19 patients, the assays showed highest sensitivity in week 3 (Vircell-IgM/A and Euroimmun-IgA: 78.9% each) and after week 7 (Vircell-IgG: 97.9%; Euroimmun-IgG: 92.1%). The antibody indices were higher in patients with fatal disease. In general, IgM/IgA assays had only limited or no benefit over IgG assays. In patients with non-SARS-CoV-2 respiratory infections, IgG assays were more specific than IgM/IgA assays, and bacterial infections were associated with more false-positive results than viral infections. The specificities in bacterial and viral infections were 68.0 and 81.3% (Vircell-IgM/IgA), 84.8 and 96.3% (Euroimmun-IgA), 97.8 and 86.0% (Vircell-IgG), and 97.8 and 99.1% (Euroimmun-IgG), respectively. Sera from patients positive for antibodies against Mycoplasma pneumoniae, Chlamydia psittaci, and Legionella pneumophila yielded particularly high rates of unspecific false-positive results in the IgM/IgA assays, which was revealed by applying a highly specific flow-cytometric assay using HEK 293 T cells expressing the SARS-CoV-2 spike protein. Positive results obtained with anti-SARS-CoV-2 IgM/IgA ELISAs require careful interpretation, especially if there is evidence for prior bacterial respiratory infections.
CRIS-Team Scopus Importer:2021-06-18
Keywords: Antibody; Bacterial infections; Coronavirus; COVID-19; Euroimmun; SARS-CoV-2; Vircell

Die Epidemiologie der peripheren arteriellen Verschlusskrankheit und deren sozioökonomische Bedeutung – Synopse - Calo, P.; Corvalan, J.; Behrendt, C. -A.; Boeckler, D.; Ruemenapf, G.; Rother, Ulrich; Uhl, C.; Goertz, H. (Gefässchirurgie, 2021)
Peripheral arterial occlusive disease (PAOD) is the manifestation of atherosclerosis as a systemic vascular disease. Worldwide there is an increasing prevalence of up to 10%, which increases with the aging of the population to 20% in patients over 70 years of age. Only 25% of patients with PAOD are symptomatic. Women tend to be diagnosed at an older age than men and are often already at the stage of critical limb ischemia (CLI). In addition to the functional impairments PAOD serves as an important marker for cardiovascular and cerebrovascular morbidity and mortality. For example, the 1‑year mortality for patients with CLI can be as high as 23%. Early diagnosis and evidence-based treatment can slow the course of this disease, improve the quality of life and reduce the rate of major amputations. The costs for inpatient and outpatient treatment of the target population are significant. In Germany it was observed that treatment costs increased by 21% from 2007 to 2009, with inpatient costs representing 4.9% of the total costs. Furthermore, the overall worldwide population over 65 years old is expected to double in the next 35 years. Thus, given recent demographic developments, PAOD represents a considerable medical and financial challenge for the healthcare system.
CRIS-Team Scopus Importer:2021-02-26
Keywords: Demographics; Health care costs; Incidence; Mortality; Prevalence

Die neue Weiterbildungsordnung – eine Herausforderung für die Viszeralchirurgie: Ergebnisse einer Umfrage unter DGAV-Mitgliedern und Lösungsstrategien der Jungen Chirurgie - Schardey, Josefine; Hüttl, Florentine; Jacobsen, Anne; Brunner, Stefanie; Tripke, Verena; Wirth, Ulrich; Werner, Jens; Kalff, Jörg C.; Sommer, Nils; Huber, Tobias (Die Chirurgie, 2024)
Background: The new competency-based further training regulations (nWBO) for surgical training have been adopted by all German state medical associations. Methods: From May to June 2023 the Young Surgeons’ Working Group (CAJC) conducted an anonymous online survey among the 5896 members of the German Society for General and Visceral Surgery (DGAV). Objective: The survey aimed to assess expectations regarding the nWBO and to develop strategies for enhancing surgical training. Results: With 488 participants (response rate 8.3%) the study is representative. The respondents consisted of 107 continuing education assistants (WBA 21.9%), 69 specialist physicians, and 188 senior physicians (specialist physicians 14.1% and senior physicians 38.5%), as well as 107 chief physicians (21.9%). The majority worked in regular care providers (44%), followed by maximum care providers (26.8%) and university clinics (20.1%). Only 22% considered the required operative spectrum of the new medical specialist training regulations (nWBO) to be realistic. Half of the respondents believed that full training in their clinic according to the new catalog will no longer be possible and 54.6% considered achieving the target numbers in 6 years to be impossible or state that they can no longer train the same number of continuing education assistants (WBAs) in the same time frame. Endoscopy (17.1–18.8%), fundoplication (15.4–17.7%) and head and neck procedures (12.1–17.1%) were consistently mentioned as bottlenecks across all levels of care. Rotations for balance were reported to be already established or not necessary in 64.7%. In 48% it was stated that the department had established the partial steps concept. The importance of a structured training concept was considered important by 85% of WBAs, compared to 53.3% of chief physicians (CÄ). If a structured training concept was present in the department, the achievability of the target numbers was significantly assessed more positively in the univariate analysis. In the multivariate analysis, male gender and the status of “habilitated/professor” were independent factors for a more positive assessment of the nWBO. Objective certification of training was considered important by 51.5%. Conclusion: Concerns surround the nWBO and the sentiment is pessimistic. Additional requirements and hospital reforms could exacerbate the situation. Collaboration and rotations are crucial but still insufficiently implemented. Quality-oriented certification could enhance the quality of training.
CRIS-Team Scopus Importer:2024-05-10
Keywords: Competency-based education; Residency; Surgical training; Survey; Visceral surgery

Die Patientenblutgruppe – der kleine, aber feine Unterschied - Zimmermann, Robert; Hackstein, Holger (Anaesthesist, 2018)
EVALuna2:213419

Die Wahrnehmung der peripheren arteriellen Verschlusskrankheit (PAVK) als Volkskrankheit: Behandeln wir nur die Spitze eines riesigen Problems? - Behrendt, Christian Alexander; Uhl, Christian; Görtz, Hartmut; Marchiori, Elena; Dovhanskiy, Dmitriy; Stavroulakis, Konstantinos; Rümenapf, Gerhard; Classen, Simon; Neufang, Achim; Larena-Avellaneda, Axel; Rother, Ulrich (Gefässchirurgie, 2022)
CRIS-Team Scopus Importer:2022-12-16

Differences in neonatal gastric tubes during insertion into a 3D model in relation to risk of potential perforation - Bartos, Hilda Brigitta; Diez, Sonja; König, Alexander; Görlach, Jannis; Besendörfer, Manuel; Mahnken, Andreas H.; Drommelschmidt, Karla; Weiss, Christel; Müller, Hanna (Journal of Pediatric Gastroenterology and Nutrition, 2024)
Objectives: Perforation of esophagus or stomach is a potential complication during and after insertion of a gastric tube in neonates. The aim of this study was to analyze different types of gastric tubes in a three-dimensional (3D) model of neonatal esophagus and stomach regarding potential perforations. Methods: A 3D model of esophagus and stomach was created based on computed tomography data of a term neonate. Three types of gastric tubes were inserted into the 3D model, the localization was examined by radioscopy and the behavior, stiffness and manageability of each gastric tube was evaluated. Results: Insertion of gastric tubes with higher stiffness was easier. The rates of correct localization differed significantly between the gastric tubes with the highest rate of correct localization in the softest tube (48.5%) and the lowest rate in the tube with the highest stiffness (21.2%). Additionally, the softest tube showed the lowest rate of localization of its tip at the stomach wall. Conclusions: The study illustrates differences between various types of gastric tubes regarding stiffness, behavior and resiliency. Softer gastric tubes may be beneficial. These differences may be relevant in neonatal care of very immature and very sick infants.
CRIS-Team Scopus Importer:2024-03-29
Keywords: esophageal perforation; gastric perforation; neonates; preterm infants

Differential Effects of Ontamalimab Versus Vedolizumab on Immune Cell Trafficking in Intestinal Inflammation and Inflammatory Bowel Disease - Schulze, Lisa; Becker, Emily; Dedden, Mark; Liu, Lijuan; Van Passen, Chiara; Mohamed Abdou, Mariam; Müller, Tanja; Wiendl, Maximilian; Ullrich, Karen; Atreya, Imke; Leppkes, Moritz; Ekici, Arif Bülent; et al. (Journal of Crohns & Colitis, 2023)
Background and Aims: The anti-MAdCAM-1 antibody ontamalimab demonstrated efficacy in a phase II trial in ulcerative colitis and results of early terminated phase III trials are pending, but its precise mechanisms of action are still unclear. Thus, we explored the mechanisms of action of ontamalimab and compared it to the anti-α4β7 antibody vedolizumab. Methods: We studied MAdCAM-1 expression with RNA sequencing and immunohistochemistry. The mechanisms of action of ontamalimab were assessed with fluorescence microscopy, dynamic adhesion and rolling assays. We performed in vivo cell trafficking studies in mice and compared ontamalimab and vedolizumab surrogate [-s] antibodies in experimental models of colitis and wound healing. We analysed immune cell infiltration under anti-MAdCAM-1 and anti-α4β7 treatment by single-cell transcriptomics and studied compensatory trafficking pathways. Results: MAdCAM-1 expression was increased in active inflammatory bowel disease. Binding of ontamalimab to MAdCAM-1 induced the internalization of the complex. Functionally, ontamalimab blocked T cell adhesion similar to vedolizumab, but also inhibited L-selectin-dependent rolling of innate and adaptive immune cells. Despite conserved mechanisms in mice, the impact of ontamalimab-s and vedolizumab-s on experimental colitis and wound healing was similar. Single-cell RNA sequencing demonstrated enrichment of ontamalimab-s-treated lamina propria cells in specific clusters, and in vitro experiments indicated that redundant adhesion pathways are active in these cells. Conclusions: Ontamalimab has unique and broader mechanisms of action compared to vedolizumab. However, this seems to be compensated for by redundant cell trafficking circuits and leads to similar preclinical efficacy of anti-α4β7 and anti-MAdCAM-1 treatment. These results will be important for the interpretation of pending phase III data.
CRIS-Team Scopus Importer:2023-12-15

Diffuse Neuromatosis of Intrahepatic and Extrahepatic Bile Ducts as a Rare Cause of Jaundice - Vassos, Nikolaos; Perrakis, Aristotelis; Schmid, Axel; Croner, Roland S.; Grützmann, Robert; Agaimy, Abbas (Visceral Medicine, 2020)
Background: Neuroma of the biliary tree is extremely rare with no more than 100 cases reported so far. They mostly present with obstructive jaundice and have been commonly described after surgery or abdominal trauma. Although involvement of the extrahepatic bile duct is far more common, occurrence in the intrahepatic ducts has not so far been reported. Case Report: We describe 3 cases of diffuse biliary tree neuroma affecting 3 females aged 53-68 years. None had a history of neurofibromatosis type1. All presented with progressive obstructive jaundice with no evidence of gallstones. A history of previous surgery was noted in 2 patients. Initial impression on clinical and imaging examination was highly suspicious for bile duct carcinoma in 2 patients. Histology showed diffuse neuromatous proliferation replacing and thickening the bile duct walls. The third patient had concurrent neuroma and recurrent cholangiocarcinoma causing great clinical confusion as initial biopsy showed only benign neuroma, but CA 19-9 was steadily increasing, necessitating a second biopsy which then confirmed recurrent carcinoma. Conclusion: This uncommon cause of long-distance bile duct stenosis and progressive jaundice should be included in the differential diagnosis of bile duct neoplasms, in particular when there is a previous surgical history in this abdominal region.
CRIS-Team Scopus Importer:2020-12-18
Keywords: Bile duct neuroma; Bile duct stenosis; Cholangiocarcinoma; Jaundice; Neuromatosis

Dipeptidyl-Peptidase-4 (DPP4) Positive Fibroblast Subpopulation Promotes Fibrosis and Are a Molecular Target for Treatment of Fibrosis - Soare, Alina; Rauber, Simon; Wohlfahrt, Thomas; Dees, Clara; Liang, Ruifang; Zhang, Yun; Chen, Chih-Wei; Distler, Oliver; Mihai, Carina; Schett, Georg; Distler, Jörg; Ramming, Andreas (2016)
EVALuna2:35065

Discrimination of pancreato-biliary cancer and pancreatitis patients by non-invasive liquid biopsy - Hartwig, Christina; Müller, Jan; Klett, Hagen; Kouhestani, Dina; Mittelstädt, Anke; Anthuber, Anna; David, Paul; Brunner, Maximilian; Jacobsen, Anne; Glanz, Karolina; Swierzy, Izabela; Roßdeutsch, Lotta; et al. (Molecular Cancer, 2024)
Background: Current diagnostics for the detection of pancreato-biliary cancers (PBCs) need to be optimized. We therefore propose that methylated cell-free DNA (cfDNA) derived from non-invasive liquid biopsies serves as a novel biomarker with the ability to discriminate pancreato-biliary cancers from non-cancer pancreatitis patients. Methods: Differentially methylated regions (DMRs) from plasma cfDNA between PBCs, pancreatitis and clinical control samples conditions were identified by next-generation sequencing after enrichment using methyl-binding domains and database searches to generate a discriminatory panel for a hybridization and capture assay with subsequent targeted high throughput sequencing. Results: The hybridization and capture panel, covering around 74 kb in total, was applied to sequence a cohort of 25 PBCs, 25 pancreatitis patients, 25 clinical controls, and seven cases of Intraductal Papillary Mucinous Neoplasia (IPMN). An unbiased machine learning approach identified the 50 most discriminatory methylation markers for the discrimination of PBC from pancreatitis and controls resulting in an AUROC of 0.85 and 0.88 for a training (n = 45) and a validation (n = 37) data set, respectively. The panel was also able to distinguish high grade from low grade IPMN samples. Conclusions: We present a proof of concept for a methylation biomarker panel with better performance and improved discriminatory power than the current clinical marker CA19-9 for the discrimination of pancreato-biliary cancers from non-cancerous pancreatitis patients and clinical controls. This workflow might be used in future diagnostics for the detection of precancerous lesions, e.g. the identification of high grade IPMNs vs. low grade IPMNs.
CRIS-Team Scopus Importer:2024-02-16
Keywords: cfDNA; cfMBD-Seq; DMRs; Hybridization and capture; IPMN; Methylation; Next-generation sequencing; Non-invasive diagnostics; Pancreatitis; Pancreato-biliary cancer

Distal pedal bypasses combined with free microsurgical flaps in chronic limb ischaemia for problematic wounds - Horch, Raymund E.; Lang, Werner; Meyer, Alexander; Schmitz, Marweh (International Wound Journal, 2014)
EVALuna2:15173

Distant metastases in colorectal carcinoma: A proposal for a new M1 subclassification - Merkel, Susanne; Weber, K.; Croner, R. S.; Golcher, H.; Göhl, Jonas; Agaimy, Abbas; Semrau, S.; Wein, Axel; Hohenberger, Werner; Wittekind, C.; Siebler, Jürgen (Ejso, 2016)
In 2010, the seventh Tumour-Node-Metastasis (TNM) cancer staging system of the International Union for Cancer Control (UICC) and the American Joint Committee of Cancer (AJCC) introduced a subdivision of M1 in the TNM classification of colorectal carcinomas. For the eighth TNM edition which will be released in the autumn of 2016 and will become effective in January 2017 new proposals are appreciated. The aim of our study was to define a new and better proposal for M1 subclassification.In a total of 814 patients with stage IV colorectal carcinoma treated between 1995 and 2013 prognostic factors were analysed in univariate and multivariate analyses.Advanced age, treatment in the earlier period 1995-2003, involvement of multiple metastatic sites, and non-curative resection were found to be independent prognostic factors. In patients with only one metastatic site, survival was good in patients with liver or lung metastasis, moderate in patients with metastasis of the peritoneum or non-regional lymph nodes and poor in patients with other rarely metastatic involved organs. The new proposal defines M1a, Metastasis confined to one organ: liver or lung (2-year survival 51.6%); M1b, Metastasis confined to one organ: peritoneum or non-regional lymph nodes, or Metastasis confined to liver plus lung (2-year survival 39.4%); and M1c, Metastasis confined to one organ: all other sites, or Metastasis in more than one organ, except liver plus lung (2-year survival 21.6%).The new proposal can identify three prognostic groups in stage IV colorectal carcinomas with significant differences in survival.
EVALuna2:2060

Distinct endocytosis and immune activation of poly lactic-co-glycolic acid nanoparticles prepared by single- and double-emulsion evaporation - Spiecker, Erdmann; Hackstein, Holger; Wu, Mingjian; Scheuer, Karl; Brox, Regine; Apeleo Zubiri, Benjamin; Pusch, Lennart; Jandt, Klaus D.; Yokosawa, Tadahiro; Fischer, Dagmar (2021)
Background: Poly lactic-co-glycolic acid (PLGA) nanoparticles can be prepared by emulsion-solvent-evaporation from o/w and w(1)/o/w(2) emulsions. Aims: To elaborate similarities and differences regarding mechanical, morphological and physicochemical properties, as well as endocytosis and dose-dependent immune responses by primary human leukocytes between nanoparticles prepared by these two methods. Methods: Fluorescently labeled as well as TLR-agonist (R848)-loaded PLGA nanoparticles were prepared via both single- and double-emulsion solvent evaporation. Results: Particles prepared by both methods were similar in chemical composition and surface charge but exhibited slight differences in size and morphology. Pronounced differences were found for loading, dissolution and mechanical properties. The particles were differently endocytosed by monocytes and induced qualitatively and quantitatively different immune responses. Conclusions: Variations in nanoparticle preparation can affect particle-derived immunological characteristics.
CRIS-Team WoS Importer:2021-09-24

Distinct mircobiomes in right- and left-sided colon cancer - Langheinrich, Melanie C.; Wirtz, Stefan; Kneis, Barbara; Weber, Klaus; Brunner, Maximilian; Krautz, Christian; Trebicka, Jonel; Agaimy, Abbas; Grützmann, Robert; Kersting, Stephan (ONCOLOGY RESEARCH AND TREATMENT, 2022)
CRIS-Team WoS Importer:2022-12-16

Distribution of Mobile Health Applications amongst Patients with Symptomatic Peripheral Arterial Disease in Germany: A Cross-Sectional Survey Study - Alushi, Kastriot; Hinterseher, Irene; Peters, Frederik; Rother, Ulrich; Bischoff, Moritz S.; Mylonas, Spyridon; Grambow, Eberhard; Gombert, Alexander; Busch, Albert; Gray, Daphne; Konstantinou, Nikolaos; Stavroulakis, Konstantinos; et al. (Journal of Clinical Medicine, 2022)
Background: Broadly available digital and mobile health applications (also known as mHealth) have recently gained increasing attention by the vascular community, but very little is known about the dissemination and acceptance of such technologies in certain target populations. The current study aimed to determine the user behaviour and acceptance of such digital technologies amongst patients with peripheral arterial disease (PAD). Methods: A cross-sectional survey of consecutively treated inpatients at 12 university institutions, as well as one non-university institution, was conducted. All admitted patients with symptomatic PAD were surveyed for 30 consecutive days within a flexible timeframe between 1 July and 30 September 2021. The factors associated with smartphone use were estimated via backward selection within a logistic regression model with clustered standard errors. Results: A total of 326 patients participated (response rate 96.3%), thereof 102 (34.0%) were treated for intermittent claudication (IC, 29.2% women, 70 years in median) and 198 were treated for chronic limb-threatening ischaemia (CLTI, 29.5% women, 70 years in median). Amongst all of the patients, 46.6% stated that they had not changed their lifestyle and health behaviour since the index diagnosis (four years in median), and 33.1% responded that they were not aware of the reasons for all of their medication orders. Amongst all those surveyed, 66.8% owned a smartphone (IC: 70.6%, CLTI: 64.1%), thereof 27.9% needed regular user support. While 42.5% used smartphone apps, only 15.0% used mobile health applications, and 19.0% owned wearables. One out of five patients agreed that such technologies could help to improve their healthy lifestyle. Only higher age was inversely associated with smartphone possession. Conclusions: The current survey showed that smartphones are prevalent amongst patients with peripheral arterial disease, but only a small proportion used mobile health applications and a considerable number of patients needed regular user support. Almost half of the patients did not change their lifestyle and one third were not aware of the reasons for their medication orders, emphasising room for improvement. These findings can further help to guide future projects using such applications to identify those target populations that are reachable with digital interventions.
CRIS-Team Scopus Importer:2022-01-28
Keywords: Peripheral arterial disease; Smartphone; Wearable electronic devices

Diverging effects of premature birth and bronchopulmonary dysplasia on exercise capacity and physical activity - A case control study - Ruf, Katharina; Thomas, Wolfgang; Brunner, Maximilian; Speer, Christian P.; Hebestreit, Helge (Respiratory Research, 2019)
Background: Extreme prematurity has been associated with exercise intolerance and reduced physical activity. We hypothesized that children with bronchopulmonary dysplasia (BPD) would be especially affected based on long-term lung function impairments. Therefore, the objective of this study was to compare exercise capacity and habitual physical activity between children born very and extremely preterm with and without BPD and term-born children. Methods: Twenty-two school-aged children (aged 8 to 12 years) born with a gestational age < 32 weeks and a birthweight < 1500 g (9 with moderate or severe BPD (=BPD), 13 without BPD (=No-BPD)) and 15 healthy term-born children (=CONTROL) were included in the study. Physical activity was measured by accelerometry, lung function by spirometry and exercise capacity by an incremental cardiopulmonary exercise test. Results: Peak oxygen uptake was reduced in the BPD-group (83 ± 11%predicted) compared to the No-BPD group (91 ± 8%predicted) and the CONTROL group (94 ± 9%predicted). In a general linear model, variance of peak oxygen uptake was significantly explained by BPD status and height but not by prematurity (p < 0.001). Compared to CONTROL, all children born preterm spent significantly more time in sedentary behaviour (BPD 478 ± 50 min, No-BPD 450 ± 52 min, CONTROL 398 ± 56 min, p < 0.05) and less time in moderate-to-vigorous-physical activity (BPD 13 ± 8 min, No-BPD 16 ± 8 min, CONTROL 33 ± 16 min, p < 0.001). Prematurity but not BPD contributed significantly to explained variance in a general linear model of sedentary behaviour and likewise moderate-to-vigorous-physical activity (p < 0.05 and p < 0.001 respectively). Conclusion: In our cohort, BPD but not prematurity was associated with a reduced exercise capacity at school-age. However, prematurity regardless of BPD was related to less engagement in physical activity and more time spent in sedentary behaviour. Thus, our findings suggest diverging effects of prematurity and BPD on exercise capacity and physical activity.
CRIS-Team Scopus Importer:2019-12-03
Keywords: Bronchopulmonary dysplasia; Exercise capacity; Exercise testing; Physical activity; Preterm birth; Sedentary behaviour

DMBT1 expression and neutrophil-to-lymphocyte ratio during necrotizing enterocolitis are influenced by impaired perfusion due to cardiac anomalies. - Diez, Sonja; Besendörfer, Manuel; Weyerer, Veronika; Hartmann, Arndt; Moosmann, Julia; Weiss, Christel; Renner, Marcus; Müller, Hanna (Molecular and Cellular Pediatrics, 2022)
BACKGROUND: Deleted in malignant brain tumors 1 (DMBT1) is involved in innate immunity and epithelial differentiation. It has been proven to play a role in various states of inflammation or hypoxia of fetal gastrointestinal and pulmonary diseases. Discrimination of pathogenesis in necrotizing enterocolitis (NEC) based on cardiac status improves the understanding of NEC in different patient subgroups. We aimed at examining DMBT1 expressions regarding their association with cardiac status leading to impaired intestinal perfusion, intraoperative bacteria proof, and a fulminant course of NEC. METHODS: Twenty-eight patients with NEC were treated surgically between 2010 and 2019 at our institution. DMBT1 expression was examined in intestinal sections using immunohistochemistry to detect DMBT1 protein. Associations of clinical parameters and DMBT1 expression were analyzed. RESULTS: We examined DMBT1 levels in 10 patients without cardiac defects and 18 patients with persisting ductus arteriosus (PDA) and congenital heart defects (CHD). Compared to patients without cardiac malformations, DMBT1 levels tended to score higher in patients with PDA/CHD (p = 0.2113) and were negatively correlated with C-reactive protein in these infants (p = 0.0172; r = - 0.5533). The number of DMBT1-expressing macrophages was elevated in the PDA/CHD-subgroup (p = 0.0399). Ratios of neutrophils and monocytes to lymphocytes were significantly higher in infants with PDA/CHD (p = 0.0319 and 0.0493). DMBT1 expression was significantly associated with positive bacterial culture of intraoperative swabs (p = 0.0252) and DMBT1 expression of the serosa was associated with a fulminant course of NEC (p = 0.0239). CONCLUSIONS: This study demonstrates that DMBT1 expression may be influenced by cardiac anomalies with an impaired intestinal perfusion in the neonatal intestine. NEC in PDA/CHD infants is associated with more DMBT1-positive macrophages and a significantly elevated neutrophil-to-lymphocyte ratio.
EVALuna2:497662
Keywords: DMBT1; Deleted in malignant brain tumors 1; Necrotizing enterocolitis; Congenital heart disease; Neutrophil-to-lymphocyte ratio; Monocyte-to-lymphocyte ratio

DNA demethylation and tri-methylation of H3K4 at the TACSTD2 promoter are complementary players for TROP2 regulation in colorectal cancer cells - Gehring, Annemarie; Hübner, Kerstin; Rani, H.; Erlenbach-Wünsch, Katharina; Merkel, Susanne; Mahadevan, Vijayalakshmi; Grützmann, Robert; Hartmann, Arndt; Schneider-Stock, Regine (Scientific Reports, 2024)
TROP2 is a powerful cancer driver in colorectal cancer cells. Divergent epigenetic regulation mechanisms for the corresponding TACSTD2 gene exist such as miRNAs or DNA methylation. However, the role of TACSTD2 promoter hypermethylation in colorectal cancer has not been investigated yet. In this study, TROP2 expression strongly correlated with promoter methylation in different colorectal tumor cell lines. Treatment with 5-Azacytidine, a DNMT1 inhibitor, led to demethylation of the TACSTD2 promoter accompanied by an increase in TROP2 protein expression. TROP2 expression correlated with promoter methylation in vivo in human colon tumor tissue, thereby verifying promoter methylation as an important factor in the regulation of TROP2 expression in colorectal cancer. When performing a ChIP-Seq analysis in HCT116 and HT29 cells, we found that TACSTD2 promoter demethylation was accompanied by tri-methylation of H3K4. In silico analysis of GSE156613 data set confirmed that a higher binding of histone mark H3K4me3 around the TACSTD2 promoter was found in TACSTD2 high expressing tumors of colon cancer patients compared to the corresponding adjacent tumor tissue. Moreover, the link between TROP2 and the H3K4me3 code was even evident in tumors showing high intratumoral heterogeneity for TROP2 staining. Our data provide novel evidence for promoter demethylation and simultaneous gains of the active histone mark H3K4me3 across CpG-rich sequences, both being complementary mechanisms in the transcriptional regulation of TACSTD2 in colon cancer. The functional consequences of TROP2 loss in colorectal cancer needs to be further investigated.
CRIS-Team Scopus Importer:2024-02-16

DNA stool test for colorectal cancer: hypermethylation of the secreted frizzled-related protein-1 gene. - Zhang, Wei; Bauer, Michael; Croner, Roland S.; Pelz, Jörg Otto Wilhelm; Lodygin, Dimitri; Hermeking, Heiko; Stürzl, Michael; Hohenberger, Werner; Matzel, Klaus (Diseases of the colon & rectum, 2007)
To investigate a potential mode of noninvasive screening for colorectal cancer, we evaluated the hypermethylation of the secreted frizzled-related protein-1 gene promoter in human stool DNA. In stool samples from 36 patients with colorectal neoplasia (7 adenoma, 29 colorectal cancer) and 17 healthy control subjects, isolated DNA was treated with sodium bisulfite and analyzed by methylation-specific polymerase chain reaction with primers specific for methylated or unmethylated promoter sequences of the secreted frizzled-related protein-1 gene. Hypermethylation of the secreted frizzled-related protein-1 promoter was present in the stool DNA of patients with adenoma and colorectal cancer. A sensitivity of 89 percent and specificity of 86 percent were achieved in the detection of colorectal neoplasia. The difference in hypermethylation status of the secreted frizzled-related protein-1 promoter between the patients with colorectal neoplasia and the control group was statistically highly significant (P < 0.001). Adenoma and early tumor Stage I (International Union Against Cancer) displayed both unmethylated and methylated secreted frizzled-related protein-1 promoter sequences, whereas advanced tumor stages showed only methylated secreted frizzled-related protein-1 (P = 0.05). The results indicate that this DNA stool test of hypermethylation of the secreted frizzled-related protein-1 promoter is a sensitive and specific method. It has the potential of a clinically useful test for the early detection of colorectal cancer. PURPOSE METHODS RESULTS CONCLUSIONS
Keywords: DNA methylation; Colorectal cancer; Secreted frizzled-related protein; Stool DNA test; Epigenetic marker; Cancer screening

Does In-transit-Metastasis in lower Extremity Melanoma Patients correlate with anatomical Lymphatic Drainage Pathways? - Müller, Kilian; Schellerer, Vera; Berking, Carola; Erdmann, Michael (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2021)
CRIS-Team WoS Importer:2021-09-24

Donor Site Morbidity of Patients Receiving Vertical Rectus Abdominis Myocutaneous Flap for Perineal, Vaginal or Inguinal Reconstruction - Schellerer, Vera; Bartholomé, Lenka; Langheinrich, Melanie; Grützmann, Robert; Horch, Raymund E.; Merkel, Susanne; Weber, Klaus (World Journal of Surgery, 2020)
Background: Management of donor site closure after harvesting a vertical rectus abdominis myocutaneous (VRAM) flap is discussed heterogeneously in the literature. We aim to analyze the postoperative complications of the donor site depending on the closure technique. Methods: During a 12-year period (2003–2015), 192 patients in our department received transpelvic VRAM flap reconstruction. Prospectively collected data were analyzed retrospectively. Results: 182 patients received a VRAM flap reconstruction for malignant, 10 patients for benign disease. The median age of patients was 62 years. 117 patients (61%) received a reconstruction of donor site by Vypro® mesh, 46 patients (24%) by Vicryl® mesh, 23 patients (12%) by direct closure and 6 patients (3%) by combination of different meshes. 32 patients (17%) developed in total 34 postoperative complications at the donor site. 22 complications (11%) were treated conservatively, 12 (6%) surgically. 17 patients (9%) developed incisional hernia during follow-up, with highest incidence in the Vicryl® group (n = 8; 17%) and lowest in the Vypro® group (n = 7; 6%). Postoperative parastomal hernias were found in 30 patients (16%) including three patients with simultaneous hernia around an urostomy and a colostomy. The highest incidence of parastomal hernia was found in patients receiving primary closure of the donor site (n = 6; 26%), the lowest incidence in the Vypro® group (n = 16; 14%). Conclusion: The use of Vypro® mesh for donor site closure appears to be associated with a low postoperative incidence of complications and can therefore be recommended as a preferred technique.
CRIS-Team Scopus Importer:2020-10-09

Do Patients with Lower Limb Melanoma have an increased Risk of a "false negative" Sentinel Node Biopsy? - Braun, L.; Schellerer, Vera; Schuler, Gerold; Goeol, J.; Erdmann, M. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2019)
CRIS-Team WoS Importer:2019-09-13

Dosing of indocyanine-green for intraoperative laser fluorescence angiography in kidney transplantation - Rother, Ulrich; Gerken, Andreas L. H.; Karampinis, Ioannis; Klumpp, Madeline; Regus, Susanne; Meyer, Alexander; Apel, Hendrik; Kraemer, Bernhard K.; Hilgers, Karl Friedrich; Lang, Werner; Nowak, Kai (Microcirculation, 2017)
Sufficient blood supply is a crucial factor determining postoperative allograft function in kidney transplantation. Therefore, besides the surgeon's individual impression a method for evaluating the quality of the organ's microperfusion is required. Laser fluorescence angiography with indocyanine-green (ICG) is an emerging tool for this purpose. However, no reproducible quantification of ICG fluorescence has been performed in transplantation so far.This retrospective two-center study was designed to evaluate the dosing of ICG for intraoperative laser fluorescence angiography in kidney transplantation. The Spy Elite(®) system (NOVADAQ, Canada) was employed for quantitative assessment of allograft microperfusion. ICG was administered systemically 5 min after reperfusion applying doses between 0.25 and 0.01 mg ICG per kg body weight. Quantitative assessment was performed with the implemented SPY-Q Software.57 kidney recipients were included in two centers. The generated curves showing ICG ingress and egress rates were not evaluable due to oversensing when doses exceeded 0.02 mg per kg body weight.Fluorescence angiography with ICG is an emerging tool for the intraoperative quality control and evaluation of microperfusion in kidney transplantation. A dose of 0.02 mg ICG per kg body weight is recommended in order to ensure the quantitative assessment with SPY-Q. This article is protected by copyright. All rights reserved.
EVALuna2:3964

Do surgical skills affect outcomes? - Tou, Samson; Gomez Ruiz, M.; Gallagher, A. G.; Eardley, N. J.; Matzel, Klaus (Colorectal Disease, 2020)
CRIS-Team WoS Importer:2020-09-25

Downregulation of SPARC Is Associated with Epithelial-Mesenchymal Transition and Low Differentiation State of Biliary Tract Cancer Cells - Aghamaliyev, Ughur; Gaitantzi, Haristi; Thomas, Maria; Simon-Keller, Katja; Gaiser, Timo; Marx, Alexander; Yagublu, Vugar; Araos, Joaquin; Cai, Chen; Valous, Nektarios A.; Halama, Niels; Kiesslich, Tobias; et al. (European Surgical Research, 2019)
Background: Biliary tract cancers (BTCs) have a poor prognosis. BTCs are characterized by a prominent desmoplastic reaction which possibly contributes to the aggressive phenotype of this tumor. The desmoplastic reaction includes excessive production and deposition of extracellular matrix proteins such as periostin, secreted protein acidic and rich in cysteine (SPARC), thrombospondin-1, as well as accumulation of α-smooth muscle actin-positive cancer-associated fibroblasts and immune cells, secreting growth factors and cytokines including transforming growth factor (TGF)-β. In the present study, we investigated the expression of SPARC in BTC as well as its possible regulation by TGF-β. Methods: Expression levels of Sparc, TGF-β1 and its receptor ALK5 were evaluated by quantitative real-time PCR in 6 biliary tract cell lines as well as 1 immortalized cholangiocyte cell line (MMNK-1). RNAs from tumor samples of 7 biliary tract cancer patients were analyzed for expression of Sparc, TGF-β type II receptor (TbRII) as well as Twist and ZO-1. MMNK-1 cells were stimulated with TGF-β for 24 h, and Sparc, ZO-1 and E-Cadherin expressions were determined. The presence of SPARC protein was analyzed by immunohistochemistry in tumor specimens from 10 patients. Results: When comparing basal Sparc transcript levels in diverse BTC cell lines to MMNK-1 cells, we found that it was strongly downregulated in all cancer cell lines. The remaining expression levels were higher in highly differentiated cell lines (CCSW1, MZChA1, MZChA2 and TFK-1) than in less differentiated and undifferentiated ones (BDC, SKChA1). Expression of Sparc in BTC patient samples showed a significant positive correlation with expression of the epithelial marker ZO-1. In contrast, the mesenchymal marker Twist and the TbRII showed a trend of negative correlation with expression of Sparc in these samples. TGF-β exposure significantly downregulated Sparc expression in MMNK-1 cholangiocytes in vitro in parallel to downregulation of epithelial markers (E-Cadherin and ZO-1). Finally, SPARC immunostaining was performed in 10 patient samples, and the correlation between absence of SPARC and survival times was analyzed. Conclusions: These data imply that a decrease in SPARC expression is correlated with dedifferentiation of BTC cells resulting in enhanced EMT being possibly mediated by TGF-β. Thereby SPARC levels might be a marker for individual prognosis of a patient, and strategies aiming at inhibition of SPARC downregulation might have potential for new future therapies.
CRIS-Team Scopus Importer:2019-06-07
Keywords: Biliary tract cancer; Cholangiocarcinoma; Desmoplastic reaction; Secreted protein acidic and rich in cysteine; Transforming growth factor-β

Downstage migration after neoadjuvant chemoradiotherapy for rectal cancer: the reverse of the Will Rogers phenomenon? - Fokas, Emmanouil; Liersch, Torsten; Fietkau, Rainer; Hohenberger, Werner; Hess, Clemens; Becker, Heinz; Sauer, Rolf; Wittekind, Christian; Roedel, Claus (Cancer, 2015)
Downstaging after neoadjuvant treatment is increasingly used as a prognostic factor and surrogate endpoint in clinical trials. However, in recent trials of neoadjuvant 5-fluorouracil-based chemoradiotherapy for rectal cancer, downstaging did not translate into a benefit with regard to either disease-free survival (DFS) or overall survival. By analyzing the 10-year outcome data of the German CAO/ARO/AIO-94 phase 3 trial, the authors demonstrated that significantly fewer patients had poor prognostic features (eg, ypT3-4, ypN1-2) after preoperative 5-fluorouracil-based chemoradiotherapy. Nevertheless, these patients with International Union for Cancer Control stage II disease were found to be at a higher risk of developing distant metastases and had poorer DFS compared with patients with corresponding TNM tumor (sub)groups in the postoperative treatment arm, whereas patients with International Union for Cancer Control stage III disease demonstrated a nonsignificant trend toward a worse outcome after preoperative treatment. Overall, DFS remained identical in both treatment arms. Thus, "downstage migration" after neoadjuvant treatment resembles the reverse of the Will Rogers phenomenon and therefore may not be a reliable endpoint for long-term outcomes.
EVALuna2:15194

Drug-induced phospholipidosis caused by combinations of common drugs in vitro - Glock, Mareike; Mühlbacher, Markus; Hurtig, Henoch; Tripal, Philipp; Kornhuber, Johannes (Toxicology in Vitro, 2016)
Drug-induced phospholipidosis (DIPLD), characterized by the accumulation of phospholipids within lysosomes, is suspected to impair lysosomal function and considered an adverse side effect of the administered medication. The increasing use of polypharmacy and the resultant elevated risks of adverse drug reactions raise the need to explore the effects of drug combinations with respect to their influence on side effects, such as DIPLD. In this study, we utilized an in vitro assay to investigate DIPLD that was caused by 24 commonly used drugs applied alone and in binary combinations with each other. Moreover, we attempted to predict the extent of DIPLD resulting from the combinations using a simple additive approach based on the increase in phospholipid levels caused by the single drugs. The results suggest that DIPLD, which was caused by combinations of drugs, occurs in an additive manner, depending on total drug concentration. Furthermore, we show that the extent of DIPLD can be predicted from the DIPLD caused by the single drugs. Thus, the simultaneous use of multiple drugs with PLD-inducing properties increases the event risk, as well as the severity of drug-induced phospholipidosis. The findings underline the importance of considering the DIPLD-inducing properties of drugs, especially in the context of polypharmacy.
EVALuna2:23782

DYNAMIC CHANGES IN O-GLCNACYLATION REGULATE OSTEOCLAST DIFFERENTIATION AND BONE LOSS IN ARTHRITIS - Chen, Chih-Wei; Li, Y. N.; Trinh, Minh Thuong; Honglin, Z.; Matei, Alexandru-Emil; Ding, Xiao; TRAN MANH, CUONG; Xu, Xiaohan; Liebel, C.; Liang, Ruifang; Huang, M. C.; Lin, N. Y.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-10-01

Dynamic changes in O-GlcNAcylation regulate osteoclast differentiation and bone loss via nucleoporin 153 - Li, Yi-Nan; Chen, Chih-Wei; Trinh, Minh Thuong; Zhu, Honglin; Matei, Alexandru-Emil; Györfi, Andrea-Hermina; Kuwert, Frederic; Hubel, Philipp; Ding, Xiao; TRAN MANH, CUONG; Xu, Xiaohan; Liebel, Christoph; et al. (Bone Research, 2022)
Bone mass is maintained by the balance between osteoclast-induced bone resorption and osteoblast-triggered bone formation. In inflammatory arthritis such as rheumatoid arthritis (RA), however, increased osteoclast differentiation and activity skew this balance resulting in progressive bone loss. O-GlcNAcylation is a posttranslational modification with attachment of a single O-linked β-D-N-acetylglucosamine (O-GlcNAc) residue to serine or threonine residues of target proteins. Although O-GlcNAcylation is one of the most common protein modifications, its role in bone homeostasis has not been systematically investigated. We demonstrate that dynamic changes in O-GlcNAcylation are required for osteoclastogenesis. Increased O-GlcNAcylation promotes osteoclast differentiation during the early stages, whereas its downregulation is required for osteoclast maturation. At the molecular level, O-GlcNAcylation affects several pathways including oxidative phosphorylation and cell-cell fusion. TNFα fosters the dynamic regulation of O-GlcNAcylation to promote osteoclastogenesis in inflammatory arthritis. Targeted pharmaceutical or genetic inhibition of O-GlcNAc transferase (OGT) or O-GlcNAcase (OGA) arrests osteoclast differentiation during early stages of differentiation and during later maturation, respectively, and ameliorates bone loss in experimental arthritis. Knockdown of NUP153, an O-GlcNAcylation target, has similar effects as OGT inhibition and inhibits osteoclastogenesis. These findings highlight an important role of O-GlcNAcylation in osteoclastogenesis and may offer the potential to therapeutically interfere with pathologic bone resorption.
CRIS-Team Scopus Importer:2022-08-05

EBV latent membrane protein-1 protects B cells from apoptosis by inhibition of BAX - Naschberger, Elisabeth; Stürzl, Michael; et al. (Blood, 2005)
Latent membrane protein 1 (LMP-1) of Epstein-Barr virus (EBV) promotes tumorigenesis by inhibiting apoptosis. We show that an important antiapoptotic activity of LMP-1 is the inhibition of Bcl2-associated protein X (Bax), a potent proapoptotic protein. BAX expression was regulated by LMP-1 activation of nuclear factor κB (NF-κB) via the C-terminal activation region 1 (CTAR-1) and CTAR-2. Interestingly, p65/p50 inhibited, whereas p50/p50 increased, BAX promoter activity as demonstrated by overexpression and selective inhibition of these NF-κB isoforms. Electrophoretic mobility shift analysis revealed that LMP-1 activates 2 of the 3 NF-κB binding sites (κB1-κB3) in the BAX promoter. LMP-1 induced binding of the NF-κB heterodimer p65/p50 to the κB2 site and of the p50/p50 homodimer to the κB3 site. Promoter mutation analysis revealed that the κB2 site is necessary for inhibition of BAX promoter activity and the κB3 site, for its activation. However, the activation of the BAX promoter by LMP-1 was observed only in the presence of specific inhibitors of p65/p50. In all other cases, LMP-1 inhibited BAX promoter activity. Most importantly, the antiapoptotic activity of LMP-1 was considerably decreased in cells deficient for BAX. These results indicate that the inhibition of Bax may be an important antiapoptotic activity of LMP-1. © 2005 by The American Society of Hematology.
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Editor's Choice – Long Term Outcomes After Invasive Treatment of Carotid Artery Stenosis: a Longitudinal Study of German Health Insurance Claims - Zimmermann, Matthias; Larena-Avellaneda, Axel; Rother, Ulrich; Lareyre, Fabien; Søgaard, Mette; Tulamo, Riikka; Venermo, Maarit; Behrendt, Christian Alexander (European Journal of Vascular and Endovascular Surgery, 2023)
Objective: There is a paucity of observational data including long term outcomes after invasive treatment for carotid artery stenosis. Methods: This retrospective study used nationwide insurance claims from the third largest provider in Germany, DAK-Gesundheit. Patients who underwent inpatient carotid endarterectomy (CEA) or carotid artery stenting (CAS) between 1 January 2008 and 31 May 2017 were included. The Elixhauser comorbidity scores from longitudinally linked hospital episodes were used. Kaplan–Meier analysis and the log rank test were used to determine long term stroke free survival. Multivariable regression models were developed to adjust for confounding. Results: A total of 22 637 individual patients (41.6% female, median age 72.5 years) were included, of whom 15 005 (66.3%) were asymptomatic and 17 955 (79.3%) underwent CEA. After a median of 48 months, 5 504 any stroke or death events were registered. The mortality rate varied between 0.4% (CEA for asymptomatic stenosis) and 2.1% (urgent CAS for acute stroke patients) at 30 days, and between 4.1% and 8.4% at one year, respectively. The rate for any stroke varied between 0.6% (CEA for asymptomatic stenosis) and 2.5% (CAS for symptomatic patients) at 30 days, and between 2.5% and 6.4% at one year, respectively. The combined rate for any stroke and mortality at one year was 6.3% (CEA for asymptomatic stenosis), 8.7% (CAS for asymptomatic stenosis), and 12.5% (urgent CAS for acute stroke patients). After five years, the overall stroke rate was 7.4% after CEA and 9.0% after CAS. In adjusted analyses, both older age and van Walraven comorbidity score were associated with events, while treatment of asymptomatic stenosis was associated with lower event rates. Conclusion: The current study revealed striking differences between previous landmark trials and real world practice. It further suggested excess deaths among invasively treated asymptomatic patients.
CRIS-Team Scopus Importer:2023-10-13
Keywords: Carotid artery stenosis; Endovascular technique; Health services research; Outcomes; Registries; Stroke

Effective local control of advanced soft tissue sarcoma with neoadjuvant chemoradiotherapy and surgery: A single institutional experience - Stubbe, Franziska; Agaimy, Abbas; Ott, O.; Lettmaier, S.; Vassos, N.; Croner, R.; Hohenberger, Werner; Fietkau, Rainer; Semrau, S. (Cancer Radiotherapie, 2016)
There is a sound theoretical basis but little clinical evidence substantiating the benefits of concurrent chemoradiotherapy with two-drug chemotherapy for locally advanced soft tissue sarcomas. Our five-year data on the feasibility and effectiveness of neoadjuvant chemoradiotherapy with systemically effective doses of adriamycin and ifosfamide combined is presented here.Between 2000 and 2011, 53 patients with UICC (2010) stage I (n=1, 1.9%), II (n=12, 22.7%) or III (n=40, 75.5%) nonmetastatic soft tissue sarcoma received neoadjuvant chemoradiotherapy with ifosfamide (1.5g/m(2)/day, d1-5, q28) and doxorubicin (50mg/m(2)/day, d3, q28) plus concurrent radiotherapy with a target dose of 50-64Gy (median 60Gy). The treatment of 34 patients (64.2%) was combined with hyperthermia.At five years, the local control rate was 89.9% (±5.7%), distant metastasis-free survival 66.6% (±7.6%), and survival 83.3% (±6%). The R0 resection rate was 81.1%. Radiotherapy was completed as planned in all patients and chemotherapy in 42/53 (70.2%). Grades III (n=21, 29.6%) and IV (n=18, 34%) leukopenia was the main acute adverse event. All acute and chronic non-hematologic toxicities were moderate.Neoadjuvant chemoradiotherapy for soft tissue sarcoma is associated with good feasibility, manageable acute and late toxicities, and high local efficacy.
EVALuna2:6741

Effect of Circular Stapler Diameter on Anastomotic Leakage Rate and Stenosis After Open Total Gastrectomy With Esophagojejunostomy: A Substantive Retrospective Propensity Score Matched Series. - Mittelstädt, Anke; Reitberger, Helena; Fleischmann, Julia; Elshafei, Moustafa; Brunner, Maximilian; Anthuber, Anna; Krautz, Christian; Lucio, Marianna; Merkel, Susanne; Grützmann, Robert; Weber, Georg (Annals of Surgery Open, 2022)
BACKGROUND: Anastomotic leakage (AL) and stenosis (AS) are two of the most severe postoperative complications after total gastrectomy with esophagojejunostomy. The stapler diameter can be chosen by the surgeon. Therefore, this study aims to assess the correlation between the stapler size as main independent variable as well as other different risk factors and AL and AS. METHODS: We conducted a retrospective analysis of data from 356 patients who underwent open total gastrectomy between 2000 and 2018, mostly due to gastric cancer (96.9%). After propensity score matching the outcome parameters AL and AS were compared between the two stapler size groups. We also assessed different risk factors for AL and AS in cancer patients using multivariate analysis. RESULTS: Small circular stapler diameter (21/25 mm; n = 147 vs 28/29/31 mm; n = 209) was identified as a significant risk factor for the occurrence of AL (10% vs 4% for smaller vs larger staplers; P = 0.042). In multivariate analysis for the occurrence of AL an ASA score ≥ 3 could be identified as a risk factor (OR 2.85; 95% CI = 1.13-7.15; P = 0.026). Additionally, smaller stapler size could be identified as a risk factor for AS (OR small 1.00, OR large 0.24; 95% CI: 0.06-0.97; P = 0.045). AL was associated with lower survival (18.1 vs 38.16 months; P = 0.0119). CONCLUSION: The application of a larger circular stapler for esophagojejunostomy in open total gastrectomy shows significantly lower rates of AL and stenosis. Therefore, the largest possible stapler diameter should be applied.
EVALuna2:547490

Effect of Flat-Knitted Medical Compression Stockings on Venous Malformations - Li, Yi; Muekke, Antje; Rother, Ulrich; Janka, Rolf Matthias; Uder, Michael; Lang, Werner; Heiß, Rafael (Journal of Clinical Medicine, 2023)
Venous malformations are one of the most common vascular anomalies. Our study aimed to investigate the effect of medical compression stockings of class I and II on the volume of venous malformations. Patients with venous malformations on upper or lower extremities were enrolled. They wore flat-knitted medical compression stockings of class I and II in a randomized order for four weeks each. Magnetic resonance imaging (MRI) and perometry were performed with and without wearing compression stockings. The 12-Item Short Form Survey (SF-12) questionnaire was performed before and after wearing compression stockings for four weeks each. A total of 18 patients completed the evaluations. Both compression classes showed a significant reduction of the volume of the venous malformations in the lesion itself based on MRI in comparison with baseline (both p < 0.001). Measurements taken with perometry did not reveal a significant difference in comparison to baseline (p = 0.09 and p = 0.22). The results of the SF-12 questionnaire demonstrated no significant differences before and after wearing the compression stockings of class I or class II for four weeks or between the two classes of compression therapy. Our results indicate that wearing medical compression stockings of both class I and class II significantly reduces the volume of venous malformation, without compromising the quality of life, while the effect of class II compression stockings on volume reduction was significantly better than that of class I.
CRIS-Team Scopus Importer:2023-04-28
Keywords: compression stockings; magnetic resonance imaging; perometry; quality of life; T2-weighted imaging; venous malformation

Effect of Hospital Volume on In-hospital Morbidity and Mortality Following Pancreatic Surgery in Germany - Krautz, Christian; Nimptsch, Ulrike; Mansky, Thomas; Grützmann, Robert; Weber, Georg (Annals of Surgery, 2017)
We aimed to determine the effect of hospital volume on in-hospital mortality, and failure to rescue following major pancreatic resections using hospital discharge data of every inpatient case in Germany.Several studies have found strong volume-outcome relationships in pancreatic surgery, with high mortality in low-volume facilities. However, their datasets were only based on portions of national populations. In addition, these studies did not assess the effect of hospital volume according to other crucial variables such as medical indications, postoperative complications, and failure to rescue.We studied all inpatient cases of major pancreatic surgery (n = 60,858) in Germany from 2009 to 2014, using national hospital discharge data. We evaluated the association between hospital volume and in-hospital mortality following major pancreatic resections by using multivariate regression methods. In addition, we analyzed rates of major complications and failure to rescue across hospital volume quintiles.Risk-adjusted in-hospital mortality varied widely across hospital volume quintiles, from 6.5% (95% CI 6.0-7.0) in very high volume hospitals to 11.5% (95% CI 10.9-12.1) in very low volume hospitals (OR 0.47, 95% CI 0.41-0.54). Rates of postoperative interventions necessary for complications and failure to rescue were lower in higher volume hospitals [eg, mortality following septic complications in very high volume hospitals: 24.2% (95% CI 22.4-26.1) vs. very low volume hospitals: 36.8% (34.9-38.7)]. Moreover, we estimated that centralization of surgical care to the minimum volume and mortality risk of the medium volume quintile could prevent at least 94 deaths per year.In Germany, patients who are undergoing major pancreatic resections have improved outcomes if they are admitted to higher volume hospitals. As current health policies failed to centralize pancreatic surgery procedures in Germany, new strategies to initiate a sufficient centralization process in the field of pancreatic surgery are needed.
EVALuna2:15282

Effect of the COVID-19 pandemic on surgery for indeterminate thyroid nodules (THYCOVID): a retrospective, international, multicentre, cross-sectional study - Medas, Fabio; Dobrinja, Chiara; Al-Suhaimi, Ebtesam Abdullah; Altmeier, Julia; Anajar, Said; Arikan, Akif Enes; Azaryan, Irina; Bains, Lovenish; Basili, Giancarlo; Bolukbasi, Hakan; Bononi, Marco; Borumandi, Farzad; et al. (Lancet Diabetes and Endocrinology, 2023)
BACKGROUND: Since its outbreak in early 2020, the COVID-19 pandemic has diverted resources from non-urgent and elective procedures, leading to diagnosis and treatment delays, with an increased number of neoplasms at advanced stages worldwide. The aims of this study were to quantify the reduction in surgical activity for indeterminate thyroid nodules during the COVID-19 pandemic; and to evaluate whether delays in surgery led to an increased occurrence of aggressive tumours. METHODS: In this retrospective, international, cross-sectional study, centres were invited to participate in June 22, 2022; each centre joining the study was asked to provide data from medical records on all surgical thyroidectomies consecutively performed from Jan 1, 2019, to Dec 31, 2021. Patients with indeterminate thyroid nodules were divided into three groups according to when they underwent surgery: from Jan 1, 2019, to Feb 29, 2020 (global prepandemic phase), from March 1, 2020, to May 31, 2021 (pandemic escalation phase), and from June 1 to Dec 31, 2021 (pandemic decrease phase). The main outcomes were, for each phase, the number of surgeries for indeterminate thyroid nodules, and in patients with a postoperative diagnosis of thyroid cancers, the occurrence of tumours larger than 10 mm, extrathyroidal extension, lymph node metastases, vascular invasion, distant metastases, and tumours at high risk of structural disease recurrence. Univariate analysis was used to compare the probability of aggressive thyroid features between the first and third study phases. The study was registered on ClinicalTrials.gov, NCT05178186. FINDINGS: Data from 157 centres (n=49 countries) on 87 467 patients who underwent surgery for benign and malignant thyroid disease were collected, of whom 22 974 patients (18 052 [78·6%] female patients and 4922 [21·4%] male patients) received surgery for indeterminate thyroid nodules. We observed a significant reduction in surgery for indeterminate thyroid nodules during the pandemic escalation phase (median monthly surgeries per centre, 1·4 [IQR 0·6-3·4]) compared with the prepandemic phase (2·0 [0·9-3·7]; p<0·0001) and pandemic decrease phase (2·3 [1·0-5·0]; p<0·0001). Compared with the prepandemic phase, in the pandemic decrease phase we observed an increased occurrence of thyroid tumours larger than 10 mm (2554 [69·0%] of 3704 vs 1515 [71·5%] of 2119; OR 1·1 [95% CI 1·0-1·3]; p=0·042), lymph node metastases (343 [9·3%] vs 264 [12·5%]; OR 1·4 [1·2-1·7]; p=0·0001), and tumours at high risk of structural disease recurrence (203 [5·7%] of 3584 vs 155 [7·7%] of 2006; OR 1·4 [1·1-1·7]; p=0·0039). INTERPRETATION: Our study suggests that the reduction in surgical activity for indeterminate thyroid nodules during the COVID-19 pandemic period could have led to an increased occurrence of aggressive thyroid tumours. However, other compelling hypotheses, including increased selection of patients with aggressive malignancies during this period, should be considered. We suggest that surgery for indeterminate thyroid nodules should no longer be postponed even in future instances of pandemic escalation.None.
CRIS-Team Scopus Importer:2023-06-30

Effects of Adjuvant Exercise and Nutrition Therapy on Muscle Fibre Biomechanics in Gastrointestinal Cancer Patients - Haug, Michael; Schwappacher, Raphaela; Pollmann, Charlotte; Ritter, Paul; Michael, Mena; Herrmann, Hans Joachim; Grützmann, Robert; Mittelstädt, Anke; Neurath, Markus; Zopf, Yurdagül; Friedrich, Oliver (Cancers, 2024)
Patients with aggressive cancer, e.g., gastrointestinal cancer, are prone (≥50% chance) to developing cancer cachexia (CC). Little is known about the effects of CC on the biomechanical function of muscle. A promising prevention strategy was found in the form of a multi-modal therapy combining mild resistance exercise (e.g., whole-body electro-myostimulation, WB-EMS) and a protein-rich diet. In a previous study of ours, this was effective in counteracting the loss of muscle mass, yet a systematic and comprehensive assessment of active and passive single muscle fibre functions was so far absent. This pilot study investigated the biomechanical function of single muscle fibres (rectus abdominis) from the biopsies of conventionally treated (pre-)cachectic cancer ((pre-)CC) patients (m = 9), those receiving the multi-modal therapy comprising WB-EMS training and protein-rich nutrition (m = 3), and a control group (m = 5). Our findings not only align with previous findings showing the absolute force loss in CC that is accelerated by atrophy but also speak in favour of a different, potentially energy- and Ca2+-homeostasis-related effect that compromises muscle contraction (F 0.9 mN vs. F 0.6 mN in control patients). However, myofibrillar Ca2+ sensitivity and the quality of contraction were unaltered (pCa50: 5.6–5.8). Single fibres from the (pre-)CC patients receiving WB-EMS training and protein supplementation were significantly more compliant (p < 0.001 at ≥130% of resting length L0). Those fibres displayed a similar softness to the ones from the control patients (axial compliance 15 m/N at ≥130% L0), while single fibres from the patients with (developing) cachexia were significantly stiffer (axial compliance 7 m/N, p < 0.001 at ≥130% L0). Adjuvant multi-modal therapy (WB-EMS training and nutritional support) contributes to maintaining the axial compliance of single fibres and potentially improves the quality of life for patients at risk of developing CC.
CRIS-Team Scopus Importer:2024-05-03
Keywords: cancer cachexia; multi-modal therapy; protein-rich diet; resistance training; single fibres; skeletal muscle

Effects of a metabolic optimized fast track concept (MOFA) on bowel function and recovery after surgery in patients undergoing elective colon or liver resection: A randomized controlled trial - Uhlig, Christopher; Rössel, Thomas; Denz, Axel; Seifert, Sven; Koch, Thea; Heller, Axel Rüdiger (BMC Anesthesiology, 2019)
Background: Enhanced recovery after surgery programs (ERAS) using thoracic epidural anesthesia and perioperative patient conditioning with omega-3 fatty acids (n3FA), glucose control (GC) and on-demand fluid therapy, respectively, showed beneficial effects. In the MOFA- study these components were used together in patients undergoing colon or liver surgery. We hypothesized that the use of a perioperative MOFA program improves intestine function represented as time to the first postoperative bowel movement in adult patients compared to standard ERAS. Methods: After BfArM and IRB approval 100 patients were enrolled in this prospective randomized controlled trial. All patients received ERAS therapy (control). In addition, the MOFA group received 0.2 g/kg fish oil (Omegaven®), preoperatively, followed by a 48 h continuous infusion of 0.2 g/kg/d n3FA; and GC was kept below < 8 mmol/L. Pre- and postoperatively energy drinks were administered. Results: As compared to control group the MOFA concept resulted in an earlier onset of flatulence by 14 h (46.6 ± 25.7, 32.0 ± 17.9, p = 0.030, hours, control vs. MOFA, respectively). Effects on onset of bowel movement were not observed (74.5 ± 30.4, 66.4 ± 29.2, p = 0.163, hours, control vs. MOFA, respectively). The disease severity (SAPS II score; p = 0.720) as well as deployment of resources (TISS 28 score, p = 0.709) did not differ between groups. No statistic significant difference between MOFA and control group regarding inflammation, impairment of coagulation, length of hospital stay or incidence of postoperative surgical complications were observed. Conclusions: The MOFA concept did not result in an improvement of intestine function or faster recovery after elective colon or liver surgery compared to standard ERAS therapy. Omega-3 fatty acids showed no impairment of coagulation or improved resolution of inflammation. Further trials in a larger patient collective are needed to investigate potential beneficial effects of omega-3 fatty acids in abdominal surgery. Trial registration: This trial was prospectively registered at the European Union Clinical Trials Register (EuDraCT 2005-004814-33, date: 10-05-2005, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2005-004814-33+).
CRIS-Team Scopus Importer:2019-08-30
Keywords: Abdominal surgery; Colon surgery; ERAS; Liver surgery; Omega-3 fatty acids; Omegaven; Randomized controlled trial; Recovery after surgery

Effects of glucose concentration in the tumor microenvironment on Non Small Lung Cancer (NSCLC) Progression - Gähler, Alexander; Hohenberger, Katja; Tausche, Patrick; Chiriac, Mircea-Teodor; Rauh, Manfred; Trufa, Denis; Geppert, Carol-Immanuel; Rieker, Ralf; Sirbu, Horia; Neurath-Finotto, Susetta (JOURNAL OF IMMUNOLOGY, 2021)
CRIS-Team WoS Importer:2021-12-03

Effects of Positive End-Expiratory Pressure and Spontaneous Breathing Activity on Regional Lung Inflammation in Experimental Acute Respiratory Distress Syndrome - Kiss, Thomas; Bluth, Thomas; Braune, Anja; Huhle, Robert; Denz, Axel; Herzog, Moritz; Herold, Johannes; Vivona, Luigi; Millone, Marco; Bergamaschi, Alice; Andreeff, Michael; Scharffenberg, Martin; et al. (Critical Care Medicine, 2019)
Objectives: To determine the impact of positive end-expiratory pressure during mechanical ventilation with and without spontaneous breathing activity on regional lung inflammation in experimental nonsevere acute respiratory distress syndrome. Design: Laboratory investigation. Setting: University hospital research facility. Subjects: Twenty-four pigs (28.1-58.2 kg). Interventions: In anesthetized animals, intrapleural pressure sensors were placed thoracoscopically in ventral, dorsal, and caudal regions of the left hemithorax. Lung injury was induced with saline lung lavage followed by injurious ventilation in supine position. During airway pressure release ventilation with low tidal volumes, positive end-expiratory pressure was set 4 cm H 2 O above the level to reach a positive transpulmonary pressure in caudal regions at end-expiration (best-positive end-expiratory pressure). Animals were randomly assigned to one of four groups (n = 6/ group; 12 hr): 1) no spontaneous breathing activity and positive end-expiratory pressure = best-positive end-expiratory pressure -4 cm H 2 O, 2) no spontaneous breathing activity and positive end-expiratory pressure = best-positive end-expiratory pressure + 4 cm H 2 O, 3) spontaneous breathing activity and positive endexpiratory pressure = best-positive end-expiratory pressure + 4 cm H 2 O, 4) spontaneous breathing activity and positive endexpiratory pressure = best-positive end-expiratory pressure 4 cm H 2 O. Measurements and Main Results: Global lung inflammation assessed by specific [18F] fluorodeoxyglucose uptake rate (median [25-75% percentiles], min-1) was decreased with higher compared with lower positive end-expiratory pressure both without spontaneous breathing activity (0.029 [0.027-0.030] vs 0.044 [0.041-0.065]; p = 0.004) and with spontaneous breathing activity (0.032 [0.028-0.043] vs 0.057 [0.042-0.075]; p = 0.016). Spontaneous breathing activity did not increase global lung inflammation. Lung inflammation in dorsal regions correlated with transpulmonary driving pressure from spontaneous breathing at lower (r = 0.850; p = 0.032) but not higher positive end-expiratory pressure (r = 0.018; p = 0.972). Higher positive end-expiratory pressure resulted in a more homogeneous distribution of aeration and regional transpulmonary pressures at end-expiration along the ventral-dorsal gradient, as well as a shift of the perfusion center toward dependent zones in the presence of spontaneous breathing activity. Conclusions: In experimental mild-to-moderate acute respiratory distress syndrome, positive end-expiratory pressure levels that stabilize dependent lung regions reduce global lung inflammation during mechanical ventilation, independent from spontaneous breathing activity.
CRIS-Team WoS Importer:2019-06-18

Efficacy and Safety of Angioplasty Balloon Interposition in CT-Guided Percutaneous Thermal Ablation of Hepatic Malignancies to Protect Adjacent Organs - Schlappa, Michael; Wuest, Wolfgang; Siebler, Jürgen; Grützmann, Robert; Uder, Michael; Schmid, Axel (Cardiovascular and Interventional Radiology, 2022)
Purpose To evaluate the feasibility and safety of placing angioplasty balloons between the liver surface and adjacent organs in CT-guided thermal ablation of subcapsular liver malignancies in case of inadequate success of conventional dissection techniques. Materials and Methods A retrospective, single-centre database query identified 327 hepatic malignancies in 153 patients treated in 215 sessions from 2016 to 2018 by thermal ablation. Demographic data, tumour size, distance to adjacent structures, complications and long-term outcomes were assessed when ancillary procedures were performed to protect adjacent organs. Results In 21 of 327 (6.4%) ablations, thermal protection was necessary. Balloon interposition was successfully performed in 9 cases in 8 patients after hydrodissection or gas insufflation failed to separate adherent organs. Median pre- and post-balloon insertion distance was 0 mm [0-2 mm] and 17 mm [8-20 mm]. No balloons were damaged, ruptured or slid away from their initial position. Technical success of MWA and protection of adherent structures were achieved in all procedures. In a median follow-up of 11.5 months [0-49 months], the local control rate was 88.9% as 1 patient was treated twice with an interval of 3 months for local recurrence. Three non-process-related major complications and 1 minor complication occurred. Conclusion Balloon interposition is a safe and feasible method to enable thermal ablation to a greater number of patients, even after established thermo-protective techniques fail to separate the colon or stomach from the liver surface.
CRIS-Team WoS Importer:2022-07-22

Elastic stable chest repair and its hybrid variants in 86 patients with pectus excavatum - Schulz-Drost, Stefan; Luber, Anna Maria; Simon, Kirsten; Schulz-Drost, Melanie; Syed, Julia; Carbon, Roman T.; Besendörfer, Manuel (Journal of Thoracic Disease, 2018)
Background: Complex and mature funnel chest deformities are traditionally managed with open surgical procedures. Elastic stable chest repair (ESCR) has been used successfully and safely for relapse corrections. Does pure plate osteosynthesis in ESCR allow comparable corrective potency and implant safety as hybrid methods with metal bars? Methods: Data from 86 patients with open funnel chest correction between 2011 and 2015 were analyzed in this retrospective study. Exclusion criteria included being under 12 years of age, and having a history of septic wound healing disorder or other malignant diseases. Main groups consisted of ESCR and hybrid techniques, subgroups were primary and recurrence correction. Correction results and follow-up examinations at six and 12 weeks and at 1 year were statistically analyzed. Results: A total of 38 ESCR and 48 hybrid methods were analyzed. Bar implantation was required in 77% (recurrence 34%) of patients. All patients received plates with different combinations e.g., longitudinal-sternal, costosternal and costo-sterno-costal. In all groups, follow-up uptake showed a funnel chest correction result at the anatomical level with healthy values according to the Haller index (ESCR 4.36-2.84, hybrid 6.99-2.74, P<0.001). No material dislocations were observed in any subgroup. Conclusions: ESCR and hybrid techniques represent promising and safe therapeutic approaches.
EVALuna2:35789

Elastic Stable Chest Repair as a Means of Stabilizing the Anterior Chest Wall in Recurrent Pectus Excavatum with Sternocostal Pseudarthrosis: An Innovative Fixation Device - Schulz-Drost, Stefan; Syed, Julia; Besendörfer, Manuel; Mauerer, Andreas; Blanke, Matthias; Schulz-Drost, Melanie; Carbon, Roman Th. (Thoracic and Cardiovascular Surgeon, 2015)
Open surgical procedures in the treatment of pectus excavatum (PE) involve predetermined incisions in the parasternal cartilage and the bony ribs. For some procedures, the ribs are even dissected from the sternum for better sternal mobilization and thus better elevation of the funnel. Secure restoration of the sternocostal junction is then required, with the consequence that healing may be quite impaired. Patients may also subsequently suffer from sternocostal nonunion, for example, pseudarthrosis, and dislocated ribs, as well as pain and a recurrence of PE.Patients underwent another open surgery with revision of the pseudarthrotic sternocostal junctions and sufficient mobilization of the anterior chest wall, followed by an open reduction and internal fixation using Matrix Rib titanium plates (Synthes, Oberdorf, Switzerland). This procedure consisted of elevating the anterior chest wall and fixing the ribs to the sternum. In 2011 and 2012, we studied this procedure, known as elastic stable chest repair (ESCR), in a series of 20 patients. The patients underwent clinical and ultrasound examinations and X-ray radiographs after the operation, after 6 weeks, and at 3- and 12-month intervals.Follow-up showed high patient tolerance, although a loose plate was observed in one patient and a broken plate in three patients. A stable union was achieved for all sternocostal pseudarthroses. PE improved highly significantly (p < 0.001), as the Haller index decreased from 3.6 (range: 2.7-6.6, standard deviation [SD]: 0.92) to 2.7 (range: 2.0-3.7, SD: 0.42). Pain in the anterior chest wall was significantly reduced after the operation in the majority of cases. All but one patient was mobilized already the day after the operation.ESCR in recurrent PE achieved functional stabilization of the anterior chest wall combined with satisfactory results.
EVALuna2:15821

Electrochemiluminescence in paired signal electrode (ECLipse) enables modular and scalable biosensing - Cho, Young Kwan; Kim, Hyunho; Benard, Alan; Woo, Hyun Kyung; Czubayko, Franziska; David, Paul; Hansen, Frederik; Lee, Jong Ik; Park, Jay Hoon; Schneck, Emmanuel; Weber, Georg; Shin, Ik Soo; et al. (Science Advances, 2022)
Electrochemiluminescence (ECL) has an inherently low background and enables precise chemical reactions through electrical control. Here, we report an advanced ECL system, termed ECLipse (ECL in paired signal electrode). We physically separated ECL generation from target detection: These two processes were carried out in isolated chambers and coupled through an electrode. The strategy allowed us to minimize cross-chemical reactions, design electrodes for high ECL signals, and integrate multiple sensors in a chip. As a proof of concept, we implemented an eight-plex ECLipse and applied it to detect host factors in human plasma. ECLipse achieved higher signal-to-noise ratio than conventional ECL assays and was >7000-fold more sensitive than enzyme-linked immunosorbent assay. In a pilot clinical study, we could detect septic conditions by measuring host factors [i.e., interleukin-3 (IL-3), IL-6, and procalcitonin (PCT)]. ECLipse assay further revealed distinct IL-3 and IL-6 patterns in patients with severe acute respiratory syndrome coronavirus 2 infection.
CRIS-Team Scopus Importer:2022-09-30

Eligibility of Endovascular Repair for Popliteal Artery Aneurysms According the Instructions for Use - Hellwig, Konstantin; Hoffmann, Lisa; Rother, Ulrich; Meyer, Alexander; Lang, Werner; Schmid, Axel (Annals of Vascular Surgery, 2020)
Background: Popliteal artery aneurysms (PAAs) are the most common peripheral aneurysms. Although rare and often asymptomatic, there is a significant risk of thrombosis, embolism, and limb loss. The aim of this study was to evaluate the eligibility for endovascular repair of patients treated for symptomatic and asymptomatic PAAs in accordance with the instructions for use (IFU). Methods: All patients treated for PAA with open surgical repair between the years 2010 and 2017 were analyzed if suitable for endovascular treatment. Preoperative imaging was reviewed for applicability with an interventional radiologist and 2 vascular surgeons. Evaluation was performed in accordance with the following criteria adopted from the IFU of the Gore ® Viabahn stent graft: at least a single-vessel tibial runoff, proximal and distal landing zone more than 2 cm, no large difference in vessel diameter proximal and distal to the aneurysm, no overstenting of significant collaterals necessary, and no inadequate kinking of the artery. The patients were classified in 3 categories: the patient was eligible, endovascular treatment was feasible, and endovascular treatment was not appropriate. Results: 51 patients with 61 symptomatic and asymptomatic PAAs were identified. Forty-five cases were asymptomatic, 11 cases showed clinical symptoms such as claudication, and in 5 cases, the patients presented with acute ischemia. Twenty-four patients were eligible for endovascular intervention, 14 cases were feasible, and in 23 cases, it was not appropriate in accordance with the IFU. Conclusions: In this study, more than one-third of the patients with PAA were not eligible for endovascular treatment in accordance with the IFU and another 23 % showed substantial reasons against endovascular treatment. These data suggest that endovascular repair remains a treatment option for selected patients only. Cross-sectional imaging is mandatory for procedure selection.
CRIS-Team Scopus Importer:2020-05-12

Emergency Use of Convalescent Plasma: Perception of the Regulatory Framework from a Clinical Perspective - Mohnle, Patrick; Humpe, Andreas; Boeck, Markus; Gruetzner, Stefanie; Hackstein, Holger; Offner, Robert; Hildebrandt, Martin (Transfusion Medicine and Hemotherapy, 2021)
The pandemic spread of an infectious disease poses a plethora of challenges to society, clinicians, health care providers and regulating authorities. In order to mount a rapid response and to provide hope in a potentially catastrophic situation as the current COVID-19 pandemic, emergency plans, regulations and funding strategies have to be developed on regional, national and international levels. The speed needed to establish rapid response programs is challenged by the dynamics of the spread of the disease, the concurrent and competing development of different and potentially more effective treatment options, and not the least by regulatory uncertainty. Convalescent plasma, that is plasma collected from patients who have recovered from COVID-19 infections, has emerged as one of the first potential treatment options in the absence of drugs or vaccines with proven efficacy against SARS-CoV-2. The societal aspects of convalescent plasma and the public awareness gave an additional boost to the rapid employment of convalescent plasma donation platforms immediately after the SARS-CoV-2 outbreak. At the same time, uncertainty remains as to the efficacy of convalescent plasma. With evidence mostly limited to empirical reports, convalescent plasma has been used for decades for the prophylaxis and treatment of various infectious diseases. Clinical trials have addressed different infectious agents, stages of disease, target groups of patients and yielded sometimes inconclusive results. The aim of this short review is to delineate the regulatory background for the emergency use of convalescent plasma in the USA, in the European Union and in Germany, and the transition to the setting of clinical trials. In addition, we describe observations made in the process of collecting COVID-19 convalescent plasma (herein referred to as CCP), and formulate proposals to further improve the framework for rapid responses in future emergency situations.
CRIS-Team WoS Importer:2021-12-03

Empfehlungen zur Implantation von bioresorbierbaren koronaren Scaffolds: Indikationen, Implantationstechnik und Nachsorge - Nef, H. M.; Möllmann, H.; Gori, T.; Elsässer, A.; Achenbach, Susanne (Der Kardiologe, 2015)
Bioresorbable scaffolds (BRS) are an option for treatment of coronary artery disease. Recent studies showed safety and efficacy; however, the long-term outcome and the potential advantages in comparison to drug-coated metal stents has to be evaluated in randomized trials. Due to the many theoretical benefits BRS are widely used in clinical practice. Nevertheless, a closer look at registries shows that unexpected events were mostly associated with procedural problems. Therefore, there are some important details regarding the implantation process even though BRS are not basically different from metal stents. This article on recommendations discusses the indications for BRS and the most important implantation techniques.
CRIS-Team Scopus Importer:2023-03-08
Keywords: Coronary stenosis; Efficacy; Long-term course; Metal stents; Safety

Endothelial CCR2 signaling induced by colon carcinoma cells enables extravasation via the JAK2-Stat5 and p38MAPK pathway. - Wolf, Monika Julia; Hoos, Alexandra; Bauer, Judith; Boettcher, Steffen; Knust, Markus; Weber, Achim; Simonavicius, Nicole; Schneider, Christoph; Lang, Matthias; Stürzl, Michael; Croner, Roland S.; Konrad, Andreas; et al. (Cancer Cell, 2012)
Increased expression of the chemokine CCL2 in tumor cells correlates with enhanced metastasis, poor prognosis, and recruitment of CCR2(+)Ly6C(hi) monocytes. However, the mechanisms driving tumor cell extravasation through the endothelium remain elusive. Here, we describe CCL2 upregulation in metastatic UICC stage IV colon carcinomas and demonstrate that tumor cell-derived CCL2 activates the CCR2(+) endothelium to increase vascular permeability in vivo. CCR2 deficiency prevents colon carcinoma extravasation and metastasis. Of note, CCR2 expression on radio-resistant cells or endothelial CCR2 expression restores extravasation and metastasis in Ccr2(-/-) mice. Reduction of CCR2 expression on myeloid cells decreases but does not prevent metastasis. CCL2-induced vascular permeability and metastasis is dependent on JAK2-Stat5 and p38MAPK signaling. Our study identifies potential targets for treating CCL2-dependent metastasis.

Endothelial cells of human colorectal cancer and healthy colon reveal phenotypic differences in culture - Stürzl, Michael; Naschberger, Elisabeth; et al. (Laboratory Investigation, 2007)
Antiangiogenic drugs have been used successfully for the treatment of colorectal cancer (CRC). Viable tumor endothelial cells (TEC) and normal endothelial cells (NEC) of uninvolved colon tissue of the same patient have not been available to optimize treatment strategies in vitro. Therefore, our target was to establish a protocol for the isolation of TEC and NEC. These cells were isolated with very high purity via magnetic cell sorting of tissue samples obtained from CRC and healthy colon of eight patients. TEC and NEC expressed CD31, CD105, VE-cadherin, VCAM-1, ICAM-1 and E-selectin, formed capillaries in basal membrane extract and were able to take up acetylated low-density lipoprotein. They were negative for podoplanin, CD45, CD68 and cytokeratin-20 indicating blood vessel endothelial lineage. Intense staining of von Willebrand factor (vWF) was observed in five of eight NEC cultures, whereas vWF was absent or only slightly expressed in all TEC cultures in vitro. Low intracellular concentration of vWF was also detected in TEC and NEC at the tissue level. This demonstrated that differences exhibited by TEC and NEC in vivo are stably perpetuated in culture. The isolated cultures may provide a useful in vitro model to elucidate epigenetic effects on angiogenesis in cancer and to optimize antiangiogenic therapy. © 2007 USCAP, Inc All rights reserved.
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Keywords: Angiogenesis; Colorectal cancer; Endothelial cells; Von Willebrand factor

Endothelial progenitor cells are integrated in newly formed capillaries and alter adjacent fibrovascular tissue after subcutaneous implantation in a fibrin matrix - Bleiziffer, Oliver; Hammon, Matthias; Naschberger, Elisabeth; Lipnik, Karoline; Arkudas, Andreas; Rath, Subha; Pryymachuk, Galyna; Beier, Justus; Stürzl, Michael; Horch, Raymund E.; Kneser, Ulrich (Journal of Cellular and Molecular Medicine, 2011)
Vascularization of bioartificial matrices is crucial for successful tissue engineering. Endothelial progenitor cells (EPC) have shown vascularization potential in ischemic conditions and may also support blood vessel formation in tissue-engineered matrices. The aim of our study was to investigate the impact of a well-characterized murine embryonal EPC line (T17b-EPC) on vascularization and fibrovascular granulation tissue formation after suspension in a fibrine matrix followed by subcutaneous implantation in a separation chamber in rats. EPC were fluorescently labelled in vitro prior to implantation. After 3, 7 or 14 days, animals were killed followed by explantation and histological analysis of the constructs. Before the end of the experiment, Bandeirea Simplicifolia lectin was intravenously injected to mark the vascular ingrowth into the implanted constructs. The transplanted cells were histologically detected at all time-points and located almost exclusively within the fibrin matrix at day 3 but the number of cells in the clot continuously decreased over day 7 to day 14. Conversely, cells were detected within the newly formed granulation tissue in increasing numbers from day 3 over day 7 to day 14. Transplanted cells were also found in the intermuscular septa. Cell viability was confirmed by use of an EPC clone expressing β-galactosidase. Fluorescence microscopy demonstrated integration of the transplanted cells in newly formed blood vessels within the fibrovascular granulation tissue adjacent to the fibrin clot. Presence of cells in the fibrin clot lead to thicker granulation tissue and an increased blood vessel diameter compared to cell-free controls. Organ standard controls showed presence of the transplanted cells in spleens at day 14 after transplantation. In summary, EPC exhibited biological activity after subcutaneous implantation in a fibrin matrix by migration from the fibrin clot into the granulation tissue and along intermuscular septae, undergoing differentiation into mature endothelial cells and integration into newly formed blood vessels and altering fibrovascular granulation tissue development. EPC may hold promise to modulate blood vessel formation in bioartificial matrices. © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.
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Keywords: Angiogenesis; Endothelial progenitor cells; Fibrin matrix; Tissue engineering

Engineering of vascularized transplantable bone tissues: induction of axial vascularization in an osteoconductive matrix using an arteriovenous loop. - Kneser, Ulrich; Polykandriotis, Elias; Ohnolz, Jan; Heidner, Kristina; Grabinger, Lucia; Euler, Simon; Amann, Kerstin Ute; Heß, Andreas; Brune, Kay; Greil, Peter; Stürzl, Michael; Horch, Raymund E. (Tissue Engineering -Larchmont, 2006)
This study demonstrates for the first time successful vascularization of solid porous matrices by means of an AV loop. Injection of osteogenic cells into axially prevascularized matrices may eventually create functional bioartificial bone tissues for reconstruction of large defects. Vascularization remains an obstacle to engineering of larger volume bone tissues. Our aim was to induce axial vascularization in a processed bovine cancellous bone (PBCB) matrix using an arteriovenous (AV) loop (artery, vein graft, and vein). Custom-made PBCB discs (9 x 5 mm) were implanted into rats. In group A (n = 19), the matrices were inserted into microsurgically constructed AV loops between the femoral vessels using a vein graft from the contralateral side. In group B (n = 19), there was no vascular carrier. The matrices were encased in isolation chambers. After 2, 4, and 8 weeks, the animals were perfused with India ink via the abdominal aorta. Matrices were explanted and subjected to histological and morphometric analysis. Results were compared with intravital dynamic micro & magnetic resonance imaging and scanning electron microscopy images of vascular corrosion replicas. In group A, significant vascularization of the matrix had occurred by the 8th week. At this time, vascular remodeling with organization into vessels of different sizes was evident. Blood vessels originated from all 3 zones of the AV loop. Group A was significantly superior to group B in terms of vascular density and vascularization kinetics. DISCUSSION INTRODUCTION METHODS RESULTS

Enhanced Acid Sphingomyelinase Activity Drives Immune Evasion and Tumor Growth in Non-Small Cell Lung Carcinoma - Kachler, Katerina; Bailer, Maximilian; Heim, Lisanne; Schumacher, Fabian; Reichel, Martin; Holzinger, Corinna D.; Trump, Sonja; Mittler, Susanne; Monti, Juliana; Trufa, Denis; Rieker, Ralf; Hartmann, Arndt; et al. (Cancer Research, 2017)
The lipid hydrolase enzyme acid sphingomyelinase (ASM) is required for the conversion of the lipid cell membrane component sphingomyelin into ceramide. In cancer cells, ASM-mediated ceramide production is important for apoptosis, cell proliferation, and immune modulation, highlighting ASM as a potential multimodal therapeutic target. In this study, we demonstrate elevated ASM activity in the lung tumor environment and blood serum of patients with non-small cell lung cancer (NSCLC). RNAi-mediated attenuation of SMPD1 in human NSCLC cells rendered them resistant to serum starvation-induced apoptosis. In a murine model of lung adenocarcinoma, ASM deficiency reduced tumor development in a manner associated with significant enhancement of Th1-mediated and cytotoxic T-cell-mediated antitumor immunity. Our findings indicate that targeting ASM in NSCLC can act by tumor cell-intrinsic and -extrinsic mechanisms to suppress tumor cell growth, most notably by enabling an effective antitumor immune response by the host. Cancer Res; 77(21); 5963-76. ©2017 AACR.
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EPIGENETIC REGULATION OF FRA2 BY JMJD3 REGULATES FIBROBLAST ACTIVATION IN SYSTEMIC SCLEROSIS - Bergmann, C.; Brandt, Adrian; Dees, Clara; Wohlfahrt, T.; Zhang, Y.; Chen, Chih-Wei; Mallano, T.; Liang, Ruifang; Kagwiria, R.; Kam, P. -S.; Bozec, Aline; Abraham, D.; et al. (2017)
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Epithelial presenilin-1 drives colorectal tumour growth by controlling EGFR-COX2 signalling - Gámez Belmonte, Maria de los Reyes; Mahapatro, Mousumi; Erkert, Lena; Gonzalez Acera, Miguel; Naschberger, Elisabeth; Yu, Yuqiang; Tena-Garitaonaindia, Mireia; Patankar, Jay; Wagner, Yara; Podstawa, Eva; Schoedel, Lena; Bubeck, Marvin; et al. (Gut, 2022)
Objective Psen1 was previously characterised as a crucial factor in the pathogenesis of neurodegeneration in patients with Alzheimer's disease. Little, if any, is known about its function in the gut. Here, we uncovered an unexpected functional role of Psen1 in gut epithelial cells during intestinal tumourigenesis. Design Human colorectal cancer (CRC) and control samples were investigated for PSEN1 and proteins of the gamma-secretase complex. Tumour formation was analysed in the AOM-DSS and Apc (min/+) mouse models using newly generated epithelial-specific Psen1 deficient mice. Psen1 deficient human CRC cells were studied in a xenograft tumour model. Tumour-derived organoids were analysed for growth and RNA-Seq was performed to identify Psen1-regulated pathways. Tumouroids were generated to study EGFR activation and evaluation of the influence of prostanoids. Results PSEN1 is expressed in the intestinal epithelium and its level is increased in human CRC. Psen1-deficient mice developed only small tumours and human cancer cell lines deficient in Psen1 had a reduced tumourigenicity. Tumouroids derived from Psen1-deficient Apc (min/+) mice exhibited stunted growth and reduced cell proliferation. On a molecular level, PSEN1 potentiated tumour cell proliferation via enhanced EGFR signalling and COX-2 production. Exogenous administration of PGE(2) reversed the slow growth of PSEN1 deficient tumour cells via PGE(2) receptor 4 (EP4) receptor signalling. Conclusions Psen1 drives tumour development by increasing EGFR signalling via NOTCH1 processing, and by activating the COX-2-PGE(2) pathway. PSEN1 inhibition could be a useful strategy in treatment of CRC.
CRIS-Team WoS Importer:2022-11-04

Erratum: Antihistone Properties of C1 Esterase Inhibitor Protect against Lung Injury - Wygrecka, Malgorzata; Wujak, Lukasz; Markart, Philipp; Kosanovic, Djuro; Müller-Redetzky, Holger C.; Witzenrath, Martin; Henneke, Ingrid; Schermuly, Ralph T.; Seeger, Werner; Schaefer, Liliana; Kwapiszewska, Grazyna; Marsh, Leigh M.; et al. (American Journal of Respiratory and Critical Care Medicine, 2022)
CRIS-Team Scopus Importer:2022-11-25

ESCP President's report - Matzel, Klaus (Colorectal Disease, 2022)
CRIS-Team WoS Importer:2022-09-23

European expert consensus on a structured approach to training robotic-assisted low anterior resection using performance metrics - Tou, Samson; Gomez Ruiz, M.; Gallagher, A. G.; Matzel, Klaus (Colorectal Disease, 2020)
Aim: The aim was to develop and operationally define ‘performance metrics’ that characterize a reference approach to robotic-assisted low anterior resection (RA-LAR) and to obtain face and content validity through a consensus meeting. Method: Three senior colorectal surgeons with robotic experience and a senior behavioural scientist formed the Metrics Group. We used published guidelines, training materials, manufacturers’ instructions and unedited videos of RA-LAR to deconstruct the operation into defined, measurable components – performance metrics (i.e. procedure phases, steps, errors and critical errors). The performance metrics were then subjected to detailed critique by 18 expert colorectal surgeons in a modified Delphi process. Results: Performance metrics for RA-LAR had 15 procedure phases, 128 steps, 89 errors and 117 critical errors in women, 88 errors and 118 critical errors in men. After the modified Delphi process the final performance metrics consisted of 14 procedure phases, 129 steps, 88 errors and 115 critical errors in women, 87 errors and 116 critical errors in men. After discussion by the Delphi panel, all procedure phases received unanimous consensus apart from phase I (patient positioning and preparation, 83%) and phase IV (docking, 94%). Conclusion: A robotic rectal operation can be broken down into procedure phases, steps, with errors and critical errors, known as performance metrics. The face and content of these metrics have been validated by a large group of expert robotic colorectal surgeons from Europe. We consider the metrics essential for the development of a structured training curriculum and standardized procedural assessment for RA-LAR.
CRIS-Team Scopus Importer:2020-09-04
Keywords: colorectal surgery; low anterior resection; metrics; proficiency-based progression; robotic surgery; training

European Society of Coloproctology Colorectal Robotic Surgery Training for the Trainers Course – the first pilot experience - Eardley, N. J.; Matzel, K. E.; Gómez Ruiz, M.; Khan, J. S.; Riley, S. A.; Donnelly, M. T.; Tou, S. (Colorectal Disease, 2020)
Aim: Currently, there is no established colorectal specific robotic surgery Train the Trainer (TTT) course. The aim was to develop and evaluate such a course which can then be further developed to be incorporated within the planned European Society of Coloproctology (ESCP)/European School of Coloproctology (ESC) robotic colorectal surgery training curriculum. Method: After identifying the need for such a course within a training programme, the course was developed by a subgroup of the ESCP/ESC. A scoping literature review was performed and the content and materials for the course were developed by a team consisting of two gastroenterologists with a combined experience of 30 years of facilitating TTT courses, a robotic surgeon and proctor with laparoscopic TTT faculty experience and experienced robotic and laparoscopic colorectal trainers. The course was evaluated by asking delegates to complete pre- and post-course questionnaires. Results: There were eight delegates on the course from across Europe. Delegates increased their knowledge of each of the course learning objectives and identified learning points in order to change practice. The feedback from the delegates of the course was positive across several areas and all felt that they had achieved their own personal objectives in attending the course. Conclusion: This pilot robotic colorectal TTT course has achieved its aim and demonstrated many positives. There is a need for such a course and the evaluation processes have provided opportunities for reflection, which will allow the development/tailoring of future robotic colorectal TTT courses to help develop robotic training further.
CRIS-Team Scopus Importer:2020-08-21
Keywords: colon; rectum; robotic surgical procedure; robotics; surgery; training

Evaluating predictive modeling algorithms to assess patient eligibility for clinical trials from routine data - Köpcke, Felix; Lubgan, Dorota; Fietkau, Rainer; Scholler, Axel; Nau, Carla; Stürzl, Michael; Croner, Roland S.; Prokosch, Hans-Ulrich; Toddenroth, Dennis (BMC Medical Informatics and Decision Making, 2013)
Background: The necessity to translate eligibility criteria from free text into decision rules that are compatible with data from the electronic health record (EHR) constitutes the main challenge when developing and deploying clinical trial recruitment support systems. Recruitment decisions based on case-based reasoning, i.e. using past cases rather than explicit rules, could dispense with the need for translating eligibility criteria and could also be implemented largely independently from the terminology of the EHR's database. We evaluated the feasibility of predictive modeling to assess the eligibility of patients for clinical trials and report on a prototype's performance for different system configurations. Methods. The prototype worked by using existing basic patient data of manually assessed eligible and ineligible patients to induce prediction models. Performance was measured retrospectively for three clinical trials by plotting receiver operating characteristic curves and comparing the area under the curve (ROC-AUC) for different prediction algorithms, different sizes of the learning set and different numbers and aggregation levels of the patient attributes. Results: Random forests were generally among the best performing models with a maximum ROC-AUC of 0.81 (CI: 0.72-0.88) for trial A, 0.96 (CI: 0.95-0.97) for trial B and 0.99 (CI: 0.98-0.99) for trial C. The full potential of this algorithm was reached after learning from approximately 200 manually screened patients (eligible and ineligible). Neither block- nor category-level aggregation of diagnosis and procedure codes influenced the algorithms' performance substantially. Conclusions: Our results indicate that predictive modeling is a feasible approach to support patient recruitment into clinical trials. Its major advantages over the commonly applied rule-based systems are its independency from the concrete representation of eligibility criteria and EHR data and its potential for automation. © 2013 Köpcke et al.; licensee BioMed Central Ltd.
UnivIS-Import:2015-04-14:Pub.2013.tech.IMMD.infome.evalua_3

Evaluation of response using FDG-PET/CT and diffusion weighted MRI after radiochemotherapy of pancreatic cancer: a non-randomized, monocentric phase II clinical trial—PaCa-DD-041 (Eudra-CT 2009-011968-11) - Zimmermann, Carolin; Distler, Marius; Jentsch, Christina; Blum, Sophia; Folprecht, Gunnar; Zöphel, Klaus; Polster, Heike; Troost, Esther G.C.; Abolmaali, Nasreddin; Weitz, Jürgen; Baumann, Michael; Saeger, Hans Detlev; et al. (Strahlentherapie und Onkologie, 2020)
Background: Pancreatic cancer is a devastating disease with a 5-year survival rate of 20–25%. As approximately only 20% of patients diagnosed with pancreatic cancer are initially staged as resectable, it is necessary to evaluate new therapeutic approaches. Hence, neoadjuvant (radio)chemotherapy is a promising therapeutic option, especially in patients with a borderline resectable tumor. The aim of this non-randomized, monocentric, prospective, phase II clinical study was to assess the prognostic value of functional imaging techniques, i.e., [18F]2-fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography (FDG-PET/CT) and diffusion weighted magnetic resonance imaging (DW-MRI), prior to and during neoadjuvant radiochemotherapy. Methods: Patients with histologically proven resectable, borderline resectable or unresectable non-metastatic pancreatic adenocarcinoma received induction chemotherapy followed by neoadjuvant radiochemotherapy. Patients underwent FDG-PET/CT and DW-MRI including T1- and T2-weighted sequences prior to and after neoadjuvant chemotherapy as well as following induction radiochemotherapy. The primary endpoint was the evaluation of the response as quantified by the standardized uptake value (SUV) measured with FDG-PET. Response to treatment was evaluated by FDG-PET and DW-MRI during and after the neoadjuvant course. Morphologic staging was performed using contrast-enhanced CT and contrast-enhanced MRI to decide inclusion of patients and resectability after neoadjuvant therapy. In those patients undergoing subsequent surgery, imaging findings were correlated with those of the pathologic resection specimen. Results: A total of 25 patients were enrolled in the study. The response rate measured by FDG-PET was 85% with a statistically significant decrease of the maximal SUV (SUVmax) during therapy (p < 0.001). Using the mean apparent diffusion coefficient (ADC), response was not detectable with DW-MRI. After neoadjuvant treatment 16 patients underwent surgery. In 12 (48%) patients tumor resection could be performed. The median overall survival of all patients was 25 months (range: 7–38 months). Conclusion: Based on these limited patient numbers, it was possible to show that this trial design is feasible and that the neoadjuvant therapy regime was well tolerated. FDG-PET/CT may be a reliable method to evaluate response to the combined therapy. In contrast, when evaluating the response using mean ADC, DW-MRI did not show conclusive results.
CRIS-Team Scopus Importer:2020-07-17
Keywords: Downstaging; Imaging; Neoadjuvant radio-/chemotherapy; Pancreas cancer; Pancreatic adenocarcinoma; PDAC; Surgery

Evaluation of the short- and long-term safety and therapy outcomes of the everolimus-eluting bioresorbable vascular scaffold system in patients with coronary artery stenosis: Rationale and design of the German-Austrian ABSORB RegIstRy (GABI-R) - Nef, Holger; Wiebe, Jens; Achenbach, Susanne; Muenzel, Thomas; Naber, Christoph; Richardt, Gert; Mehilli, Julinda; Woehrle, Jochen; Neumann, Till; Biermann, Janine; Zahn, Ralf; Kastner, Johannes; et al. (Cardiovascular Revascularization Medicine, 2016)
Third-generation drug-eluting metal stents are the gold standard for treatment of coronary artery disease. The permanent metallic caging of the vessel, however, can result in limited vasomotion, chronic inflammation, and late expansive remodeling, conditions that can lead to late and very late stent thrombosis. The development of bioresorbable scaffolds (BRSs) promises advantages over metal stents due to complete biodegradation within 2-4years. Theoretically, since vessel scaffolding is temporary and no permanent implant remains in the vessel, BRSs, as opposed to metal stents, once degraded would no longer be potential triggers for stent-related adverse events or side effects.The short- and long-term outcome after implantation of an everolimus-eluting, poly-L-lactic acid-based bioresorbable scaffold system (ABSORB, Abbott Vascular, Santa Clara, CA, USA) in the world-wide greatest all-comers cohort will be evaluated in the prospective, non-interventional, multicenter German-Austrian ABSORB RegIstRy (GABI-R). GABI-R will include over 5000 patients from about 100 study sites in Austria and Germany. Safety endpoints such as cardiac death, myocardial infarction, and clinically driven percutaneous or surgical target lesion and vessel revascularization will be evaluated during hospitalization and in the follow-up period (minimum of 5years).Although two randomized controlled trials and several registries have documented safety and efficacy as well as non-inferiority of this everolimus-eluting ABSORB device compared with drug-eluting metal stents, the current knowledge regarding clinical application, treatment success, and long-term safety of using this BRS in daily routine is limited. Thus, the goal of GABI-R is to address this lack of information.
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Evidence-Based Surgical Treatments for Chronic Pancreatitis - Kleeff, Joerg; Stoess, Christian; Mayerle, Julia; Stecher, Lynne; Maak, Matthias; Simon, Peter; Nitsche, Ulrich; Friess, Helmut (Deutsches Ärzteblatt international, 2016)
If conservative treatment of chronic pancreatitis is unsuccessful, surgery is an option. The choice of the most suitable surgical method can be difficult, as the indications, advantages, and disadvantages of the available methods have not yet been fully documented with scientific evidence.In April 2015, we carried out a temporally unlimited systematic search for publications on surgery for chronic pancreatitis. The target parameters were morbidity, mortality, pain, endocrine and exocrine insuffi - ciency, weight gain, quality of life, length of hospital stay, and duration of urgery. Differences between surgical methods were studied with network meta-analysis, and duodenum-preserving operations were compared with partial duodenopancreatectomy with standard meta-analysis.Among the 326 articles initially identified, 8 randomized controlled trials on a total of 423 patients were included in the meta-analysis. The trials were markedly heterogeneous in some respects. There was no significant difference among surgical methods with respect to perioperative morbidity, pain, endocrine and exocrine insufficiency, or quality of life. Duodenumpreserving procedures, compared to duodenopancreatectomy, were associated with a long-term weight gain that was 3 kg higher (p <0.001; three trials), a mean length of hospital stay that was 3 days shorter (p = 0.009; six trials), and a duration of surgery that was 2 hours shorter (p <0.001; five trials).Duodenum-preserving surgery for chronic pancreatitis is superior to partial duodenopancreatectomy in multiple respects. Only limited recommendations can be given, however, on the basis of present data. The question of the best surgical method for the individual patient, in view of the clinical manifestations, anatomy, and diagnostic criteria, remains open.
EVALuna2:15260

Evidence for PTGER4, PSCA, and MBOAT7 as risk genes for gastric cancer on the genome and transcriptome level - Heinrichs, Sophie K. M.; Hess, Timo; Becker, Jessica; Hamann, Lutz; Vashist, Yogesh K.; Butterbach, Katja; Schmidt, Thomas; Alakus, Hakan; Krasniuk, Iurii; Hoeblinger, Aksana; Lingohr, Philipp; Ludwig, Monika; et al. (Cancer Medicine, 2018)
Genetic associations between variants on chromosome 5p13 and 8q24 and gastric cancer (GC) have been previously reported in the Asian population. We aimed to replicate these findings and to characterize the associations at the genome and transcriptome level. We performed a fine-mapping association study in 1926 GC patients and 2012 controls of European descent using high dense SNP marker sets on both chromosomal regions. Next, we performed expression quantitative trait locus (eQTL) analyses using gastric transcriptome data from 143 individuals focusing on the GC associated variants. On chromosome 5p13 the strongest association was observed at rs6872282 (P = 2.53 × 10 ) and on chromosome 8q24 at rs2585176 (P = 1.09 × 10 ). On chromosome 5p13 we found cis-eQTL effects with an upregulation of PTGER4 expression in GC risk allele carrier (P = 9.27 × 10 ). On chromosome 8q24 we observed cis-eQTL effects with an upregulation of PSCA expression in GC risk allele carrier (P = 2.17 × 10 ). In addition, we found trans-eQTL effects for the same variants on 8q24 with a downregulation of MBOAT7 expression in GC risk allele carrier (P = 3.11 × 10 ). In summary, we confirmed and refined the previously reported GC associations at both chromosomal regions. Our data point to shared etiological factors between Asians and Europeans. Furthermore, our data imply an upregulated expression of PTGER4 and PSCA as well as a downregulated expression of MBOAT7 in gastric tissue as risk-conferring GC pathomechanisms.
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Evidenzbasierte antithrombotische Therapie der peripheren arteriellen Verschlusskrankheit (PAVK) - Behrendt, Christian Alexander; Larena-Avellaneda, Axel; Gombert, Alexander; Rother, Ulrich (Gefässchirurgie, 2023)
The evidence-based guideline-compliant antithrombotic treatment of patients with peripheral arterial occlusive disease (PAOD) has for a long time been a challenge in the routine clinical practice of vascular specialists. For the first time in 2023 clinical practice guidelines of the European Society for Vascular Surgery (ESVS) that explicitly deal with the antithrombotic treatment of patients with vascular diseases are expected. Many decisions and guideline recommendations have been based on studies from other medical specialties as no suitable evidence base exists. Most recently, innovative studies were published that introduced more knowledge but also new challenges for healthcare professionals. This article provides an overview of the current study situation and its relevance in clinical practice. Thereby, it explicitly discusses the different treatment options (conservative, endovascular, open surgery) and the difficult balance between efficacy and safety of antithrombotic drugs. The advantages and disadvantages of composite endpoints of current studies as well as the inherent selection bias and risk for major bleeding events are meticulously discussed. Simultaneously, the current treatment reality including the prescription practice is also presented.
CRIS-Team Scopus Importer:2023-03-31
Keywords: Antithrombotic treatment; Guideline recommendations; Study situation; Treatment options; Treatment reality

Exercise training for intermittent claudication: critical analysis - Rumenapf, G.; Rother, Ulrich; Behrendt, C.; Uhl, C.; Gortz, H.; Morbach, S.; Sigl, M. (Gefässchirurgie, 2020)
Background The guidelines for the treatment of intermittent claudication (IC) recommend lifestyle improvement, risk factor management, pharmacotherapy for improvement of blood flow, as well as structured supervised exercise training (SET). Revascularization is not advised as the first line treatment. In Germany, the guideline recommendations and treatment reality of IC are substantially different. Methods The systematic literature search for the S3 guidelines on peripheral arterial occlusive disease (PAOD) of the German Society of Angiology (DGA) from 2014 was updated to 2020. Results If the pattern of arterial occlusions is suitable, a consistent implementation of SET can significantly enhance the walking distance. In general, however, the efficacy, availability and practicability of SET are limited and patient adherence is low. In contrast, revascularization for IC can improve or normalize the walking capacity faster than SET, with continuously increasing sustainability. The best results are obtained by the combination of revascularization and SET. Conclusion Revascularization plays an important role in the treatment of patients with IC, particularly as conservative treatment strategies using SET are not recognizably implemented in the German healthcare system. Better availability of SET could decrease the number of revascularizations, enhance the long-term success and reduce the cardiovascular risk.
CRIS-Team WoS Importer:2021-01-08

Expansion of IL-23 receptor bearing TNFR2+ T cells is associated with molecular resistance to anti-TNF therapy in Crohn's disease - Schmitt, Heike; Billmeier, Ulrike; Dieterich, Walburga; Rath, Timo; Sonnewald, Sophia; Reid, Stephen; Hirschmann, Simon; Hildner, Kai; Waldner, Maximilian; Mudter, Jonas; Hartmann, Arndt; Grützmann, Robert; et al. (Gut, 2018)
OBJECTIVE: Anti-tumour necrosis factor (TNF) antibodies are successfully used for treatment of Crohn's disease. Nevertheless, approximately 40% of patients display failure to anti-TNF therapy. Here, we characterised molecular mechanisms that are associated with endoscopic resistance to anti-TNF therapy. DESIGN: Mucosal and blood cells were isolated from patients with Crohn's disease prior and during anti-TNF therapy. Cytokine profiles, cell surface markers, signalling proteins and cell apoptosis were assessed by microarray, immunohistochemistry, qPCR, ELISA, whole organ cultures and FACS. RESULTS: Responders to anti-TNF therapy displayed a significantly higher expression of TNF receptor 2 (TNFR2) but not IL23R on T cells than non-responders prior to anti-TNF therapy. During anti-TNF therapy, there was a significant upregulation of mucosal IL-23p19, IL23R and IL-17A in anti-TNF non-responders but not in responders. Apoptosis-resistant TNFR2+IL23R+ T cells were significantly expanded in anti-TNF non-responders compared with responders, expressed the gut tropic integrins α4β7, and exhibited increased expression of IFN-γ, T-bet, IL-17A and RORγt compared with TNFR2+IL23R- cells, indicating a mixed Th1/Th17-like phenotype. Intestinal TNFR2+IL23R+ T cells were activated by IL-23 derived from CD14+ macrophages, which were significantly more present in non-responders prior to anti-TNF treatment. Administration of IL-23 to anti-TNF-treated mucosal organ cultures led to the expansion of CD4+IL23R+TNFR2+ lymphocytes. Functional studies demonstrated that anti-TNF-induced apoptosis in mucosal T cells is abrogated by IL-23. CONCLUSIONS: Expansion of apoptosis-resistant intestinal TNFR2+IL23R+ T cells is associated with resistance to anti-TNF therapy in Crohn's disease. These findings identify IL-23 as a suitable molecular target in patients with Crohn's disease refractory to anti-TNF therapy.
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Expert consensus on a train-the-trainer curriculum for robotic colorectal surgery - Gómez Ruiz, M.; Alfieri, S.; Becker, T.; Bergmann, M.; Boggi, U.; Collins, J.; Figueiredo, N.; Gögenur, I.; Matzel, Klaus; Miskovic, D.; Parvaiz, A.; Pratschke, J.; et al. (Colorectal Disease, 2019)
Aim: Robotic techniques are being increasingly used in colorectal surgery. There is, however, a lack of training opportunities and structured training programmes. Robotic surgery has specific problems and challenges for trainers and trainees. Ergonomics, specific skills and user–machine interfaces are different from those in traditional laparoscopic surgery. The aim of this study was to establish expert consensus on the requirements for a robotic train-the-trainer curriculum amongst robotic surgeons and trainers. Method: This is a modified Delphi-type study involving 14 experts in robotic surgery teaching. A reiterating 19-item questionnaire was sent out to the same group and agreement levels analysed. A consensus of 0.8 or higher was considered to be high-level agreement. Results: Response rates were 93–100% and most items reached high levels of agreement within three rounds. Specific requirements for a robotic faculty development curriculum included maximizing dual-console teaching, theatre team training, nontechnical skills training, patient safety, user–machine interface training and telementoring. Conclusion: A clear need for the development of a train-the-trainer curriculum has been identified. Further research is needed to assess feasibility, effectiveness and clinical impact of a robotic train-the-trainer curriculum.
CRIS-Team Scopus Importer:2019-06-04
Keywords: Delphi; Robotic surgery; trainer; training

Expression and localization of axin 2 in colorectal carcinoma and its clinical implication - Schaal, Ute; Grenz, Sandra; Merkel, Susanne; Rau, Tilman; Hadjihannas, Michel; Kremmer, Elisabeth; Chudasama, Priya; Croner, Roland S.; Behrens, Jürgen; Stürzl, Michael; Naschberger, Elisabeth (International Journal of Colorectal Disease, 2013)
Purpose: Aberrant activation of the Wnt/β-catenin pathway plays a major role in the development of colorectal carcinoma (CRC). Axin 2 is a key protein of this pathway and is upregulated in CRC. Here, we investigated RNA- and protein expression of axin 2 in CRC tissues at the single cell level. Moreover, the association of axin 2 with prognosis and survival was investigated in a large cohort of CRC patients (n = 280). Methods: Localization and expression of axin 2 and β-catenin was investigated using in situ hybridization and immunohistochemical staining. The quantitative expression levels of axin 2 were determined using RT-qPCR. The association of axin 2 expression with prognosis and survival of the patients was determined by statistical analysis (logrank test, Kaplan-Meier). Results: Our results confirmed the upregulation of axin 2 in CRC and showed that it is broadly expressed in the cytoplasm of the tumor epithelial cells both, in the tumor center and at the invasion front. Axin 2 was rarely expressed by tumor stromal cells and only weakly by normal colonic epithelial cells. Staining of β-catenin and axin 2 in consecutive CRC tissue sections revealed that nuclear translocation of β-catenin in the tumor front was not associated with changes in the cytoplasmic localization of axin 2. Axin 2 did not show any association with proven prognostic factors or survival of the CRC patients. Conclusion: The generally increased expression of axin 2 in all tumor stages as compared to normal tissue suggests an initiating pathogenic function in the development of CRC. © 2013 Springer-Verlag Berlin Heidelberg.
Created from Fastlane, Scopus look-up
Keywords: β-Catenin; Axin 2; Colorectal carcinoma; Wnt/β-catenin signaling

Expression and role of the immune checkpoint regulator PD-L1 in the tumor-stroma interplay of pancreatic ductal adenocarcinoma - Daunke, Tina; Beckinger, Silje; Rahn, Sascha; Krüger, Sandra; Heckl, Steffen; Schäfer, Heiner; Wesch, Daniela; Pilarsky, Christian; Eckstein, Markus; Hartmann, Arndt; Röcken, Christoph; Wandmacher, Anna Maxi; et al. (Frontiers in Immunology, 2023)
Introduction: Immune checkpoint inhibitors (ICI), e.g., targeting programmed cell death protein 1-ligand 1 (PD-L1) or its receptor PD-1, have markedly improved the therapy of many cancers but so far failed in pancreatic ductal adenocarcinoma (PDAC). Macrophages represent one of the most abundant immune cell populations within the tumor microenvironment (TME) of PDAC being able to either support or restrain tumor progression depending on their phenotype. To better understand treatment failure of PD-L1/PD-1 inhibitors in PDAC, this study examined PD-L1 expression in the context of a dynamic TME in PDAC with a particular focus on the impact of macrophages. Methods: Formalin-fixed and paraffin embedded tissue samples of primary PDAC tissues and corresponding liver metastases were used for immunohistochemical analyses. Serial sections were stained with antibodies detecting Pan-Cytokeratin, CD68, CD163, CD8, and PD-L1.To investigate whether the PD-1/PD-L1 axis and macrophages contribute to immune escape of PDAC cells, a stroma enriched 3D spheroid coculture model was established in vitro, using different PDAC cell lines and macrophages subtypes as well as CD8+ T cells. Functional and flow cytometry analyses were conducted to characterize cell populations. Results: Immunohistochemical analyses revealed that PD-L1 is mainly expressed by stroma cells, including macrophages and not PDAC cells in primary PDAC tissues and corresponding liver metastases. Notably, high local abundance of macrophages and strong PD-L1 staining were commonly found at invasion fronts of tumoral lesions between CD8+ T cells and tumor cells. In order to investigate whether PD-L1 expressing macrophages impact the response of PDAC cells to treatment with PD-L1/PD-1 inhibitors, we developed a spheroid model comprising two different PDAC cell lines and different ratios of in vitro differentiated primary M1- or M2-like polarized macrophages. In line with our in situ findings, high PD-L1 expression was observed in macrophages rather than PDAC cells, which was further increased by the presence of PDAC cells. The effector phenotype of co-cultured CD8+ T cells exemplified by expression of activation markers and release of effector molecules was rather enhanced by PDAC macrophage spheroids, particularly with M1-like macrophages compared to mono-culture spheroids. However, this was not associated with enhanced PDAC cell death. ICI treatment with either Durvalumab or Pembrolizumab alone or in combination with Gemcitabine hardly affected the effector phenotype of CD8+ T cells along with PDAC cell death. Thus, despite strong PD-L1 expression in macrophages, ICI treatment did not result in an enhanced activation and cytotoxic phenotype of CD8+ T cells. Conclusion: Overall, our study revealed novel insights into the interplay of PDAC cells and macrophages in the presence of ICI.
CRIS-Team Scopus Importer:2023-08-25
Keywords: 3D co-culture; immune checkpoint inhibitor; immune evasion; macrophages; pancreatic cancer; tumor microenvironment

Expression of adhesion molecules, platelet-activating factor, and chemokines by Kaposi's sarcoma cells. - Sciacca, Francesca L; Stürzl, Michael; Bussolino, Federico; Sironi, Manuela; Brandstetter, Hans; Zietz, C; Zhou, D; Matteucci, C; Peri, G; Sozzani, Silvano (Journal of Immunology, 1994)
The present study was designed to investigate whether cells cultured from Kaposi's sarcoma (KS), a vascular tumor with a prominent leukocyte infiltration, express molecules important for the recruitment and activation of leukocytes. KS cells expressed intercellular adhesion molecule-1, which was augmented by exposure to IL-1 beta or TNF-alpha. Unlike endothelial cells, resting or cytokine-activated KS cells did not express appreciable levels of intercellular adhesion molecule-2, vascular cell adhesion molecule-1, and E-selectin on their surface. Weak expression of vascular cell adhesion molecule-1 mRNA was detectable by Northern blot analysis and, most clearly, by PCR analysis. Upon exposure to inflammatory cytokines, KS cells produced the attractant/activating lipid platelet-activating factor. KS cells expressed appreciable levels of the chemotactic cytokines, monocyte chemotactic protein-1 (MCP-1) and IL-8, as determined by Northern blot analysis, immunoassay, or bioassay. Chemokine production was augmented by IL-1 beta or TNF-alpha. MCP-1 expression was also detected in KS lesions by in situ hybridization. The set of molecules identified in the present study is probably important in determining the prominent leukocyte infiltration observed in KS. Tumor-associated leukocytes may amplify autocrine/paracrine circuits that sustain KS proliferation and contribute to recruitment of host vascular cells.

Expression of calcitonin receptor-like receptor in human vascular tumours. - Hagner, Stefanie; Stahl, Ulrich; Grimm, T.; Stürzl, Michael; Lang, R. E. (Journal of Clinical Pathology, 2006)
Background: Vascular tumours such as Kaposi’s sarcoma and capillary haemangioma are characterised by abnormal vascularisation and proliferation of endothelial cells or neoplastic cells. Adrenomedullin, a potent vasodilative peptide, and its receptor, calcitonin receptor-like receptor (CRLR), play an important part in angiogenesis. Aim: To establish whether this system also plays a part in vascular diseases, showing abnormal proliferation such as vascular tumours. Methods: CRLR expression was investigated in several specimens of Kaposi’s sarcoma and other vascular tumours, using immunohistochemical analysis with a previously described CRLR-specific polyclonal antibody and reverse transcriptase-polymerase chain reaction. Results: Intense and specific CRLR-immunoreactive staining of neoplastic cells was observed in all specimens, which was of greater intensity than similar staining of adjacent normal endothelium. Conclusions: CRLR is expressed in vascular tumours and, with adrenomedullin, may have a role in neoplastic vascular growth.

Expression of K13/v-FLIP gene of human herpesvirus 8 and apoptosis in Kaposi's sarcoma spindle cells. - Stürzl, Michael; Hohenadl, Christine; Zietz, Christian; Castanos-Velez, Esmeralda; Wunderlich, Anneliese; Ascherl, Gudrun; Biberfeld, Peter; Monini, Paolo; Browning, Philip J.; Ensoli, Barbara (Journal of the National Cancer Institute, 1999)
Human herpesvirus 8 (HHV8) infection is associated with all forms of Kaposi's sarcoma (KS). The HHV8 genome locus ORFK13-72-73 (ORF = open reading frame) encodes proteins that may be important in HHV8-mediated pathogenesis, i.e., the latency-associated nuclear antigen (encoded by ORF73), viral-cyc-D (v-cyc-D), a viral homologue of cellular cyclin D (encoded by ORF72), and viral-FLIP (v-FLIP), a homologue of the cellular FLICE (Fas-associated death domain-like interleukin 1 beta-converting enzyme) inhibitory protein (encoded by ORFK13; is an inhibitor of apoptosis [programmed cell death]). Through differential splicing events, this locus expresses individual RNA transcripts that encode all three proteins (tricistronic transcripts) or just two of them (v-FLIP and v-cyc-D; bicistronic transcripts). We examined expression of these transcripts in KS tissues. We collected tissues from patients with KS of different stages. By use of an optimized in situ hybridization procedure, we examined different ORFK13-72-73 locus transcripts in HHV8-infected cells in skin lesions and in one adjacent lymph node. Apoptosis in KS lesions was determined by use of an in situ assay. Our results indicate the following: 1) Transcripts from the ORFK13-72-73 locus appear to be spliced differentially in latently infected KS cells in skin lesions and in HHV8-infected cells in lymph nodes; specifically, ORFK13-ORF72 bicistronic transcripts were expressed abundantly in KS cells, whereas ORFK13-ORF72-ORF73 tricistronic transcripts were detected only in lymph node cells. 2) Sequences encoding the antiapoptotic protein v-FLIP are expressed at very low levels in early KS lesions, but expression increases dramatically in late-stage lesions. 3) The increase in expression of v-FLIP-encoding transcripts is associated with a reduction in apoptosis in KS lesions. These data suggest that functional v-FLIP is produced in vivo and that antiapoptotic mechanisms may be involved in the rapid growth of KS lesions, where only a few cells undergoing mitosis are generally observed. BACKGROUND METHODS RESULTS AND CONCLUSIONS IMPLICATIONS

Expression of platelet-derived growth factor and its receptor in AIDS-related Kaposi sarcoma in vivo suggests paracrine and autocrine mechanisms of tumor maintenance. - Stürzl, Michael; Roth, W K; Brockmeyer, Norbert H.; Zietz, C; Speiser, B; Hofschneider, Peter Hans (Proceedings of the National Academy of Sciences of the United States of America, 1992)
As previously described, proliferation of Kaposi sarcoma (KS)-derived cells in vitro is dependent on the presence of platelet-derived growth factor (PDGF). To test the hypothesis that PDGF may also be a major growth factor for KS cells in vivo, we performed in situ hybridization and immunohistochemical staining for PDGF and PDGF receptors in tissue sections of AIDS-related KS. The data suggest that KS consists of two types of tumor cells. (i) The main population are spindle-shaped cells with elongated nuclei (KS-s cells). They reveal a strong expression of PDGF beta receptors but do not express the PDGF-A and PDGF-B isoforms. (ii) A minor population of KS cells express PDGF beta receptor as well as PDGF-A and PDGF-B (KS-p cells). These cells are often grouped in whorls and surrounding vascular slits. They reveal spherical nuclei with evenly distributed chromatin and inconspicuous nucleoli. PDGF alpha receptor is not expressed in either form of KS cells. The results suggest that the isoforms of PDGF and the PDGF beta receptor are differentially expressed in two different cell types in KS and that PDGF isoforms may contribute to the pathogenesis of KS.

Extracorporeal Free Flap Perfusion in Case of Prolonged Ischemia Time - Taeger, Christian; Präbst, Konstantin; Beier, Justus; Meyer, A.; Horch, Raymund E. (Plastic and Reconstructive Surgery Global Open, 2016)
In free flap surgery, a clinically established concept still has to be found for the reduction of ischemia-related cell damage in the case of prolonged ischemia. Although promising results using extracorporeal free flap perfusion in the laboratory have been published in the past, until now this concept has not yet paved its way into clinical routine. This might be due to the complexity of perfusion systems and a lack of standardized tools. Here, we want to present the results of the first extracorporeal free flap perfusion in a clinical setting using a simple approach without the application of a complex perfusion machinery.
EVALuna2:15616

Factors influencing downstaging after neoadjuvant long-course chemoradiotherapy in rectal carcinoma - Kohl, Valerie; Weber, Klaus; Brunner, Maximilian; Geppert, Carol-Immanuel; Fietkau, Rainer; Grützmann, Robert; Semrau, Sabine; Merkel, Susanne (International Journal of Colorectal Disease, 2022)
Purpose This single-centre cohort study was designed to identify factors that can predict primary tumour downstaging by neoadjuvant chemoradiotherapy (nCRT) in rectal carcinoma. Methods Prospectively collected data from 555 patients with clinical T category (cT) cT3-4 rectal carcinoma treated between 1995 and 2019 were retrospectively analysed. All patients received long-term neoadjuvant chemoradiotherapy followed by surgery with curative intent at the Department of Surgery, University Hospital Erlangen, Germany. Patient-, tumour- and treatment-related factors with a potential impact on the downstaging of rectal carcinoma to pathological T category (pT) ≤ ypT2 and ypT0 were analysed in univariate and multivariate logistic regression analyses. The prognosis of patients with and without downstaging of the primary tumour was compared. Results A total of 288 (51.9%) patients showed downstaging to ≤ ypT2. Eighty-six (15.5%) patients achieved clinical complete regression (ypT0). In the multivariate logistic regression analysis, the factors cT category, BMI, ECOG score, CEA, histological type, extension in the rectum and year of the start of treatment were found to be independent factors for predicting downstaging to ≤ ypT2 after neoadjuvant chemoradiotherapy. The year of treatment initiation also remained an independent significant predictor for pathological complete regression. The prognosis was superior in patients with downstaging to ≤ ypT2 in terms of locoregional and distant recurrence as well as disease-free and overall survival. Conclusion Factors predicting downstaging after long-term nCRT could be identified. This may be helpful for counselling patients and selecting the optimal treatment for patients with advanced rectal carcinoma.
CRIS-Team WoS Importer:2022-05-27
Keywords: Rectal carcinoma; Neoadjuvant chemoradiotherapy; Downstaging; Tumour regression; Prediction of pathological response; Prognostic factors

FAM13A is associated with non-small cell lung cancer (NSCLC) progression and controls tumor cell proliferation and survival - Eisenhut, Felix; Heim, Lisanne; Trump, Sonja; Mittler, Susanne; Sopel, Nina; Andreev, Katerina; Ferrazzi, Fulvia; Ekici, Arif Bülent; Rieker, Ralf; Springel, Rebekka; Assmann, Vera Elisabeth; Lechmann, Matthias; et al. (OncoImmunology, 2017)
Genome-wide association studies (GWAS) associated Family with sequence similarity 13, member A (FAM13A) with non-small cell lung cancer (NSCLC) occurrence. Here, we found increased numbers of FAM13A protein expressing cells in the tumoral region of lung tissues from a cohort of patients with NSCLC. Moreover, FAM13A inversely correlated with CTLA4 but directly correlated with HIF1? levels in the control region of these patients. Consistently, FAM13A RhoGAP was found to be associated with T cell effector molecules like HIF1? and Tbet and was downregulated in immunosuppressive CD4(+)CD25(+)Foxp3(+)CTLA4(+) T cells. TGF?, a tumor suppressor factor, as well as siRNA to FAM13A, suppressed both isoforms of FAM13A and inhibited tumor cell proliferation. RNA-Seq analysis confirmed this finding. Moreover, siRNA to FAM13A induced TGF? levels. Finally, in experimental tumor cell migration, FAM13A was induced and TGF? accelerated this process by inducing cell migration, HIF1?, and the FAM13A RhoGAP isoform. Furthermore, siRNA to FAM13A inhibited tumor cell proliferation and induced cell migration without affecting HIF1?. In conclusion, FAM13A is involved in tumor cell proliferation and downstream of TGF? and HIF1?, FAM13A RhoGAP is associated with Th1 gene expression and lung tumor cell migration. These findings identify FAM13A as key regulator of NSCLC growth and progression.
EVALuna2:6835

Fast whole-slide cartography in colon cancer histology using superpixels and CNN classification - Wilm, Frauke; Benz, Michaela; Bruns, Volker; Baghdadlian, Serop; Dexl, Jakob; Hartmann, David; Kuritcyn, Petr; Weidenfeller, Martin; Wittenberg, Thomas; Merkel, Susanne; Hartmann, Arndt; Eckstein, Markus; et al. (Journal of Medical Imaging, 2022)
Purpose: Automatic outlining of different tissue types in digitized histological specimen provides a basis for follow-up analyses and can potentially guide subsequent medical decisions. The immense size of whole-slide-images (WSIs), however, poses a challenge in terms of computation time. In this regard, the analysis of nonoverlapping patches outperforms pixelwise segmentation approaches but still leaves room for optimization. Furthermore, the division into patches, regardless of the biological structures they contain, is a drawback due to the loss of local dependencies.
CRIS-Team WoS Importer:2022-05-13

Fatal Puumala Hantavirus Infection in a Patient with Common Variable Immunodeficiency (CVID) - Steininger, Philipp; Herbst, Larissa; Bihlmaier, Karl; Willam, Carsten; Koerper, Sixten; Schrezenmeier, Hubert; Klueter, Harald; Pfister, Frederick; Amann, Kerstin Ute; Weiss, Sabrina; Krueger, Detlev H.; Zimmermann, Robert; et al. (Microorganisms, 2023)
Puumala hantavirus (PUUV) infections usually show a mild or moderate clinical course, but may sometimes also lead to life-threatening disease. Here, we report on a 60-year-old female patient with common variable immunodeficiency (CVID) who developed a fatal PUUV infection with persistent renal failure, thrombocytopenia, and CNS infection with impaired consciousness and tetraparesis. Hantavirus-specific antibodies could not be detected due to the humoral immunodeficiency. Diagnosis and virological monitoring were based on the quantitative detection of PUUV RNA in blood, cerebrospinal fluid, bronchial lavage, and urine, where viral RNA was found over an unusually extended period of one month. Due to clinical deterioration and virus persistence, treatment with ribavirin was initiated. Additionally, fresh frozen plasma (FFP) from convalescent donors with a history of PUUV infection was administered. Despite viral clearance, the clinical condition of the patient did not improve and the patient died on day 81 of hospitalization. This case underlines the importance of the humoral immune response for the course of PUUV disease and illustrates the need for PCR-based virus diagnostics in those patients. Due to its potential antiviral activity, convalescent plasma should be considered in the therapy of severe hantavirus diseases.
CRIS-Team Scopus Importer:2023-03-10
Keywords: common variable immunodeficiency; convalescent plasma; encephalitis; Puumala hantavirus; ribavirin

Femoral Placement of Totally Implantable Venous Access Ports in Patients with Bilateral Breast Cancer - Almási-Sperling, Veronika; Hieber, Sabrina; Lermann, J.; Strahl, Olga; Beckmann, Matthias; Lang, Werner; Sagban, T. A. (Geburtshilfe und Frauenheilkunde, 2016)
Purpose: Aim of this study was to determine the rate of complications following femoral placement of totally implantable venous access ports (f-TIVAP) in women with bilateral breast cancer, with a special focus on long-term function, deep vein thrombosis (DVT), and port infection. Methods: 73 patients with bilateral breast cancer treated between October 2000 and January 2013 with placement of an f-TIVAP using a transfemoral approach were retrospectively reviewed. All patients were followed up, and all complications of f-TIVAP were recorded. Results: The median age was 62.5 years (range: 35-86 years). Four patients received f-TIVAP under local anesthesia, and 69 underwent placement under general anesthesia. Mean follow-up was 33.7 months (SD 25.9; range: 0.2-93.5 months). Complications over the entire period of observation included infections in 21 %, DVT in 19 % and catheter occlusion in 12 %. Patients receiving chemotherapy who developed leukopenia were more likely to experience DVT at the access site (p = 0.037). There was a trend towards a higher infection rate when the device was used more often (p = 0.084). Conclusion: Although the rates of complications in the longer term, especially device infections and DVTs, appeared to be relatively high, TIVAP implantation using femoral vein access is recommended in patients with bilateral breast cancer not suitable for cephalic vein cut-down.
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Fibrin gel-immobilized VEGF and bFGF efficiently stimulate angiogenesis in the AV loop model. - Arkudas, Andreas; Tjiawi, Jimmy; Bleiziffer, Oliver; Grabinger, Lucia; Polykandriotis, Elias; Beier, Justus P.; Stürzl, Michael; Horch, Raymund E.; Kneser, Ulrich (Molecular Medicine, 2007)
The modulation of angiogenic processes in matrices is of great interest in tissue engineering. We assessed the angiogenic effects of fibrin-immobilized VEGF and bFGF in an arteriovenous loop (AVL) model in 22 AVLs created between the femoral artery and vein in rats. The loops were placed in isolation chambers and were embedded in 500 microL fibrin gel (FG) (group A) or in 500 microL FG loaded with 0.1 ng/microL VEGF and 0.1 ng/microL bFGF (group B). After two and four weeks specimens were explanted and investigated using histological, morphometrical, and ultramorphological [scanning electron microscope (SEM) of vascular corrosion replicas] techniques. In both groups, the AVL induced formation of densely vascularized connective tissue with differentiated and functional vessels inside the fibrin matrix. VEGF and bFGF induced significantly higher absolute and relative vascular density and a faster resorption of the fibrin matrix. SEM analysis in both groups revealed characteristics of an immature vascular bed, with a higher vascular density in group B. VEGF and bFGF efficiently stimulated sprouting of blood vessels in the AVL model. The implantation of vascular carriers into given growth factor-loaded matrix volumes may eventually allow efficient generation of axially vascularized, tissue-engineered composites.
Keywords: Vascular Endothelial Growth Factor (VEGF); Fibrin Matrix; Arteriovenous Loop (AVL); Vascular Carrier; High Vascular Density

Fibroblast Subpopulations in Systemic Sclerosis: Functional Implications of Individual Subpopulations and Correlations with Clinical Features - Zhu, Honglin; Luo, Hui; Skaug, Brian; Tabib, Tracy; Li, Yi; Tao, Yongguang; Matei, Alexandru-Emil; Lyons, Marka A.; Schett, Georg; Lafyatis, Robert; Assassi, Shervin; Distler, Jörg (Journal of Investigative Dermatology, 2024)
Fibroblasts constitute a heterogeneous population of cells. In this study, we integrated single-cell RNA-sequencing and bulk RNA-sequencing data as well as clinical information to study the role of individual fibroblast populations in systemic sclerosis (SSc). SSc skin demonstrated an increased abundance of COMP+, COL11A1+, MYOC+, CCL19+, SFRP4/SFRP2+, and PRSS23/SFRP2+ fibroblasts signatures and decreased proportions of CXCL12+ and PI16+ fibroblast signatures in the Prospective Registry of Early Systemic Sclerosis and Genetics versus Environment in Scleroderma Outcome Study cohorts. Numerical differences were confirmed by multicolor immunofluorescence for selected fibroblast populations. COMP+, COL11A1+, SFRP4/SFRP2+, PRSS23/SFRP2+, and PI16+ fibroblasts were similarly altered between normal wound healing and patients with SSc. The proportions of profibrotic COMP+, COL11A1+, SFRP4/SFRP2+, and PRSS23/SFRP2+ and proinflammatory CCL19+ fibroblast signatures were positively correlated with clinical and histopathological parameters of skin fibrosis, whereas signatures of CXCL12+ and PI16+ fibroblasts were inversely correlated. Incorporating the proportions of COMP+, COL11A1+, SFRP4/SFRP2+, and PRSS23/SFRP2+ fibroblast signatures into machine learning models improved the classification of patients with SSc into those with progressive versus stable skin fibrosis. In summary, the profound imbalance of fibroblast subpopulations in SSc may drive the progression of skin fibrosis. Specific targeting of disease-relevant fibroblast populations may offer opportunities for the treatment of SSc and other fibrotic diseases.
CRIS-Team Scopus Importer:2024-02-16
Keywords: Dermal fibrosis; Disease outcomes; Fibroblasts; SSc; Subpopulations

Filamin A Is a Potential Driver of Breast Cancer Metastasis via Regulation of MMP-1 - Zhou, Jie; Wu, Lvying; Xu, Pengyan; Li, Yue; Ji, Zhiliang; Kang, Xinmei (Frontiers in Oncology, 2022)
Recurrent metastasis is a major fatal cause of breast cancer. Regretfully, the driving force and the molecular beneath have not been fully illustrated yet. In this study, a cohort of breast cancer patients with locoregional metastasis was recruited. For them, we collected the matched samples of the primary tumor and metastatic tumor, and then we determined the mutation profiles with whole-exome sequencing (WES). On basis of the profiles, we identified a list of deleterious variants in eight susceptible genes. Of them, filamin A (FLNA) was considered a potential driver gene of metastasis, and its low expression could enhance 5 years’ relapse survival rate by 15%. To prove the finding, we constructed a stable FLNA knockout tumor cell line, which manifested that the cell abilities of proliferation, migration, and invasion were significantly weakened in response to the gene knockout. Subsequently, xenograft mouse experiments further proved that FLNA knockout could inhibit local or distal metastasis. Putting all the results together, we consolidated that FLNA could be a potential driver gene to metastasis of breast cancer, in particular triple-negative breast cancer. Additional experiments also suggested that FLNA might intervene in metastasis via the regulation of MMP-1 expression. In summary, this study demonstrates that FLNA may play as a positive regulator in cancer proliferation and recurrence. It provides new insight into breast cancer metastasis and suggests a potential new therapeutic target for breast cancer therapy.
CRIS-Team Scopus Importer:2022-04-15
Keywords: breast cancer; EMT; FLNA; metastasis; MMP-1

Filarial extract of Litomosoides sigmodontis induces a type 2 immune response and attenuates plaque development in hyperlipidemic ApoE-knockout mice - Kühn, Constanze; Tauchi, Miyuki; Furtmair, Roman; Urschel, Katharina; Raaz-Schrauder, Dorette; Neumann, Anna Lena; Frohberger, Stefan J.; Hoerauf, Achim; Regus, Susanne; Lang, Werner; Sagban, Tolga Atilla; Stumpfe, Florian Matthias; et al. (The FASEB Journal, 2019)
A type 1 immune response is involved in atherosclerosis progression, whereas the role of a type 2 polarization, especially with regard to an enhanced T helper (Th)2 cell differentiation, is still unclear. Helminths trigger type 2 immune responses, protecting the host from inflammatory disorders. We investigated whether an increased type 2 polarization by administration of Litomosoides sigmodontis adult worm extract (LsAg) affects atherosclerosis in apolipoprotein E-deficient (ApoE-/-) mice. Injections of 50 µg LsAg, i.p. into ApoE-/- mice induced a type 2 immune response shown by increased frequencies of peritoneal eosinophils and alternatively activated macrophages. To analyze the effect of LsAg on atherosclerosis initiation, ApoE-/- mice received a high-fat diet for 12 wk and weekly injections of 50 µg LsAg from wk 5 to 12. Therapeutic effects on advanced atherosclerosis were analyzed in mice that were fed a high-fat diet for 12 wk followed by 12 wk of normal chow and weekly LsAg injections. Both preventive and therapeutic LsAg application significantly decreased plaque size. Therapeutic treatment even caused regression of plaque size and macrophage density in the aortic root and reduced Th1-specific gene expression and intraplaque inflammation. In addition, plaque size after therapeutic treatment was inversely correlated with plaque-infiltrated alternatively activated macrophages. In vitro, LsAg treatment of HUVECs reduced intracellular levels of phosphorylated NF-κB-p65, IκB-α, and JNK1/2. In bifurcation flow-through slides, THP-1 cell adhesion to a HUVEC monolayer was decreased by LsAg in regions of nonuniform shear stress. Applying inhibitors of the respective kinases suggests JNK1/2 inhibition is involved in the suppressed cell adhesion. A switch to an enhanced type 2 immune response by LsAg exerts antiatherogenic effects on murine plaque development, indicating a protective role of a hampered type 1 polarization. In vitro, LsAg affects endothelial signaling pathways, among which JNK1/2 inhibition seems to be involved in the suppression of monocytic cell adhesion under proatherogenic shear stress.-Constanze, K., Tauchi, M., Furtmair, R., Urschel, K., Raaz-Schrauder, D., Neumann, A.-L., Frohberger, S. J., Hoerauf, A., Regus, S., Lang, W., Sagban, T. A., Stumpfe, F. M., Achenbach, S., Hübner, M. P., Dietel, B. Filarial extract of Litomosoides sigmodontis induces a type 2 immune response and attenuates plaque development in hyperlipidemic ApoE-knockout mice.
CRIS-Team Scopus Importer:2019-05-21
Keywords: atherosclerosis; endothelial activation; helminth; inflammation; JNK

Final Analysis of DeCOG-SLT Trial: No Survival Benefit for Complete Lymph Node Dissection in Patients With Melanoma With Positive Sentinel Node - Leiter, Ulrike; Stadler, Rudolf; Mauch, Cornelia; Hohenberger, Werner; Brockmeyer, Norbert H.; Sunderkötter, Cord; Kaatz, Martin; Schatton, Kerstin; Lehmann, Percy; Vogt, Thomas; Ulrich, Jens; Herbst, Rudolf; et al. (Journal of Clinical Oncology, 2019)
PURPOSE: We have previously reported on the 3-year results of the phase III German Dermatologic Cooperative Oncology Group trial (DeCOG; ClinicalTrials.gov identifier: NCT02434107) comparing distant metastasis-free survival (DMFS), recurrence-free survival (RFS), and overall survival (OS) in patients with positive sentinel lymph-node biopsy who were randomly assigned to complete lymph node dissection (CLND) or observation. Here, we report the final analysis with 72 months of median follow up. PATIENTS AND METHODS: The multicenter randomized phase III trial included patients with cutaneous melanoma of the trunk and extremities who were randomly assigned (1:1) to undergo CLND or observation. DMFS was analyzed as the primary end point, and RFS, OS, and recurrences in the regional lymph node basin were secondary end points. The analysis was by intention to treat. Disease and survival information were collected quarterly. RESULTS: From January 2006 to December 2014, 5,547 patients were screened to identify 1,256 with metastases in the sentinel lymph node (SLN). Of these, 483 (39%) were included: 241 in the observation arm and 242 in the CLND arm. In the final analysis, median follow up was 72 months (interquartile range, 67-77 months). No significant treatment-related difference was seen in the 5-year DMFS between the observation and CLND arms (67.6% v 64.9%, respectively; hazard ratio [HR], 1.08; P = .87). The 5-year RFS and OS also showed no difference (HR, 1.01 and 0.99, respectively). Grade 3 and 4 adverse effects occurred in 32 patients (13%) in the CLND arm; lymphedema (n = 20) and delayed wound healing (n = 5) were most common and no serious adverse events were reported. CONCLUSION: The final results of the German Dermatologic Cooperative Oncology Group trial with a median follow up of 72 months showed higher event rates, but similar HRs compared with those at the 3-year analysis. These results confirm that immediate CLND in SLN-positive patients is not superior to observation in terms of DMFS, RFS, or OS and support not recommending CLND in patients with SLN metastasis.
CRIS-Team Scopus Importer:2019-11-15

First comparative analysis concerning the plasma platelet contamination during MNC collection - Pfeiffer, Hella; Achenbach, Susanne; Strobel, Joachim; Zimmermann, Robert; Eckstein, Reinhold; Strasser, Erwin (Transfusion and Apheresis Science, 2017)
BACKGROUND AND OBJECTIVES: Monocytes can be cultured into dendritic cells with addition of autologous plasma, which is highly prone to platelet contamination due to the apheresis process. Since platelets affect the maturation process of monocytes into dendritic cells and might even lead to a diminished harvest of dendritic cells, it is very important to reduce the platelet contamination. A new collection device (Spectra Optia) was analyzed, compared to two established devices (COM.TEC, Cobe Spectra) and evaluated regarding the potential generation of source plasma. MATERIALS AND METHODS: Concurrent plasma collected during leukapheresis was analyzed for residual cell contamination in a prospective study with the new Spectra Optia apheresis device (n=24) and was compared with COM.TEC and Cobe Spectra data (retrospective analysis, n=72). Donor pre-donation counts of platelets were analyzed for their predictive value of contaminating PLTs in plasma harvests. RESULTS: The newest apheresis device showed the lowest residual platelet count of the collected concurrent plasma (median 3.50×109/l) independent of pre-donation counts. The other two devices and sets had a higher platelet contamination. The contamination of the plasma with leukocytes was very low (only 2.0% were higher than 0.5×109/l). CONCLUSIONS: This study showed a significant reduction of platelet contamination of the concurrent plasma collected with the new Spectra Optia device. This plasma product with low residual platelets and leukocytes might also be used as plasma for fractionation.
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First comparative evaluation of a new leukapheresis technology in non-cytokine-stimulated donors - Steininger, Philipp; Strasser, Erwin; Weiss, D.; Achenbach, Susanne; Zimmermann, Rüdiger; Eckstein, Reinhold (Vox Sanguinis, 2014)
Leukapheresis is an important source for mononuclear cells (MNCs) used in adoptive immunotherapies. Differences in the apheresis technology concerning physical conditions during cell separation and the optical detection system can affect the product's cellular content.In a paired analysis, twenty healthy non-cytokine-stimulated donors underwent MNC collection at the Spectra Optia (Terumo BCT, Lakewood, CO, USA) and the COM.TEC (Fresenius Kabi, Bad Homburg, Germany) device. In twelve donors, apheresis was additionally performed with the Amicus (Fenwal Inc., Lake Zurich, IL, USA). Donor response to leukapheresis and product composition was compared.Mean yields of CD14(+) (CD3(+) ) cells were 1·64 ± 0·70x10(9) (2·36 ± 0·96 × 10(9) ) in the Spectra Optia, 1·45 ± 0·50 × 10(9) (3·03 ± 1·04 × 10(9) ) in the COM.TEC and 1·20 ± 0·37 × 10(9) (2·80 ± 1·00 × 10(9) ) in the Amicus products, respectively. The Spectra Optia collected significantly more CD14(+) monocytes than the Amicus and significantly less CD3(+) T cells than the COM.TEC (P = 0·002 and P = 0·021). Apheresis products of the Spectra Optia showed the significantly lowest red blood cell yields while the Amicus generated products with the significantly lowest platelet contents.Leukaphereses with the three devices resulted in almost equal total MNC yields. MNC products of the Spectra Optia and the Amicus could be used in preference for the monocyte enrichment by the Elutra system and the leukapheresis procedures could be also favourably applied in patients with low platelet counts. The COM.TEC is more efficient in monocyte and T-cell collection with the disadvantage of high residual non-target cell content in the products.
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Flow cytometry for intracellular SPION quantification: specificity and sensitivity in comparison with spectroscopic methods - Friedrich, Ralf P.; Janko, Christina; Poettler, Marina; Tripal, Philipp; Zaloga, Jan; Cicha, Iwona; Dürr, Stephan; Nowak, Johannes; Odenbach, Stefan; Slabu, Ioana; Liebl, Maik; Trahms, Lutz; et al. (International Journal of Nanomedicine, 2015)
Due to their special physicochemical properties, iron nanoparticles offer new promising possibilities for biomedical applications. For bench to bedside translation of super-paramagnetic iron oxide nanoparticles (SPIONs), safety issues have to be comprehensively clarified. To understand concentration-dependent nanoparticle-mediated toxicity, the exact quantification of intracellular SPIONs by reliable methods is of great importance. In the present study, we compared three different SPION quantification methods (ultraviolet spectrophotometry, magnetic particle spectroscopy, atomic adsorption spectroscopy) and discussed the shortcomings and advantages of each method. Moreover, we used those results to evaluate the possibility to use flow cytometric technique to determine the cellular SPION content. For this purpose, we correlated the side scatter data received from flow cytometry with the actual cellular SPION amount. We showed that flow cytometry provides a rapid and reliable method to assess the cellular SPION content. Our data also demonstrate that internalization of iron oxide nanoparticles in human umbilical vein endothelial cells is strongly dependent to the SPION type and results in a dose-dependent increase of toxicity. Thus, treatment with lauric acid-coated SPIONs (SEON(LA)) resulted in a significant increase in the intensity of side scatter and toxicity, whereas SEON(LA) with an additional protein corona formed by bovine serum albumin (SEON(LA-BSA)) and commercially available Rienso(®) particles showed only a minimal increase in both side scatter intensity and cellular toxicity. The increase in side scatter was in accordance with the measurements for SPION content by the atomic adsorption spectroscopy reference method. In summary, our data show that flow cytometry analysis can be used for estimation of uptake of SPIONs by mammalian cells and provides a fast tool for scientists to evaluate the safety of nanoparticle products.
EVALuna2:19955

Forty-Two Years' Experience with Pulmonary Resections of Metastases from Colorectal Cancer - Dudek, Wojciech; Schreiner, Waldemar; Hohenberger, Werner; Klein, Peter; Sirbu, Horia (Thoracic and Cardiovascular Surgeon, 2016)
Background Pulmonary metastasectomy is a commonly performed surgery in patients with controlled metastatic colorectal cancer (CRC). We reviewed our long-term single institution experience with lung resections for colorectal metastases to assess the factors influencing patient survival. Materials and Methods A cohort of 220 patients (138 men and 82 women; median age, 59 years) who underwent complete pulmonary metastasectomy for CRC with curative intent between 1972 and 2014 was retrospectively analyzed. The impact of factors related to primary tumor, metastases, and associated therapy on patient survival was assessed. Results Two postoperative inhospital deaths occurred. The median interoperative interval was 26 months. The overall 5-year survival rate after pulmonary metastasectomy was 49.4%. In univariable analysis, bilateral pulmonary metastases (log rank p = 0.02), multiple metastases (log rank p = 0.005), and stage IV UICC (the International Union Against Cancer) CRC at the time of initial presentation (log rank p = 0.008) were significantly associated with poor outcome. Multivariable Cox analysis demonstrated that stage IV CRC (p = 0.02) and multiple metastases (p = 0.0019) were statistically significant predictors of survival after the pulmonary metastasectomy. There was no significant difference in survival between patients with high versus low preoperative carcinoembryonic antigen serum level (p = 0.149), high versus low preoperative carbohydrate antigen 19-9 serum level (p = 0.291), and primary tumor location in rectum versus colon (p = 0.845). Conclusion Patients with unilateral metastasis and stages I to III primary tumor benefited most from pulmonary metastasectomy for CRC.
EVALuna2:15229

Four-and-a-Half LIM-Domain Protein 2 (FHL2) Induces Neuropeptide Y (NPY) in Macrophages in Visceral Adipose Tissue and Promotes Diet-Induced Obesity - Sommer, Judith; Ehnis, Hanna; Seitz, Tatjana; Schneider, Julia; Wild, Andreas; Moceri, Sandra; Buechler, Christa; Bozec, Aline; Weber, Georg; Merkel, Susanne; Beckervordersandforth, Ruth; Steinkasserer, Alexander; et al. (International Journal of Molecular Sciences, 2023)
Obesity is characterized by the expansion of the adipose tissue, usually accompanied by inflammation, with a prominent role of macrophages infiltrating the visceral adipose tissue (VAT). This chronic inflammation is a major driver of obesity-associated comorbidities. Four-and-a-half LIM-domain protein 2 (FHL2) is a multifunctional adaptor protein that is involved in the regulation of various biological functions and the maintenance of the homeostasis of different tissues. In this study, we aimed to gain new insights into the expression and functional role of FHL2 in VAT in diet-induced obesity. We found enhanced FHL2 expression in the VAT of mice with Western-type diet (WTD)-induced obesity and obese humans and identified macrophages as the cellular source of enhanced FHL2 expression in VAT. In mice with FHL2 deficiency (FHL2KO), WTD feeding resulted in reduced body weight gain paralleled by enhanced energy expenditure and uncoupling protein 1 (UCP1) expression, indicative of activated thermogenesis. In human VAT, FHL2 was inversely correlated with UCP1 expression. Furthermore, macrophage infiltration and the expression of the chemokine MCP-1, a known promotor of macrophage accumulation, was significantly reduced in WTD-fed FHL2KO mice compared with wild-type (wt) littermates. While FHL2 depletion did not affect the differentiation or lipid metabolism of adipocytes in vitro, FHL2 depletion in macrophages resulted in reduced expressions of MCP-1 and the neuropeptide Y (NPY). Furthermore, WTD-fed FHL2KO mice showed reduced NPY expression in VAT compared with wt littermates, and NPY expression was enhanced in VAT resident macrophages of obese individuals. Stimulation with recombinant NPY induced not only UCP1 expression and lipid accumulation but also MCP-1 expression in adipocytes. Collectively, these findings indicate that FHL2 is a positive regulator of NPY and MCP-1 expression in macrophages and herewith closely linked to the mechanism of obesity-associated lipid accumulation and inflammation in VAT. Thus, FHL2 appears as a potential novel target to interfere with the macrophage–adipocyte crosstalk in VAT for treating obesity and related metabolic disorders.
CRIS-Team Scopus Importer:2023-11-03
Keywords: adipocytes; FHL2; macrophages; MCP-1; NPY; obesity; thermogenesis

Fra-2 regulates B cell development by enhancing IRF4 and Foxo1 transcription - Ubieta, Kenia; Garcia, Mireia; Groetsch, Bettina; Uebe, Steffen; Stein, Merle; Ekici, Arif Bülent; Schett, Georg; Mielenz, Dirk; Bozec, Aline; Weber, Georg (Journal of Experimental Medicine, 2017)
The role of AP-1 transcription factors in early B cell development and function is still incompletely characterized. Here we address the role of Fra-2 in B cell differentiation. Deletion of Fra-2 leads to impaired B cell proliferation in the bone marrow. In addition, IL-7-stimulated pro-B cell cultures revealed a reduced differentiation from large pre-B cells to small B cells and immature B cells. Gene profiling and chromatin immunoprecipitation sequencing analyses unraveled a transcriptional reduction of the transcription factors Foxo1, Irf4, Ikaros, and Aiolos in Fra-2-deficient B cells. Moreover, expression of IL7R? and Rag 1/2, downstream targets of Irf4 and Foxo1, were also reduced in the absence of Fra-2. Pro-B cell proliferation and small pre-B cell differentiation were fully rescued by expression of Foxo1 and Irf4 in Fra-2-deficient pro-B cells. Hence, Fra-2 is a key upstream regulator of Foxo1 and Irf4 expression and influences proliferation and differentiation of B cells at multiple stages.
EVALuna2:9366

Fractal and Euclidean descriptors of platelet shape - Kraus, Max-Joseph; Neeb, Heiko; Strasser, Erwin F. (Platelets, 2014)
Platelet shape change is a dynamic membrane surface process that exhibits remarkable morphological heterogeneity. Once the outline of an irregular shape is identified and segmented from a digital image, several mathematical descriptors can be applied to numerical characterize the irregularity of the shapes surface. 13072 platelet outlines (PLO) were segmented automatically from 1928 microscopic images using a newly developed algorithm for the software product Matlab R2012b. The fractal dimension (FD), circularity, eccentricity, area and perimeter of each PLO were determined. 972 PLO were randomly assigned for computer-assisted manual measurement of platelet diameter as well as number, width and length of filopodia per platelet. FD can be used as a surrogate parameter for determining the roughness of the PLO and circularity can be used as a surrogate to estimate the number and length of filopodia. The relationship between FD and perimeter of the PLO reveals the existence of distinct groups of platelets with significant structural differences which may be caused by platelet activation. This new method allows for the standardized continuous numerical classification of platelet shape and its dynamic change, which is useful for the analysis of altered platelet activity (e.g. inflammatory diseases, contact activation, drug testing).
EVALuna2:15973

Fraktionelle Flussreserve in der Diagnostik der koronaren Herzerkrankung: Klinische Bedeutung, Durchführung und Interpretation - Möllmann, H.; Rudolph, T.; Rieber, J.; Eggebrecht, H.; Richardt, G.; Schmitz, T.; Werner, N.; Achenbach, Susanne (Der Kardiologe, 2016)
Invasive measurement of the fractional flow reserve (FFR) allows determination of the hemodynamic relevance of a given coronary artery stenosis. Several clinical trials could demonstrate the superiority of FFR-based decision-making for or against percutaneous coronary intervention (PCI) in comparison to visual quantification of the severity of a stenosis. These results led to measurement of the FFR being included in the current guideline recommendations on myocardial revascularization. This article elaborates the theoretical background of measurement of the FFR, summarizes the decisive clinical data and provides comprehensive practical instructions for the safe and rapid measurement of FFR in routine clinical practice.
CRIS-Team Scopus Importer:2023-03-08
Keywords: Adenosine; Coronary arteries; Outcome; Revascularization; Stenoses

Free-Breathing Low-Field MRI of the Lungs Detects Functional Alterations Associated With Persistent Symptoms After COVID-19 Infection. - Levy, Simon; Heiß, Rafael; Grimm, Robert; Grodzki, David; Hadler, Dominique; Voskrebenzev, Andreas; Vogel-Claussen, Jens; Fuchs, Florian; Strauss, Richard; Achenbach, Susanne; Hinsen, Maximilian; Klett, Daniel; et al. (Investigative Radiology, 2022)
OBJECTIVES: With the COVID-19 pandemic, repetitive lung examinations have become necessary to follow-up symptoms and associated alterations. Low-field MRI, benefiting from reduced susceptibility effects, is a promising alternative for lung imaging to limit radiations absorbed by patients during CT examinations, which also have limited capability to assess functional alterations. The aim of this investigative study was to explore the functional abnormalities that free-breathing 0.55 T MRI in combination with the phase-resolved functional lung (PREFUL) analysis could identify in patients with persistent symptoms after COVID-19 infection. MATERIALS AND METHODS: Seventy-four COVID-19 patients and 8 healthy volunteers were prospectively scanned in free-breathing with a balanced steady-state free-precession sequence optimized at 0.55 T, 5 months postinfection on average. Normalized perfusion (Q), fractional ventilation (FV), and flow-volume loop correlation (FVLc) maps were extracted with the PREFUL technique. Q, FV, and FVLc defects as well as defect overlaps between these metrics were quantified. Morphological turbo-spin-echo images were also acquired, and the extent of abnormalities was scored by a board-certified radiologist. To investigate the functional correlates of persistent symptoms, a recursive feature elimination algorithm was applied to find the most informative variables to detect the presence of persistent symptoms with a logistic regression model and a cross-validation strategy. All MRI metrics, sex, age, body mass index, and the presence of preexisting lung conditions were included. RESULTS: The most informative variables to detect persistent symptoms were the percentage of concurrent Q and FVLc defects and of areas free of those defects. A detection accuracy of 71.4% was obtained with these 2 variables when fitting the model on the entire dataset. Although none of the single variables differed between patients with and without persistent symptoms ( P > 0.05), the combined score of these 2 variables did ( P < 0.02). This score also showed a consistent increase from healthy volunteers (7.7) to patients without persistent symptoms (8.2) and with persistent symptoms (8.6). The morphological abnormality score showed poor correlation with the functional parameters. CONCLUSIONS: Functional pulmonary examinations using free-breathing 0.55 T MRI with PREFUL analysis revealed potential quantitative markers of impaired lung function in patients with persistent symptoms after COVID-19 infection, potentially complementing morphologic imaging. Future work is needed to explore the translational relevance and clinical implication of these findings.
EVALuna2:506323

From pullout-techniques to modular elastic stable chest repair: the evolution of an open technique in the correction of pectus excavatum - Schulz-Drost, Stefan; Syed, Julia; Luber, Anna-Maria; Carbon, Roman T.; Besendörfer, Manuel (Journal of Thoracic Disease, 2019)
Background: Traditionally open procedures have been replaced by minimally invasive techniques in the correction of pectus excavatum. Efforts to improve the extent of mobilization of the chest wall and its stabilization have led to constant modifications. There is currently no consensus about the best procedure for correction of pectus excavatum.
CRIS-Team WoS Importer:2019-08-13

Functional Heterogeneity of Umbilical Cord Blood Monocyte-Derived Dendritic Cells - Schweiger, Petra; Hamann, Livia; Strobel, Julian; Weisbach, Volker; Wandersee, Alexandra; Christ, Julia; Kehl, Sven; Weidenthaler, Filip; Antoniadis, Sophia; Hackstein, Holger; Cunningham, Sarah (Journal of Immunology, 2024)
Human umbilical cord blood (UCB) represents a unique resource for hematopoietic stem cell transplantation for children and patients lacking suitable donors. UCB harbors a diverse set of leukocytes such as professional APCs, including monocytes, that could act as a novel source for cellular therapies. However, the immunological properties of UCB monocytes and monocyte-derived dendritic cells (MoDCs) are not fully characterized. In this study, we characterized the phenotype and functions of UCB-MoDCs to gauge their potential for future applications. UCB exhibited higher frequencies of platelets and lymphocytes as well as lower frequencies of neutrophils in comparison with adult whole blood. Leukocyte subset evaluation revealed significantly lower frequencies of granulocytes, NK cells, and CD14+CD16− monocytes. Surface marker evaluation revealed significantly lower rates of costimulatory molecules CD80 and CD83 while chemokine receptors CCR7 and CXCR4, as well as markers for Ag presentation, were similarly expressed. UCB-MoDCs were sensitive to TLR1–9 stimulation and presented quantitative differences in the release of proinflammatory cytokines. UCB-MoDCs presented functional CCR7-, CXCR4-, and CCR5-associated migratory behavior as well as adequate receptor- and micropinocytosis-mediated Ag uptake. When cocultured with allogeneic T lymphocytes, UCB-MoDCs induced weak CD4+ T lymphocyte proliferation, CD71 expression, and release of IFN-γ and IL-2. Taken together, UCB-MoDCs present potentially advantageous properties for future medical applications.<br

Functional implications of novel human acid sphingomyelinase splice variants - Rhein, Cosima; Tripal, Philipp; Seebahn, Angela; Konrad, Alice; Kramer, Marcel; Nagel, Christine; Kemper, Jonas; Bode, Jens; Mühle, Christiane; Gulbins, Erich; Reichel, Martin; Becker, Cord-Michael; et al. (PLoS ONE, 2012)
Acid sphingomyelinase (ASM) hydrolyses sphingomyelin and generates the lipid messenger ceramide, which mediates a variety of stress-related cellular processes. The pathological effects of dysregulated ASM activity are evident in several human diseases and indicate an important functional role for ASM regulation. We investigated alternative splicing as a possible mechanism for regulating cellular ASM activity.We identified three novel ASM splice variants in human cells, termed ASM-5, -6 and -7, which lack portions of the catalytic- and/or carboxy-terminal domains in comparison to full-length ASM-1. Differential expression patterns in primary blood cells indicated that ASM splicing might be subject to regulatory processes. The newly identified ASM splice variants were catalytically inactive in biochemical in vitro assays, but they decreased the relative cellular ceramide content in overexpression studies and exerted a dominant-negative effect on ASM activity in physiological cell models.These findings indicate that alternative splicing of ASM is of functional significance for the cellular stress response, possibly representing a mechanism for maintaining constant levels of cellular ASM enzyme activity.
EVALuna2:4672

Gamma interferon-induced guanylate binding protein 1 is a novel actin cytoskeleton remodeling factor - Ostler, Nicole; Britzen-Laurent, Nathalie; Liebl, Andrea; Naschberger, Elisabeth; Lochnit, Guenter; Ostler, Markus; Forster, Florian; Kunzelmann, Peter; Ince, Semra; Supper, Verena; Praefcke, Gerrit J. K.; Schubert, Dirk W.; et al. (Molecular and Cellular Biology, 2014)
Gamma interferon (IFN-?) regulates immune defenses against viruses, intracellular pathogens, and tumors by modulating cell proliferation, migration, invasion, and vesicle trafficking processes. The large GTPase guanylate binding protein 1 (GBP-1) is among the cellular proteins that is the most abundantly induced by IFN-? and mediates its cell biologic effects. As yet, the molecular mechanisms of action of GBP-1 remain unknown. Applying an interaction proteomics approach, we identified actin as a strong and specific binding partner of GBP-1. Furthermore, GBP-1 colocalized with actin at the subcellular level and was both necessary and sufficient for the extensive remodeling of the fibrous actin structure observed in IFN-?-exposed cells. These effects were dependent on the oligomerization and the GTPase activity of GBP-1. Purified GBP-1 and actin bound to each other, and this interaction was sufficient to impair the formation of actin filaments in vitro, as demonstrated by atomic force microscopy, dynamic light scattering, and fluorescence-monitored polymerization. Cosedimentation and band shift analyses demonstrated that GBP-1 binds robustly to globular actin and slightly to filamentous actin. This indicated that GBP-1 may induce actin remodeling via globular actin sequestering and/or filament capping. These results establish GBP-1 as a novel member within the family of actin-remodeling proteins specifically mediating IFN-?-dependent defense strategies.
EVALuna2:15143

Gastric cancer patients less than 50 years of age exhibit significant downregulation of E-cadherin and CDX2 compared to older reference populations - Schildberg, Claus Wilhelm; Abba, Mohammed; Merkel, Susanne; Agaimy, Abbas; Dimmler, Arno; Schlabrakowski, Anne; Croner, Roland; Leupold, Joerg Hendrik; Hohenberger, Werner; Allgayer, Heike (Advances in Medical Sciences, 2014)
There is an increasing need to identify molecular markers, which can be used to prognosticate patient populations in gastric cancer. Whereas a significant number have been identified, very few have been characterized in the context of their ability to discriminate between young and old age groups in which a survival difference clearly exists.In this study, using immunohistochemistry, we evaluated three markers with proven involvement in gastric cancer. The p53 tumor suppressor, the cell adhesion glycoprotein epithelial cadherin (CDH1) and the caudal-related homeobox transcription factor (CDX2) all of these have important roles in the aetiopathogenesis and/or progression of gastric cancer.After adjustments for TNM stage, tumor grade, histopathological characteristics (Lauren classification), we found significant differences in the expression of these proteins, particularly E-cadherin and CDX2 between young and elderly patients. However, these differences did not amount to a significant difference in survival.This study demonstrates that the protein expression of p53, CDH1 and CDX2 significantly discriminates young patients with gastric cancer who have a better prognostic outlook from older patients, but this difference in expression does not contribute to a survival benefit.
EVALuna2:6583

Gastrointestinal schwannomas: a rare but important differential diagnosis of mesenchymal tumors of gastrointestinal tract - Mekras, Alexandros; Krenn, Veit; Perrakis, Aristotelis; Croner, Roland S.; Kalles, Vasileios; Atamer, Cem; Grützmann, Robert; Vassos, Nikolaos (BMC Surgery, 2018)
BACKGROUND: Schwannomas of gastrointestinal tract are rare, mostly benign and notably different neoplasms from conventional schwannomas that arise in soft tissue or the central nervous system. These tumors are of clinical importance since they should always be considered in the differential diagnosis of submucosal lesions of gastrointestinal tract. METHODS: Seven patients with a pathologically proven gastrointestinal schwannoma were identified in our series of mesenchymal tumors and reviewed retrospectively. Clinicopathological and immunohistochemical parameters along with the follow-up results were analysed. RESULTS: The series included two males and five females, with a mean age 69 years (range, 39-81). Most patients were asymptomatic on presentation, except for two patients with abdominal pain. In the other cases (n = 5), the tumor was an incidental finding during other medical, imaging or surgical procedures. The tumors were located in the stomach (n = 4) and in the small intestine (n = 3) with an average size of 29 mm (range, 12-70). A preoperative diagnosis was achieved only in one case with a CT-guided core biopsy. Otherwise the clinical, intraoperative, endoscopic or radiological findings were unspecific. Patients with gastric tumor underwent either laparoscopic (n = 2) or open (n = 2) gastric wedge resection of the tumor; in the cases of intestinal tumor (n = 3) a segmentectomy was performed. Pathological examination revealed solid homogenous tumors, which were highly cellular and composed of spindle cells with positive staining for S100 protein, and confirmed the diagnosis of schwannoma. All tumors were negative for c-Kit, smooth muscle actin, desmin and DOG-1 and showed very low proliferation index. There were negative resection margins and no malignant variants were recognized. At an average follow-up of 60 months (range, 24-185) all patients were free of disease with no signs of recurrence or metastases and acceptable gastrointestinal function. CONCLUSIONS: Schwannomas are rare, slow-growing and mostly asymptomatic gastrointestinal mesenchymal tumors. They are difficult to be diagnosed preoperatively as endoscopic and radiological findings are nonspecific but histological and immunohistochemical features are of paramount importance to differentiate between benign and malignant schwannomas, or other spindle cell sarcomas. The treatment of choice is complete surgical excision without a conclusive preoperative diagnosis, and the long-term outcome is excellent as these lesions are mostly benign.
EVALuna2:210708

GATA4 and GATA6 loss-of-expression is associated with extinction of the classical programme and poor outcome in pancreatic ductal adenocarcinoma - De Andres, Monica P.; Jackson, Richard J.; Felipe, Irene; Zagorac, Sladjana; Pilarsky, Christian; Schlitter, Anna Melissa; Martinez De Villareal, Jaime; Jang, Gun Ho; Costello, Eithne; Gallinger, Steve; Ghaneh, Paula; Greenhalf, William; et al. (Gut, 2022)
Objective GATA6 is a key regulator of the classical phenotype in pancreatic ductal adenocarcinoma (PDAC). Low GATA6 expression associates with poor patient outcome. GATA4 is the second most expressed GATA factor in the pancreas. We assessed whether, and how, GATA4 contributes to PDAC phenotype and analysed the association of expression with outcome and response to chemotherapy. Design We analysed PDAC transcriptomic data, stratifying cases according to GATA4 and GATA6 expression and identified differentially expressed genes and pathways. The genome-wide distribution of GATA4 was assessed, as well as the effects of GATA4 knockdown. A multicentre tissue microarray study to assess GATA4 and GATA6 expression in samples (n=745) from patients with resectable was performed. GATA4 and GATA6 levels were dichotomised into high/low categorical variables; association with outcome was assessed using univariable and multivariable Cox regression models. Results GATA4 messenger RNA is enriched in classical, compared with basal-like tumours. We classified samples in 4 groups as high/low for GATA4 and GATA6. Reduced expression of GATA4 had a minor transcriptional impact but low expression of GATA4 enhanced the effects of GATA6 low expression. GATA4 and GATA6 display a partially overlapping genome-wide distribution, mainly at promoters. Reduced expression of both proteins in tumours was associated with the worst patient survival. GATA4 and GATA6 expression significantly decreased in metastases and negatively correlated with basal markers. Conclusions GATA4 and GATA6 cooperate to maintain the classical phenotype. Our findings provide compelling rationale to assess their expression as biomarkers of poor prognosis and therapeutic response.
CRIS-Team WoS Importer:2022-09-30

Gata6+ Pericardial Cavity Macrophages Relocate to the Injured Heart and Prevent Cardiac Fibrosis - Deniset, Justin F.; Belke, Darrell; Lee, Woo Yong; Jorch, Selina K.; Deppermann, Carsten; Hassanabad, Ali Fatehi; Turnbull, Jeannine D.; Teng, G.; Rozich, Isaiah; Hudspeth, K.; Kanno, Yuka; Brooks, Stephen R.; et al. (Immunity, 2019)
Macrophages play an important role in structural cardiac remodeling and the transition to heart failure following myocardial infarction (MI). Previous research has focused on the impact of blood-derived monocytes on cardiac repair. Here we examined the contribution of resident cavity macrophages located in the pericardial space adjacent to the site of injury. We found that disruption of the pericardial cavity accelerated maladaptive post-MI cardiac remodeling. Gata6+ macrophages in mouse pericardial fluid contributed to the reparative immune response. Following experimental MI, these macrophages invaded the epicardium and lost Gata6 expression but continued to perform anti-fibrotic functions. Loss of this specialized macrophage population enhanced interstitial fibrosis after ischemic injury. Gata6+ macrophages were present in human pericardial fluid, supporting the notion that this reparative function is relevant in human disease. Our findings uncover an immune cardioprotective role for the pericardial tissue compartment and argue for the reevaluation of surgical procedures that remove the pericardium. Deniset et al. describe the pericardial cavity as an important source of resident macrophages that migrate into the heart following ischemic injury and prevent detrimental repair caused by excessive fibrosis.
CRIS-Team Scopus Importer:2019-07-09
Keywords: fibrosis; myocardial infarction; Pericardial macrophage

GBP-1 acts as a tumor suppressor in colorectal cancer cells - Britzen-Laurent, Nathalie; Lipnik, Karoline; Ocker, Matthias; Naschberger, Elisabeth; Schellerer, Vera; Croner, Roland S.; Vieth, Michael; Waldner, Maximilian; Steinberg, Pablo; Hohenadl, Christine; Stürzl, Michael (Carcinogenesis, 2013)
The human guanylate-binding protein 1 (GBP-1) is among the proteins the most highly induced by interferon-γ (IFN-γ) in every cell type investigated as yet. In vivo, GBP-1 expression is associated with the presence of inflammation and has been observed in autoimmune diseases, inflammatory bowel diseases (IBD) and cancer. In colorectal carcinoma (CRC), the expression of GBP-1 in the desmoplastic stroma has been previously reported to correlate with the presence of an IFN-γ-dominated T helper type 1 (Th1) micromilieu and with an increased cancer-related 5-year survival. In the present study, the analysis of GBP-1 expression in a series of 185 CRCs by immunohistochemistry confirmed that GBP-1 is expressed in stroma cells of CRCs and revealed a significantly less frequent expression in tumor cells, which was contradictory with the broad inducibility of GBP-1. Furthermore, three of six CRC cell lines treated with IFN-γ were unable to express GBP-1 indicating that colorectal tumor cells tend to downregulate GBP-1. On the contrary, non-transformed colon epithelial cells strongly expressed GBP-1 in vitro in presence of IFN-γ and in vivo in inflammatory bowel diseases. Reconstitution of GBP-1 expression in a negative CRC cell line inhibited cell proliferation, migration and invasion. Using RNA interference, we showed that GBP-1 mediates the antitumorigenic effects of IFN-γ in CRC cells. In addition, GBP-1 was able to inhibit tumor growth in vivo. Altogether, these results suggested that GBP-1 acts directly as a tumor suppressor in CRC and the loss of GBP-1 expression might indicate tumor evasion from the IFN-γ-dominated Th1 immune response. © The Author 2012. Published by Oxford University Press. All rights reserved.
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Gemeinsam klug entscheiden – Diabetisches Fußsyndrom - Uhl, C.; Heller, A.; Rother, Ulrich; Hatzl, J.; Böckler, D. (Gefässchirurgie, 2021)
In this article the strong recommendations (grade A) of the Association of the Scientific Medical Societies in Germany (AWMF) guidelines on the topic of “National treatment guidelines for type 2 diabetes: preventive and treatment strategies for foot complications” (version 2.8, February 2010) for the areas of extended diagnostics, therapeutic procedures and amputation are summarized and discussed. Restrictively, it has to be noted that the validity of the guidelines has expired. A current version was not yet available when this article was written, therefore the authors of this article used the last available version as a reference. Additionally, the current European Society for Vascular Surgery (ESVS) guidelines on chronic limb-threatening ischemia (CLTI) were also taken into account. The grades of recommendation were assigned by a formal consensus procedure between the participating authors of the guidelines. Due to the low level of recommendation, the grade B and grade 0 recommendations are not discussed in this article.
CRIS-Team Scopus Importer:2021-04-23
Keywords: Amputation; Antibiotics; Diabetes mellitus; Revascularization; Wounds

Gene expression analysis of ischaemia and reperfusion in human microsurgical free muscle tissue transfer. - Dragu, Adrian; Schnuerer, Stefan; Surmann-Schmitt, Cordula; von der Mark, Klaus; Stürzl, Michael; Unglaub, Frank; Wolf, Maya B.; Leffler, Mareike; Beier, Justus; Kneser, Ulrich; Horch, Raymund E. (Journal of Cellular and Molecular Medicine, 2011)
The aim of this study was to analyse various gene expression profiles of muscle tissue during normoxia, ischaemia and after reperfusion in human muscle free flaps, to gain an understanding of the occurring regulatory, inflammatory and apoptotic processes on a cellular and molecular basis. Eleven Caucasian patients with soft tissue defects needing coverage with microsurgical free muscle flaps were included in this study. In all patients, the muscle samples were taken from free myocutaneous flaps. The first sample was taken before induction of ischaemia in normoxia (I), another one after ischaemia (II), and the last one was taken after reperfusion (III). The samples were analysed using DNA-microarray, real-time-quantitative-PCR and immunohistochemistry. DNA-microarray analysis detected multiple, differentially regulated genes when comparing the different groups (I-III) with statistical significance. Comparing ischaemia (II) versus normoxia (I) educed 13 genes and comparing reperfusion (III) versus ischaemia (II) educed 19 genes. The comparison of reperfusion (III) versus normoxia (I) yielded 100 differentially regulated genes. Real-time-quantitative-PCR confirmed the results of the DNA-microarrays for a subset of four genes (CASP8, IL8, PLAUR and S100A8). This study shows that ischaemia and reperfusion induces alterations on the gene expression level in human muscle free flaps. Data may suggest that the four genes CASP8, IL8, PLAUR and S100A8 are of great importance in this context. We could not confirm the DNA-microarry and real-time-quantitative-PCR results on the protein level. Finally, these findings correspond with the surgeon's clinical experience that the accepted times of ischaemia, generally up to 90 min., are not sufficient to induce pathophysiological processes, which can ultimately lead to flap loss. When inflammatory and apoptotic proteins are expressed at high levels, flap damage might occur and flap loss is likely. The sole expression on mRNA level might explain why flap loss is unlikely.

Gene Expression in Solitary Fibrous Tumors (SFTs) Correlates with Anatomic Localization and NAB2-STAT6 Gene Fusion Variants - Bieg, Matthias; Moskalev, Evgeny; Will, Rainer; Hebele, Simone; Schwarzbach, Matthias; Schmeck, Sanja; Hohenberger, Peter; Jakob, Jens; Kasper, Bernd; Gaiser, Timo; Ströbel, Philip; Wardelmann, Eva; et al. (American Journal of Pathology, 2021)
Solitary fibrous tumors (SFTs) harbor recurrent NAB2-STAT6 gene fusions, promoting constitutional up-regulation of oncogenic early growth response 1 (EGR1)-dependent gene expression. SFTs with the most common canonical NAB2 exon 4–STAT6 exon 2 fusion variant are often located in the thorax (pleuropulmonary) and are less cellular with abundant collagen. In contrast, SFTs with NAB2 exon 6–STAT6 exon 16/17 fusion variants typically display a cellular round to ovoid cell morphology and are often located in the deep soft tissue of the retroperitoneum and intra-abdominal pelvic region or in the meninges. Here, we employed next-generation sequencing–based gene expression profiling to identify significant differences in gene expression associated with anatomic localization and NAB2-STAT6 gene fusion variants. SFTs with the NAB2 exon 4–STAT6 exon 2 fusion variant showed a transcriptional signature enriched for genes involved in DNA binding, gene transcription, and nuclear localization, whereas SFTs with the NAB2 exon 6–STAT6 exon 16/17 fusion variants were enriched for genes involved in tyrosine kinase signaling, cell proliferation, and cytoplasmic localization. Specific transcription factor binding motifs were enriched among differentially expressed genes in SFTs with different fusion variants, implicating co–transcription factors in the modification of chimeric NGFI-A binding protein 2 (NAB2)-STAT6–dependent deregulation of EGR1-dependent gene expression. In summary, this study establishes a potential molecular biologic basis for clinicopathologic differences in SFTs with distinct NAB2-STAT6 gene fusion variants.
CRIS-Team Scopus Importer:2021-04-02

Generation of Reliable Red Cell Concentrate Requirement Lists for Operations and Interventions from Data Warehouse Data and Patient-Related Batch Documentation of Blood Components - Zimmermann, Robert; Becker, Andreas; Hackstein, Holger; Ganslandt, Thomas (Transfusionsmedizin, 2021)
Failure to perform transfusion-preparatory diagnostics and to order a sufficient number of blood components prior to surgery is increasingly leading to clinical emergencies and avoidable risks for patients. The mandatory preparation of blood requirement lists often fails due to the availability of suitable data. The University Hospital Erlangen is a tertiary care hospital with 1400 beds. Since 2010, all relevant data for the interpretation of patterns in the use of blood components have been continuously collected here. We are able to integrate the clinical data warehouse components of the personal data of red blood cell (RBC) recipients, the codes of inpatients in the German Diagnosis Related Group (G-DRG) system, ICD codes, OPS codes and the data of the RBC components from the blood bank's IT system. The obtained DRGs, ICD codes and OPS codes are linked to the data of blood component consumption on an individual basis. Analyses can be carried out for the entire hospital as well as for specific departments. Ongoing refinement of the database queries improves the ability to correctly estimate blood requirements for standard surgery and interventions. The results differ considerably from the surgeons' estimates of the probability of a transfusion, i.e. the probability of a transfusion is often underestimated. Correct compliance with the 10 percent transfusion probability limit for the question of early preoperative provision of cross blood can be improved by such queries. Counteracting the phenomenon of "delayed transfusion" is becoming an increasingly important task for the clinically active transfusion medicine specialist. Creating statistics on the probability of transfusion by linking data warehouse data and batch documentation data from blood banks can provide the necessary tools.
CRIS-Team WoS Importer:2021-03-26

Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms - Schafmayer, Clemens; Harrison, James William; Buch, Stephan; Lange, Christina; Reichert, Matthias C.; Hofer, Philipp; Cossais, François; Kupcinskas, Juozas; von Schönfels, Witigo; Schniewind, Bodo; Kruis, Wolfgang; Tepel, Jürgen; et al. (Gut, 2019)
OBJECTIVE: Diverticular disease is a common complex disorder characterised by mucosal outpouchings of the colonic wall that manifests through complications such as diverticulitis, perforation and bleeding. We report the to date largest genome-wide association study (GWAS) to identify genetic risk factors for diverticular disease. DESIGN: Discovery GWAS analysis was performed on UK Biobank imputed genotypes using 31 964 cases and 419 135 controls of European descent. Associations were replicated in a European sample of 3893 cases and 2829 diverticula-free controls and evaluated for risk contribution to diverticulitis and uncomplicated diverticulosis. Transcripts at top 20 replicating loci were analysed by real-time quatitative PCR in preparations of the mucosal, submucosal and muscular layer of colon. The localisation of expressed protein at selected loci was investigated by immunohistochemistry. RESULTS: We discovered 48 risk loci, of which 12 are novel, with genome-wide significance and consistent OR in the replication sample. Nominal replication (p<0.05) was observed for 27 loci, and additional 8 in meta-analysis with a population-based cohort. The most significant novel risk variant rs9960286 is located near CTAGE1 with a p value of 2.3×10-10 and 0.002 (ORallelic=1.14 (95% CI 1.05 to 1.24)) in the replication analysis. Four loci showed stronger effects for diverticulitis, PHGR1 (OR 1.32, 95% CI 1.12 to 1.56), FAM155A-2 (OR 1.21, 95% CI 1.04 to 1.42), CALCB (OR 1.17, 95% CI 1.03 to 1.33) and S100A10 (OR 1.17, 95% CI 1.03 to 1.33). CONCLUSION: In silico analyses point to diverticulosis primarily as a disorder of intestinal neuromuscular function and of impaired connective fibre support, while an additional diverticulitis risk might be conferred by epithelial dysfunction.
CRIS-Team Scopus Importer:2019-05-02
Keywords: diverticular disease; genetic polymorphisms; intestinal motility

Genome-wide association study identifies inversion in the CTRB1-CTRB2 locus to modify risk for alcoholic and non-alcoholic chronic pancreatitis - Rosendahl, Jonas; Kirsten, Holger; Hegyi, Eszter; Kovacs, Peter; Weiss, Frank Ulrich; Laumen, Helmut; Lichtner, Peter; Ruffert, Claudia; Chen, Jian-Min; Masson, Emmanuelle; Beer, Sebastian; Zimmer, Constantin; et al. (Gut, 2017)
Alcohol-related pancreatitis is associated with a disproportionately large number of hospitalisations among GI disorders. Despite its clinical importance, genetic susceptibility to alcoholic chronic pancreatitis (CP) is poorly characterised. To identify risk genes for alcoholic CP and to evaluate their relevance in non-alcoholic CP, we performed a genome-wide association study and functional characterisation of a new pancreatitis locus.1959 European alcoholic CP patients and population-based controls from the KORA, LIFE and INCIPE studies (n=4708) as well as chronic alcoholics from the GESGA consortium (n=1332) were screened with Illumina technology. For replication, three European cohorts comprising 1650 patients with non-alcoholic CP and 6695 controls originating from the same countries were used.We replicated previously reported risk loci CLDN2-MORC4, CTRC, PRSS1-PRSS2 and SPINK1 in alcoholic CP patients. We identified CTRB1-CTRB2 (chymotrypsin B1 and B2) as a new risk locus with lead single-nucleotide polymorphism (SNP) rs8055167 (OR 1.35, 95% CI 1.23 to 1.6). We found that a 16.6 kb inversion in the CTRB1-CTRB2 locus was in linkage disequilibrium with the CP-associated SNPs and was best tagged by rs8048956. The association was replicated in three independent European non-alcoholic CP cohorts of 1650 patients and 6695 controls (OR 1.62, 95% CI 1.42 to 1.86). The inversion changes the expression ratio of the CTRB1 and CTRB2 isoforms and thereby affects protective trypsinogen degradation and ultimately pancreatitis risk.An inversion in the CTRB1-CTRB2 locus modifies risk for alcoholic and non-alcoholic CP indicating that common pathomechanisms are involved in these inflammatory disorders.
EVALuna2:4780

Genome-Wide CRISPR Screening Identifies DCK and CCNL1 as Genes That Contribute to Gemcitabine Resistance in Pancreatic Cancer - Yang, Hai; Liu, Bin; Liu, Dongxue; Yang, Zhirong; Zhang, Shuman; Xu, Pengyan; Xing, Yuming; Kutschick, Isabella; Pfeffer, Sina; Britzen-Laurent, Nathalie; Grützmann, Robert; Pilarsky, Christian (Cancers, 2022)
Pancreatic cancer is one of the most lethal cancers. Due to the difficulty of early diagnosis, most patients are diagnosed with metastasis or advanced-stage cancer, limiting the possibility of surgical treatment. Therefore, chemotherapy is applied to improve patient outcomes, and gemcitabine has been the primary chemotherapy drug for pancreatic cancer for over a decade. However, drug resistance poses a significant challenge to the efficacy of chemotherapy. The CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) gene-editing system is a powerful tool, and researchers have developed CRISPR/Cas9 library screening as a means to identify the genes associated with specific phenotype changes. We performed genomewide CRISPR/Cas9 knockout screening in the mouse pancreatic cancer cell line TB32047 with gemcitabine treatment and identified deoxycytidine kinase (DCK) and cyclin L1 (CCNL1) as the top hits. We knocked out DCK and CCNL1 in the TB32047 and PANC1 cell lines and confirmed that the loss of DCK or CCNL1 enhanced gemcitabine resistance in pancreatic cells. Many researchers have addressed the mechanism of DCK-related gemcitabine resistance; however, no study has focused on CCNL1 and gemcitabine resistance. Therefore, we explored the mechanism of CCNL1-related gemcitabine resistance and found that the loss of CCNL1 activates the ERK/AKT/STAT3 survival pathway, causing cell resistance to gemcitabine treatment.
CRIS-Team Scopus Importer:2022-07-15
Keywords: CCNL1; CRISPR-Cas9; DCK; gemcitabine resistance; library screening; pancreatic cancer

Genomic analyses identify molecular subtypes of pancreatic cancer - Bailey, Peter; Chang, David K.; Nones, Katia; Johns, Amber L.; Patch, Ann-Marie; Gingras, Marie-Claude; Miller, David K.; Christ, Angelika N.; Bruxner, Tim J. C.; Quinn, Michael C.; Nourse, Craig; Murtaugh, L. Charles; et al. (Nature, 2016)
Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-?, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63?N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.
EVALuna2:15255

Geschlechterspezifische Unterschiede bei der endovaskulären Behandlung der peripheren arteriellen Verschlusskrankheit – Eine systematische Literaturübersicht - Behrendt, C. -A.; Rother, Ulrich; Ruemenapf, G.; Uhl, C.; Boeckler, D.; Goertz, H.; Heidemann, F. (Gefässchirurgie, 2020)
Background: There is evidence for gender disparities in the development, diagnostics and treatment of symptomatic peripheral arterial occlusive disease (PAOD). Although women represent 50% of treated cohorts in the literature, they only make up a small proportion in randomized trials on PAOD. Up to now, guidelines have included hardly any gender-sensitive recommendations and the results of observational studies are contradictory. This systematic literature review is aimed at identifying available observational studies on gender differences in the endovascular treatment of symptomatic PAOD. Materials and Methods: A systematic review of the literature was carried out using PubMed, focusing on retrospective observational studies comparing outcomes between men and women. Results: A total of 37 articles were identified, constituting a cohort of 5,489,558 patients of both genders (40.3% women). Propensity score matching was used in five studies to address confounders. Twenty-three studies reported outcomes beyond the index hospital stay and 30 days, respectively. While 10 studies were able to identify disadvantages in females, 6 studies reported disadvantages in men. A further 21 studies were not able to identify any clear disparities. Conclusions: Owing to methodological limitations and the inadequate comparability of the studies included, the available real-world evidence does not allow any distinct conclusions regarding gender-specific disparities in the endovascular treatment of PAOD.
CRIS-Team Scopus Importer:2020-10-02
Keywords: Endovascular techniques; Gender; Health care research; Quality indicator; Real world evidence

Gleiche Langzeitergebnisse der laparoskopischen Resektion nach neoadjuvanter Radiochemotherapie beim lokal fortgeschrittenen Rektumkarzinom wie durch konventionelle offene Chirurgie - Hohenberger, Werner (Strahlentherapie und Onkologie, 2015)
EVALuna2:15197

Glucose-Restricted Diet Regulates the Tumor Immune Microenvironment and Prevents Tumor Growth in Lung Adenocarcinoma - Gähler, Alexander; Trufa, Denis; Chiriac, Mircea-Teodor; Tausche, Patrick; Hohenberger, Katja; Brunst, Ann-Kathrin; Rauh, Manfred; Geppert, Carol-Immanuel; Rieker, Ralf; Krammer, Susanne; Leberle, Anna; Neurath, Markus; et al. (Frontiers in Oncology, 2022)
BackgroundLung cancer is the second common cancer type in western countries and has a high mortality. During the development and progression of the tumor, the nutrients in its environment play a central role. The tumor cells depend crucially on glucose metabolism and uptake. Tumor cell metabolism is dominated by the Warburg effect, where tumor cells produce large amounts of lactate from pyruvate under aerobic conditions. We thus reasoned that, reducing carbohydrates in the diet might support anti-tumoral effects of current immunotherapy and additionally target tumor immune escape. ObjectivesThe link between reducing carbohydrates to improve current immunotherapy is not clear. We thus aimed at analyzing the effects of different glucose levels on the tumor development, progression and the anti-tumoral immune response. MethodsWe correlated the clinical parameters of our LUAD cohort with different metabolic markers. Additionally, we performed cell culture experiments with A549 tumor cell line under different glucose levels. Lastly, we investigated the effect of low and high carbohydrate diet in an experimental murine model of lung cancer on the tumor progression and different immune subsets. ResultsHere we found a positive correlation between the body mass index (BMI), blood glucose levels, reduced overall survival (OS) and the expression of Insulin-like growth factor-1 receptor (IGF1R) in the lung tumoral region of patients with lung adenocarcinoma (LUAD). Furthermore, increasing extracellular glucose induced IGF1R expression in A549 LUAD cells. Functional studies in a murine model of LUAD demonstrated that, glucose restricted diet resulted in decreased tumor load in vivo. This finding was associated with increased presence of lung infiltrating cytotoxic CD8+ T effector memory (TEM), tissue resident memory T (TRM) and natural killer cells as well as reduced IGFR mRNA expression, suggesting that glucose restriction regulates lung immunity in the tumor microenvironment. ConclusionsThese results indicate that, glucose restricted diet improves lung immune responses of the host and suppresses tumor growth in experimental lung adenocarcinoma. As glucose levels in LUAD patients were negatively correlated to postoperative survival rates, glucose-restricted diet emerges as therapeutic avenue for patients with LUAD.
CRIS-Team WoS Importer:2022-05-27

Goal-directed-perfusion in neonatal aortic arch surgery - Cesnjevar, Robert; Purbojo, Ariawan; Münch, Frank; Juengert, Joerg; Rueffer, Andre (Translational Pediatrics, 2016)
Reduction of mortality and morbidity in congenital cardiac surgery has always been and remains a major target for the complete team involved. As operative techniques are more and more standardized and refined, surgical risk and associated complication rates have constantly been reduced to an acceptable level but are both still present. Aortic arch surgery in neonates seems to be of particular interest, because perfusion techniques differ widely among institutions and an ideal form of a so called "total body perfusion (TBP)" is somewhat difficult to achieve. Thus concepts of deep hypothermic circulatory arrest (DHCA), regional cerebral perfusion (RCP/with cardioplegic cardiac arrest or on the perfused beating heart) and TBP exist in parallel and all carry an individual risk for organ damage related to perfusion management, chosen core temperature and time on bypass. Patient safety relies more and more on adequate end organ perfusion on cardiopulmonary bypass, especially sensitive organs like the brain, heart, kidney, liver and the gut, whereby on adequate tissue protection, temperature management and oxygen delivery should be visualized and monitored.
EVALuna2:34094

Granulocytapheresis with modified fluid gelatin versus high-molecular-weight hydroxyethyl starch: a matched-pair analysis - Dullinger, Katharina; Pamler, Irene; Brosig, Andreas; Mohrez, Morad; Hähnel, Viola; Offner, Robert; Dormann, Frauke; Becke, Christine; Holler, Ernst; Ahrens, Norbert (Transfusion, 2017)
BACKGROUND: Granulocyte apheresis requires a sedimentation agent. Usually, hydroxyethyl starch (HES) is administered to donors for this purpose and, as granulocyte concentrate (GC) ingredient, also to patients. Authorities recently recommended suspending market authorizations for starch-containing products due to side effects. Therefore, we tested the efficacy of modified fluid gelatin (MFG, Gelafundin 4%) versus hetastarch (Hespan) for GC apheresis. STUDY DESIGN AND METHODS: This retrospective matched-pair analysis compared MFG- and hetastarch-derived GCs. Each group consisted of 15 unrelated male donors mobilized with dexamethasone and granulocyte-colony-stimulating factor for apheresis on 1 or 2 days with the COBE Spectra's PMN program. RESULTS: In each group, 24 GCs were collected from 15 male donors and analyzed. None of the HES-derived products, but two of the MFG-derived products (8.3%), had aggregates and could not be used. The HES-derived products had significantly higher neutrophil counts on the first day (7.7 × 1010/unit vs. 4.0 × 1010/unit; p = 0.00005) as well as second day of apheresis (4.0 × 1010/unit vs. 1.1 × 1010/unit; p = 0.0002). Median white blood cell collection efficacies were lower with MFG than with HES on Day 1 (24% vs. 43%) and Day 2 (15% vs. 37%). Twenty-one percent of the MFG-derived products had less than 1 × 1010granulocytes. CONCLUSION: These results indicate that granulocyte apheresis is feasible with MFG as well as with hetastarch and that the latter is superior for GC production, if used in the same dosage. In addition, aggregates in GC from the COBE Spectra were observed in the MFG group but not in the hetastarch group.
EVALuna2:32781

Grundlagen der Oligometastasierung und Stellenwert der Lokaltherapie - Ricke, J.; Guckenberger, M.; Grützmann, Robert (Onkologe, 2020)
A distinction has traditionally been made in oncology between locally limited and systemically metastasized disease stages, in which local therapies pursued a curative or palliative goal. The term oligometastasis describes a vaguely defined intermediate stage in which randomized studies have demonstrated survival benefits of selected patient groups by using local ablative techniques. Currently, oligometastasis is defined by a limited number of metastases and affected organ systems independent of the tumor entity. Classical empirical evidence of the biological aggressiveness of metastasized tumors, such as disease-free interval or response to chemotherapy is not found in current recommendations. The biological background of a limited metastatic capacity is insufficiently understood as is the detection by biomarkers or gene expression profiles in order to be able to make an even more precise patient selection for a local therapeutic approach in addition to an optimal systemic therapy.
CRIS-Team Scopus Importer:2020-08-07
Keywords: Biomarkers; Chemotherapy; Clinical decision making; Quality of life; Radiotherapy

Guanylate-binding protein 1 expression from embryonal endothelial progenitor cells reduces blood vessel density and cellular apoptosis in an axially vascularised tissue-engineered construct - Bleiziffer, Oliver; Hammon, Matthias; Arkudas, Andreas; Taeger, Christian; Beier, Justus; Amann, Kerstin Ute; Naschberger, Elisabeth; Stürzl, Michael; Horch, Raymund E.; Kneser, Ulrich (BMC Biotechnology, 2012)
Background: Guanylate binding protein-1 (GBP-1) is a large GTPase which is actively secreted by endothelial cells. It is a marker and intracellular inhibitor of endothelial cell proliferation, migration, and invasion. We previously demonstrated that stable expression of GBP-1 in murine endothelial progenitor cells (EPC) induces their premature differentiation and decreases their migration capacity in vitro and in vivo. The goal of the present study was to assess the antiangiogenic capacity of EPC expressing GBP-1 (GBP-1-EPC) and their impact on blood vessel formation in an axially vascularized 3-D bioartificial construct in vivo.Results: Functional in vitro testing demonstrated a significant increase in VEGF secretion by GBP-1-EPC after induction of cell differentiation. Undifferentiated GBP-1-EPC, however, did not secrete increased levels of VEGF compared to undifferentiated control EPC expressing an empty vector (EV-EPC). In our In vivo experiments, we generated axially vascularized tissue-engineered 3-D constructs. The new vascular network arises from an arterio-venous loop (AVL) embedded in a fibrin matrix inside a separation chamber. Total surface area of the construct as calculated from cross sections was larger after transplantation of GBP-1-EPC compared to control EV-EPC. This indicated reduced formation of fibrovascular tissue and less resorption of fibrin matrix compared to constructs containing EV-EPC. Most notably, the ratio of blood vessel surface area over total construct surface area in construct cross sections was significantly reduced in the presence of GBP-1-EPC. This indicates a significant reduction of blood vessel density and thereby inhibition of blood vessel formation from the AVL constructs caused by GBP-1. In addition, GBP-1 expressed from EPC significantly reduced cell apoptosis compared to GBP-1-negative controls.Conclusion: Transgenic EPC expressing the proinflammatory antiangiogenic GTPase GBP-1 can reduce blood vessel density and inhibit apoptosis in a developing bioartificial vascular network and may become a new powerful tool to manipulate angiogenetic processes in tissue engineering and other pathological conditions such as tumour angiogenesis. © 2012 Bleiziffer et al.; licensee BioMed Central Ltd.
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Keywords: Angiogenesis; Endothelial progenitor cells; Guanylate-binding protein 1; In vivo tissue engineering

Guanylate-binding protein-1 expression is selectively induced by inflammatory cytokines and is an activation marker of endothelial cells during inflammatory diseases - Naschberger, Elisabeth; Stürzl, Michael; et al. (American Journal of Pathology, 2002)
During angiogenesis and inflammatory processes, endothelial cells acquire different activation phenotypes, whose identification may help in understanding the complex network of angiogenic and inflammatory interactions in vivo. To this goal we investigated the expression of the human guanylate-binding protein (GBP)-1 that is highly induced by inflammatory cytokines (ICs) and, therefore, may characterize IC-activated cells. Using a new rat monoclonal antibody raised against GBP-1, we show that GBP-1 is a cytoplasmic protein and that its expression in endothelial cells is selectively induced by interferon-γ, interleukin-1α, interleukin-1β, or tumor necrosis factor-α, but not by other cytokines, chemokines, or growth factors. Moreover, we found that GBP-1 expression is highly associated with vascular endothelial cells as confirmed by the simultaneous detection of GBP-1 and the endothelial cell-associated marker CD31 in a broad range of human tissues. Notably, GBP-1 expression was undetectable in the skin, but it was highly induced in vessels of skin diseases with a high-inflammatory component including psoriasis, adverse drug reactions, and Kaposi's sarcoma. These results indicate that GBP-1 is a novel cellular activation marker that characterizes the IC-activated phenotype of endothelial cells.
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Guanylate binding protein-1 inhibits spreading and migration of endothelial cells through induction of integrin α4 expression - Weinlaender, Kristina; Naschberger, Elisabeth; Lehmann, Michael H.; Tripal, Philipp; Paster, Wolfgang; Stockinger, Hannes; Hohenadl, Christine; Stürzl, Michael (The FASEB Journal, 2008)
Human guanylate binding protein-1 (GBP-1) is a large GTPase that is induced by inflammatory cytokines and acts antiangiogenically through the inhibition of endothelial cell proliferation and migration. In this study, we detected that GBP-1-expressing cells show a significantly reduced spreading and migration on fibronectin matrices. Investigating possible mechanisms of these effects, we found that integrin α4 (ITGA4) was consistently up-regulated at both the RNA and protein level in GBP-1-expressing cell cultures. Inhibition of cell spreading and migration by GBP-1 was dependent on the binding of ITGA4 to fibronectin. The inflammatory cytokines IL-1β and TNF-α induced ITGA4 expression in HUVECs and inhibited spreading and migration. Knockdown of GBP-1 by shRNA abrogated inflammatory cytokine induced ITGA4 expression and restored spreading and migration capabilities of the cells. These results show that inhibition of endothelial cell spreading and migration by inflammatory cytokines is mediated by GBP-1 through induction of ITGA4 expression. Endothelial cell migration is a key process during angiogenesis. Therefore, ITGA4 may be a novel molecular target to modulate angiogenesis in human disease. © FASEB.
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Keywords: Angiogenesis; Inflammation; Integrins; Large GTPase

Guanylate binding protein 1-mediated interaction of T cell antigen receptor signaling with the cytoskeleton - Forster, Florian; Paster, Wolfgang; Supper, Verena; Schatzlmaier, Philipp; Sunzenauer, Stefan; Ostler, Nicole; Saliba, Anna; Eckerstorfer, Paul; Britzen-Laurent, Nathalie; Schuetz, Gerhard; Schmid, Johannes A.; Zlabinger, Gerhard J.; et al. (Journal of Immunology, 2014)
GTPases act as important switches in many signaling events in cells. Although small and heterotrimeric G proteins are subjects of intensive studies, little is known about the large IFN-inducible GTPases. In this article, we show that the IFN-?-inducible guanylate binding protein 1 (GBP-1) is a regulator of T cell activation. Silencing of GBP-1 leads to enhanced activation of early T cell Ag receptor/CD3 signaling molecules, including Lck, that is translated to higher IL-2 production. Mass spectrometry analyses showed that regulatory cytoskeletal proteins, like plastin-2 that bundles actin fibers and spectrin ?-chain, brain 1 that links the plasma membrane to the actin cytoskeleton, are binding partners of GBP-1. The spectrin cytoskeleton influences cell spreading and surface expression of TCR/CD3 and the leukocyte phosphatase CD45. We found higher cell spreading and enhanced surface expression of TCR/CD3 and CD45 in GBP-1 silenced T cells that explain their enhanced TCR/CD3 signaling. We conclude that GBP-1 is a downstream processor of IFN-? via which T cells regulate cytoskeleton-dependent cell functions.
EVALuna2:15147

Gynecomastia Surgery in 4996 Male Patients Over 14 Years: A Retrospective Analysis of Surgical Trends, Predictive Risk Factors, and Short-Term Outcomes - Knoedler, Leonard; Knoedler, Samuel; Alfertshofer, Michael; Hansen, Frederik; Schenck, Thilo; Sofo, Giuseppe; Obed, Doha; Hollmann, Katharina; Siegwart, Laura C.; Vollbach, Felix H.; Bigdeli, Amir K.; Kauke-Navarro, Martin; et al. (Aesthetic Plastic Surgery, 2024)
Background: The high prevalence of benign male breast tissue enlargement (gynecomastia) has resulted in a marked increase of gynecomastia cases. While about one third of male adults experience some form of gynecomastia, gynecomastia surgery (GS) outcome research is limited to small study populations and single-center/-surgeon databases. In this study, we aimed to access the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database to identify preoperative risk factors for complications and investigate postoperative outcomes of GS. Methods: In this retrospective study, we queried the ACS-NSQIP database from 2008 to 2021 to identify male adult patients who underwent GS. Postoperative outcomes involved the occurrence of any, surgical and medical complications, as well as reoperation, readmission, and mortality within a 30-day postoperative time period. Univariable and multivariable assessment were performed to identify risk factors for complications while adjusting for possible confounders. Results: The study included 4,996 GS patients with a mean age of 33.7 ± 15 years and BMI of 28.2 ± 5.1 kg/m2. White patients constituted 54% (n = 2713) of the cohort, and 27% (n = 1346) were obese. Except for 2020, there was a steady increase in GS cases over the study period. Outpatient surgeries were most common at 95% (n = 4730), while general surgeons performed the majority of GS (n = 3580; 72%). Postoperatively, 91% (n = 4538) of patients were discharged home; 4.4% (n = 222) experienced any complications. Multivariable analysis identified inpatient setting (p < 0.001), BMI (p = 0.023), prior sepsis (p = 0.018), and bleeding disorders (p = 0.047) as independent risk factors for complications. Conclusion: In this study, we analyzed 4996 male adult GS patients from the ACS-NSQIP database, revealing an increased caseload and significant general surgeon involvement. Risk factors like bleeding disorders, inpatient status, and prior sepsis were linked to postoperative complications, while BMI was crucial for predicting adverse events. Overall, our findings may aid in enhancing patient care through advanced preoperative screening and closer perioperative management. Level of Evidence III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.
CRIS-Team Scopus Importer:2024-06-21
Keywords: ACS-NSQIP; Big data database; Gynecomastia; Gynecomastia surgery; Male breast enlargement; Risk factors

Halitosis in Oral and Maxillofacial Surgery Patients-a Pilot Study - Willershausen, Ines; Krautkremer, Franziska; Sagheb, Kawe; Weider, Matthias; Weusmann, Jens; Mittermeier, Fabienna; Erhard, Julia; Sagheb, Keyvan; Gölz, Lina; Walter, Christian (Clinical Laboratory, 2021)
Background: Halitosis is a relatively inhomogeneous pathology with an extremely high prevalence in the population. Potential risk factors for bad breath include bacterial decomposition of organic material as well as numerous general and systemic diseases. The aim of the present study was to analyze whether certain subgroups of oral and maxillofacial surgery patients have a higher risk of halitosis. Further the impact of halitosis on the patient's quality of life was ascertained.
CRIS-Team WoS Importer:2021-12-10

Hattori-Zyste – eine seltene Läsion im posterioren Mediastinum - Elsner, Felix; Khamitov, Koblandy; Hinsen, Maximilian; Sirbu, Horia; Hartmann, Arndt (Die Pathologie, 2024)
CRIS-Team Scopus Importer:2024-05-24

Health related Quality of Life over time in German sarcoma patients. An analysis of associated factors - results of the PROSa study - Eichler, Martin; Hentschel, Leopold; Singer, Susanne; Hornemann, Beate; Richter, Stephan; Hofbauer, Christine; Hohenberger, Peter; Kasper, Bernd; Andreou, Dimosthenis; Pink, Daniel; Jakob, Jens; Grützmann, Robert; et al. (Frontiers in Endocrinology, 2023)
Introduction: Sarcomas are rare cancers and very heterogeneous in their location, histological subtype, and treatment. Health-Related Quality of Life (HRQoL) of sarcoma patients has rarely been investigated in longitudinal studies. Methods: Here, we assessed adult sarcoma patients and survivors between September 2017 and February 2020, and followed-up for one year in 39 study centers in Germany. Follow-up time points were 6 (t1) and 12 months (t2) after inclusion. We used a standardized, validated questionnaire (the European Organisation for Research and Treatment of Cancer Quality of Life Core Instrument (EORTC QLQ-C30) and explored predictors of HRQoL in two populations (all patients (Analysis 1), patients in ongoing complete remission (Analysis 2)) using generalized linear mixed models. Results: In total we included up to 1111 patients at baseline (915 at t1, and 847 at t2), thereof 387 participants were in complete remission at baseline (334 at t1, and 200 at t2). When analyzing all patients, HRQoL differed with regard to tumor locations: patients with sarcoma in lower extremities reported lower HRQoL values than patients with sarcomas in the upper extremities. Treatment which included radiotherapy and/or systemic therapy was associated with lower HRQoL. For patients in complete remission, smoking was associated with worse HRQoL-outcomes. In both analyses, bone sarcomas were associated with the worst HRQoL values. Being female, in the age group 55-<65 years, having lower socioeconomic status, and comorbidities were all associated with a lower HRQoL, in both analyses. Discussion: HRQoL increased partially over time since treatment and with sporting activities. HRQoL improved with time since treatment, although not in all domains, and was associated with lifestyle and socioeconomic factors. Bone sarcomas were the most affected subgroup. Methods to preserve and improve HRQoL should be developed for sarcoma patients.
CRIS-Team Scopus Importer:2023-09-22
Keywords: EORTC QLQ-C30; GIST; health-related quality of life; longitudinal observational cohort; patient reported outcomes; sarcoma

HHV-8 and multistep tumorigenesis. - Ensoli, Barbara; Stürzl, Michael (Trends in Microbiology, 1999)
Human herpesvirus 8 [HHV-8 or Kaposi’s sarcoma-associated herpesvirus (KSHV)] is associated with pleural effusion lymphoma (PEL), multicentric Castleman’s disease (MCD) and Kaposi’s sarcoma (KS) 1. These diseases are rare, but HHV-8 can infect more than 50% of the general population, depending on the geographical area. This indicates that additional factors are required for HHV-8 pathogenicity 1. This is not surprising, as the concept of multistep tumorigenesis is now generally accepted and it does not rule out an etiologic role for HHV-8 in tumor development.
Keywords: Virology; Microbiology; Cell biology; Kaposi's sarcoma; Human herpesvirus-8; Cytokine; Angiogenesis; Pleural effusion lymphomas; Multicentric Castelman's disease

HiatoGast 1: An exploring, semiblinded trial establishing a new endoscopical categorisation of axial hiatal hernias - Eckhardt, Daniel; Engel, Matthias; Golcher, Henriette; Krautz, Christian; Grützmann, Robert; Elshafei, Moustafa (BMJ Global Health, 2019)
Introduction Axial hiatal hernias are a common incidental finding in endoscopical examinations, but reflux symptoms do not necessarily correspond to the presence of hiatal hernias. Diagnosing a reflux disease is difficult due to a leak of existing distinct criteria, especially in order to evaluate a surgical indication. Also a preoperative measurement of the hernia is necessary to choose between surgical options. Methods and analysis We planned a semiblinded trial including a questionnaire and an oesophagogastroduodenoscopy afterwards. While the endoscopy is done, the hiatus oesophagi should be measured in inversion technique under maximum insufflation including length, width and herniated volume. A sample of 210 participants until December 2020 is determined to evaluate the primary endpoint: we look forward to evaluate the anatomical parameters of reflux and non-reflux participants. Ethics and Dissemination The study has been approved by the local ethics committee on 12th February 2019, the data will bei published after closure of inclusion. Trial registration number German Clinical Trials Register (DRKS00016863).
CRIS-Team Scopus Importer:2019-07-02
Keywords: endoscopical technique; gastroscopy; hiatal hernia; reflux

High locoregional Control Rates after Radio (chemo) Therapy in anaplastic Thyroid Carcinoma - a monocentric Analysis - Schmied, M.; Semrau, Sabine; Hecht, Markus; Lettmaier, Sebastian; Mantsopoulos, K.; Traxdorf, Maximilian; Iro, Heinrich; Denz, Axel; Grützmann, Robert; Fietkau, Rainer; Haderlein, Marlen (STRAHLENTHERAPIE UND ONKOLOGIE, 2020)
CRIS-Team WoS Importer:2020-10-02

High throughput screening of gene functions in mammalian cells using reversely transfected cell arrays: review and protocol. - Stürzl, Michael; Konrad, Andreas; Sander, Gaby; Wies, Effi; Neipel, Frank; Naschberger, Elisabeth; Reipschlaeger, Simone; Gonin-Laurent, Nathalie; Horch, Raymund E.; Kneser, Ulrich; Hohenberger, Werner; Erfle, Holger; et al. (Combinatorial Chemistry & High Throughput Screening, 2008)
Reversely transfected cell microarrays (RTCM) have been introduced as a method for parallel high throughput analysis of gene functions in mammalian cells. Hundreds to thousands of different recombinant DNA or RNA molecules can be transfected into different cell clusters at the same time on a single glass slide with this method. This allows either the simultaneous overexpression or–by using the recently developed RNA interference (RNAi) techniques–knockdown of a huge number of target genes. A growing number of sophisticated detection systems have been established to determine quantitatively the effects of the transfected molecules on the cell phenotype. Several different cell types have been successfully used for this procedure. This review summarizes the presently available knowledge on this technique and provides a laboratory protocol.

Histamine in atrial fibrillation (AF)–is there any connection? Results from an unselected population - Layritz, C. M.; Hagel, Alexander; Graf, V.; Reiser, C.; Klinghammer, Lutz; Ropers, Dieter; Achenbach, Susanne; Raithel, M. (International Journal of Cardiology, 2014)
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Histology-Depended Pattern of Patho-Histological Response After Induction Therapy in Locally Advanced Non-Small Cell Lung Cancer - Schreiner, Waldemar; Dudek, Wojciech; Rieker, Ralf; Fietkau, Rainer; Sirbu, Horia (JOURNAL OF THORACIC ONCOLOGY, 2019)
CRIS-Team WoS Importer:2019-11-08

HIV-1 Tat increases the adhesion of monocytes and T-cells to the endothelium in vitro and in vivo: implications for AIDS-associated vasculopathy. - Matzen, Kathrin; Dirkx, Anita E.M; Egbrink, Mirjam G.Aoude; Speth, Cornelia; Götte, Matthias; Ascherl, Gudrun; Grimm, Thomas; Griffioen, Arjan W; Stürzl, Michael (Virus Research, 2004)
HIV-1-infected patients exhibit severe damages of the aortic endothelium, develop angioproliferative lesions such as Kaposi's sarcoma (KS), and have an increased risk of cardiovascular diseases and atherosclerosis. An increased adhesion of leukocytes to the endothelium is a common pathogenic parameter of AIDS-associated vascular diseases. Here we show that the HIV-1 Tat protein, a regulatory protein of HIV-1 released by infected cells, and TNF-alpha, a cytokine increased in sera and tissues of HIV-1-infected patients, activate synergistically the adhesion of leukocytes to endothelial cells both in vitro and in vivo. This effect is selectively mediated by HIV-1 Tat, since HIV-1 Nef, another HIV-1 regulatory protein, and the HIV-1 envelope protein gp41, had no effect. In vitro adhesion assays with PBMC and quantitative cell type analysis of adherent cells by FACS demonstrated that HIV-1 Tat selectively activates the adhesion of T-cells and monocytes but not of B-cells. Intravital microscopic studies in mice confirmed the synergistic activity of HIV-1 Tat and TNF-alpha on leukocyte adhesion to the endothelium in vivo. These data indicate that HIV-1 Tat in cooperation with TNF-alpha may contribute to the vascular damage and cardiovascular diseases observed in AIDS patients but also to the prominent extravasation of T-cells and monocytes which is a key process in the formation and progression of KS lesions.

HLA-C*04:09N is expressed at the cell surface and triggers peptide-specific T-cell activation. - Welters, Carlotta; Welters, Marthe Lina; Stadler, Serena; Bullinger, Lars; Strobel, Julian; Hackstein, Holger; Dhamodaran, Arunraj; Blankenstein, Thomas; Hansmann, Leo (Haematologica, 2024)
The null allele HLA-C*04:09N differs from HLA-C*04:01 in a frameshift mutation within its cytoplasmic domain, resulting in translation of 32 additional amino acids that are assumed to prevent cell surface expression. However, we recently identified a multiple myeloma-reactive T-cell receptor (TCR) that appeared to recognize antigen presented on HLA-C*04:09N and encouraged us to ask whether HLA-C*04:09N, albeit not easily detectable at the cell surface, can present antigen sufficient for T-cell activation. We generated two HLA-class I-deficient cell lines, re-expressed HLAC* 04:09N, detected HLA expression by flow cytometry, and tested for T-cell activation using a cytomegalovirus peptide- specific HLA-C*04:01-restricted TCR. In both cell lines, HLA-C*04:09N expression was detectable at the cell surface and could be enhanced by IFN-γ exposure. Recombinant HLA-C*04:09N expression was sufficient for T-cell activation in vitro, which could be blocked by an HLA-class I-specific antibody, suggesting HLA-TCR interaction at the cell surface. Peripheral blood mononuclear cells isolated from an individual who physiologically expressed HLA-C*04:09N triggered peptide-specific T-cell activation, confirming our results with cells with natural HLA expression levels. In conclusion, we present peptide-specific HLA-C*04:09N-restricted T-cell activation and suggest consideration of this allele in the appropriate clinical context, such as allogeneic stem cell transplantation, or in the setting of cellular therapy.
EVALuna2:540386

HNF4A and GATA6 Loss Reveals Therapeutically Actionable Subtypes in Pancreatic Cancer - Brunton, Holly; Caligiuri, Giuseppina; Cunningham, Richard; Upstill-Goddard, Rosie; Bailey, Ulla Maja; Garner, Ian M.; Nourse, Craig; Dreyer, Stephan; Jones, Marc; Moran-Jones, Kim; Wright, Derek W.; Paulus-Hock, Viola; et al. (Cell Reports, 2020)
Pancreatic ductal adenocarcinoma (PDAC) can be divided into transcriptomic subtypes with two broad lineages referred to as classical (pancreatic) and squamous. We find that these two subtypes are driven by distinct metabolic phenotypes. Loss of genes that drive endodermal lineage specification, HNF4A and GATA6, switch metabolic profiles from classical (pancreatic) to predominantly squamous, with glycogen synthase kinase 3 beta (GSK3β) a key regulator of glycolysis. Pharmacological inhibition of GSK3β results in selective sensitivity in the squamous subtype; however, a subset of these squamous patient-derived cell lines (PDCLs) acquires rapid drug tolerance. Using chromatin accessibility maps, we demonstrate that the squamous subtype can be further classified using chromatin accessibility to predict responsiveness and tolerance to GSK3β inhibitors. Our findings demonstrate that distinct patterns of chromatin accessibility can be used to identify patient subgroups that are indistinguishable by gene expression profiles, highlighting the utility of chromatin-based biomarkers for patient selection in the treatment of PDAC. Brunton et al. demonstrate that differential chromatin accessibility can predict responsiveness and tolerance to GSK3β inhibitors in the squamous subtype of PDAC. This study provides an important proof of concept that chromatin accessibility can be used to identify additional PDAC subgroups with potential therapeutic utility.
CRIS-Team Scopus Importer:2020-05-19
Keywords: chromatin landscapes; GATA6; GSK3B; HNF4A; intronic and distal promoters; metabolic targeting; PDAC subtypes; therapeutic tolerance

Hospital Volume, In-Hospital Mortality, and Failure to Rescue in Esophageal Surgery - Nimptsch, Ulrike; Haist, Thomas; Krautz, Christian; Grützmann, Robert; Mansky, Thomas; Lorenz, Dietmar (Deutsches Ärzteblatt international, 2018)
BACKGROUND: In Germany, complex esophageal surgery is often performed in hospitals with low case numbers. For these procedures, an association exists between hospital case numbers and treatment outcomes, possibly because of differences in complication management. This aspect of the association between volume and outcome in esophageal surgery has not yet been studied in Germany. METHODS: On the basis of nationwide hospital discharge data (DRG statistics) from the years 2010 to 2015, the association between volume and outcome was analyzed in relation to in-hospital mortality, the frequency of complications, and the mortality of patients who had complications. RESULTS: 22 700 cases of complex esophageal surgery were identified. The probability of dying after esophageal surgery was much lower in hospitals with very high case numbers (median, 62 per year) than in those with very low case numbers (median, two per year), with an odds ratio (OR) of 0.50 (95% confidence interval, [0.42; 0.60]). At least one complication was documented for more than half of all patients; no association was found between the frequency of complications and the hospital case volume. The in-hospital mortality among patients who had complications was 12.3% [11.1; 13.7] in hospitals with very high case numbers and 20.0% [18.5; 21.6] in hospitals with very low case numbers. Of the 4032 procedures performed in 2015, 83% were for cancer of the esophagus. CONCLUSION: These findings indicate that the quality of care for patients undergoing esophageal surgery in Germany could be improved if more patients were treated in hospitals with high case numbers. The observed association between case numbers and outcomes is tightly linked to failure to rescue.
EVALuna2:210705

How German vascular surgeons and angiologists judge walking exercise for patients with PAD: Results from a nationwide survey amongst 743 members of two major scientific societies - Rother, Ulrich; Dörr, Gesine; Malyar, Nasser; Müller, Oliver J.; Steinbauer, Markus; Ito, Wulf; Cotta, Livia; Espinola-Klein, Christine; Heckenkamp, Jörg; Behrendt, Christian Alexander (Vasa-Journal of Vascular Diseases, 2023)
Background: To determine the physician s perspective and perception on walking exercise as well as barriers in guideline-directed best medical treatment of patients with lower extremity peripheral arterial disease (PAD). Patients and methods: All members of the German Society for Vascular Surgery and Vascular Medicine and of the German Society for Angiology Society for Vascular Medicine with valid email address were invited to participate in an electronic survey on walking exercise for treatment of intermittent claudication that was developed by the authors. Results: Amongst 3910 invited participants, 743 (19%) provided valid responses (33% females, 84% vascular surgery, 15% angiology). Thereof, 65% were employed by non-university hospitals, 16% by university institutions, and 18% by outpatient facilities. A mean of 14 minutes were spent per patient to counsel and educate, while only 53% responded they had enough time in everyday clinical practice. While 98% were aware of the beneficial impact of structured exercise training (SET) on pain free walking distance and 90% advise their patients to adhere to SET, only 44% provided useful guidance to patients to find local SET programmes and merely 42% knew how to prescribe SET as service that can be reimbursed by medical insurances. Approximately 35% knew a local SET programme and appropriate contact person. Health-related quality of life was assessed in a structured way by only 11%. Forty-seven percent responded that medical insurances should be responsible to implement and maintain SET programmes, while only 4% held hospital physicians responsible to achieve this task. Conclusions: This nationwide survey study amongst vascular specialists illustrates the current insufficient utilisation of SET as an evidence-based therapeutic cornerstone in patients with lower extremity PAD in Germany. The study also identified several barriers and flaws from the physician s perspectives which should be addressed collectively by all health care providers aiming to increase the SET use and eventually its impact on patients with PAD.
CRIS-Team Scopus Importer:2023-07-21
Keywords: best medical treatment; health behaviour; health services research; intermittent claudication; peripheral arterial disease; Walking exercise

HPA Frequencies in the Syrian Population - Hauck-Dlimi, Barbara; Damrah, Nouraldin; Achenbach, Susanne; Zimmermann, Robert; Zingsem, Jürgen; Ott, Stephan; Strobel, Joachim (Clinical Laboratory, 2019)
Background: Exposure to allogenic Human Platelet Antigens (HPAs) can lead to antibody formation causing different immunological reactions. Frequencies of common HPA antigens differ between ethnic groups and should be known to calculate potential alloimmunization risk. Syrian refugees are the largest group of applicants for asylum in Germany in 2017. However, no study on HPA antigen frequencies in the Syrian population exists.
CRIS-Team WoS Importer:2019-03-22

Human glycoprotein-2 expressed in Brunner glands – A putative autoimmune target and link between Crohn's and coeliac disease - Roggenbuck, Dirk; Goihl, Alexander; Sowa, Mandy; Lopens, Steffi; Rödiger, Stefan; Schierack, Peter; Conrad, Karsten; Sommer, Ulrich; Jöhrens, Korinna; Grützmann, Robert; Reinhold, Dirk; Laass, Martin W. (Clinical Immunology, 2023)
Glycoprotein 2 (GP2) is an autoantigen in Crohn's (CD) and coeliac disease (CeD). We assessed GP2-isoform (GP21–4)-expression in intestinal biopsies of paediatric patients with CD, CeD, ulcerative colitis (UC), and healthy children (HC). Transcription of GP21–4 was elevated in proximal small intestine in CeD and CD patients (only GP22/4) compared to jejunum (CeD/CD) and large bowel (CD). CeD patients demonstrated higher duodenal GP22/4-mRNA levels compared to HC/UC patients whereas CD patients showed higher GP24-mRNA levels compared to UC patients. Duodenal synthesis of only small GP2 isoforms (GP23/4) was demonstrated in epithelial cells in patients/HC and in Brunner glands (also large isoforms) with a more frequent apical location in CD/CeD patients. All four GP2 isoforms interacted with gliadin and phosphopeptidomannan. Gliadin digestion improved binding to GP2 isoforms. GP21–4 binding to CeD/CD-related antigens, elevated duodenal GP21–4-mRNA transcription, and GP2-protein secretion in Brunner glands of CeD/CD patients suggest an autoimmune CeD/CD link.
CRIS-Team Scopus Importer:2023-02-24
Keywords: Celiac disease; Crohn's disease; Zymogen granule membrane glycoprotein GP2

Human guanylate binding protein-1 (hGBP-1) characterizes and establishes a non-angiogenic endothelial cell activation phenotype in inflammatory diseases - Naschberger, Elisabeth; Stürzl, Michael; et al. (Advances in Enzyme Regulation, 2005)
Blood vessel activation in inflammatory diseases is triggered by a myriad of different factors that partially reveal opposite activities on endothelial cells (EC). For example, inflammatory cytokines (IC) inhibit EC proliferation and induce cell adhesiveness for leukocytes. In contrast, angiogenic growth factors (AGF) activate EC proliferation and inhibit cell adhesiveness for leukocytes. In consequence, IC and AGF may induce two different activation phenotypes in EC that appear in a temporally and/or spatially coordinated manner in inflammatory tissues. Human guanylate binding protein-1 (hGBP-1) is a member of the large GTPase protein family. New results demonstrate that hGBP-1 is a specific marker of IC-activated EC that allows to differentiate the IC- and AGF-activated phenotype of EC at the single cell level, both in vitro and in vivo. In addition, hGBP-1 is the key mediator of the inhibitory effects of IC on EC proliferation and invasiveness. Both the expression pattern of hGBP-1 and its activity in EC supported the hypothesis that IC- and AGF-activation induce distinct adversely related phenotypes in EC. In future, hGBP-1 may be used as a marker to monitor the IC-induced phenotype of EC in inflammation and may also be exploited as a target to modulate EC activity in inflammatory diseases and tumor angiogenesis. © 2005 Elsevier Ltd. All rights reserved.
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Human guanylate binding protein-1 is a secreted GTPase present in increased concentrations in the cerebrospinal fluid of patients with bacterial meningitis - Naschberger, Elisabeth; Stürzl, Michael; et al. (American Journal of Pathology, 2006)
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Human herpesvirus-8 and Kaposi's sarcoma: relationship with the multistep concept of tumorigenesis. - Stürzl, Michael; Zietz, Christian; Monini, Paolo; Ensoli, Barbara (Advances in Cancer Research, 2001)
Kaposi's sarcoma (KS) develops through discrete inflammatory-angiogenic stages of polyclonal nature (early-stage lesions) to monomorphic nodules of spindle-shaped cells that can be clonal (late-stage lesions) and resemble true sarcomas. Molecular and epidemiological studies indicate that development of KS is tightly associated with infection by the human herpesvirus-8 (HHV-8). However, only individuals with specific conditions of immunodysregulation develop KS. In these individuals the systemic and tissue increase of Th-1-type cytokines (IC) reactivate HHV-8 infection, leading to increased viral load, antibody titers, and an expanded cell tropism that precedes the clinical appearance of KS. Recruitment of the virus into tissues by infected monocytes and other cell types is facilitated by the endothelial cell activation due to IC. In clinical lesions, HHV-8 infection increases with lesion stage and in late-stage lesions most of the spindle cells are latently infected, whereas only few lyrically infected cells are present, suggesting that latent genes may have a role in the transformation of the early inflammatory-hyperplastic lesion into a real sarcoma. The development of tumors, however, is regulated through a multistep process based on the acquisition by cells of several different capabilities leading to malignant growth. Here we review the available data on the expression of HHV-8-encoded genes in primary KS lesions and, in view of their biological activity, analyze their potential function in different steps of tumorigenesis. By this pragmatic approach interesting insights into potential key functions of HHV-8-encoded genes are found and steps of potential cooperativity with other viral factors (HIV-1-Tat) in the pathogenesis of KS are identified.

Human herpesvirus-8 (HHV-8) gene expression in Kaposi's sarcoma (KS) primary lesions: an in situ hybridization study. - Stürzl, Michael; Wunderlich, A; Ascherl, Gudrun; Hohenadl, C; Monini, Paolo; Zietz, Christian; Browning, Philip J.; Neipel, Frank; Biberfeld, Peter; Ensoli, Barbara (Leukemia, 1999)

Human Neutrophil Alloantigen Genotype Frequencies Among Syrian Population - Hauck-Dlimi, Barbara; Damrah, Mohammed; Achenbach, Susanne; Ott, Stephan; Zimmermann, Robert; Zingsem, Jürgen; Strobel, Julian (Clinical Laboratory, 2018)
BACKGROUND: Human neutrophil antigens (HNA) are able to provoke allo- and autoimmune antibodies which lead to reactions like autoimmune and neonatal neutropenia. However, until now no data about HNA genotype distribution in Syrian population exists. The aim of this study was to determine the HNA allele frequencies in the largest group asking for asylum in Germany since 2015. Allele frequencies were compared to data from German blood donors. Therefore, we calculated the risk of alloimmunization and associated transfusion reactions, as well as the risk of developing neonatal neutropenia for newborns of mixed race couples. METHODS: We isolated DNA from blood samples of 100 Syrian volunteers and typed them for HNA-1, -3, -4, and -5 by using a commercial polymerase chain reaction kit with sequence-specific primers (SSP-PCR). Then, we compared the HNA genotype distribution with data from Germans and different populations from literature. RESULTS: In Syrian population the gene frequencies for HNA-1a, HNA-1b, and HNA-1c were 0.375, 0.580, and 0.040, for HNA-3a and -3b 0.742 and 0.258, for HNA-4a and -4b 0.860 and 0.140, and for HNA-5a and -5bw 0.660 and 0.340, respectively. No statistically significant differences between Syrian and German gene frequencies were found. CONCLUSIONS: This study is the first to report HNA gene frequencies in Syrian population. There is no significant difference of HNA genotype frequencies compared to the German population. Therefore, no elevated alloimmunization risks in transfusion of blood and blood components and in pregnancy of mixed race couples exist.
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Human T cells loaded with superparamagnetic iron oxide nanoparticles retain antigen-specific TCR functionality. - Pfister, Felix; Dörrie, Jan; Schaft, Niels; Buchele, Vera; Unterweger, Harald; Carnell, Lucas R.; Schreier, Patrick; Stein, René; Kubánková, Markéta; Guck, Jochen; Hackstein, Holger; Alexiou, Christoph; et al. (Frontiers in Immunology, 2023)
BACKGROUND: Immunotherapy of cancer is an emerging field with the potential to improve long-term survival. Thus far, adoptive transfer of tumor-specific T cells represents an effective treatment option for tumors of the hematological system such as lymphoma, leukemia or myeloma. However, in solid tumors, treatment efficacy is low owing to the immunosuppressive microenvironment, on-target/off-tumor toxicity, limited extravasation out of the blood vessel, or ineffective trafficking of T cells into the tumor region. Superparamagnetic iron oxide nanoparticles (SPIONs) can make cells magnetically controllable for the site-specific enrichment. METHODS: In this study, we investigated the influence of SPION-loading on primary human T cells for the magnetically targeted adoptive T cell therapy. For this, we analyzed cellular mechanics and the T cell response after stimulation via an exogenous T cell receptor (TCR) specific for the melanoma antigen MelanA or the endogenous TCR specific for the cytomegalovirus antigen pp65 and compared them to T cells that had not received SPIONs. RESULTS: SPION-loading of human T cells showed no influence on cellular mechanics, therefore retaining their ability to deform to external pressure. Additionally, SPION-loading did not impair the T cell proliferation, expression of activation markers, cytokine secretion, and tumor cell killing after antigen-specific activation mediated by the TCR. CONCLUSION: In summary, we demonstrated that SPION-loading of T cells did not affect cellular mechanics or the functionality of the endogenous or an exogenous TCR, which allows future approaches using SPIONs for the magnetically enrichment of T cells in solid tumors.
EVALuna2:539766
Keywords: Adoptive T cell therapy; superparamagnetic iron oxide nanoparticles (SPIONs); antigen-specific T cell response; targeted immune therapy; cell deformability

Hybrid ultrasound and single wavelength optoacoustic imaging reveals muscle degeneration in peripheral artery disease - Träger, Anna P.; Günther, Josefine; Raming, Roman; Paulus, Lars-Philip; Lang, Werner; Meyer, Alexander; Kempf, Julius; Caranovic, Milenko; Li, Yi; Wagner, Alexandra; Tan, Lina; Danko, Vera; et al. (Photoacoustics, 2024)
Peripheral arterial disease (PAD) leads to chronic vascular occlusion and results in end organ damage in critically perfused limbs. There are currently no clinical methods available to determine the muscular damage induced by chronic mal-perfusion. This monocentric prospective cross-sectional study investigated n = 193 adults, healthy to severe PAD, in order to quantify the degree of calf muscle degeneration caused by PAD using a non-invasive hybrid ultrasound and single wavelength optoacoustic imaging (US/SWL-OAI) approach. While US provides morphologic information, SWL-OAI visualizes the absorption of pulsed laser light and the resulting sound waves from molecules undergoing thermoelastic expansion. US/SWL-OAI was compared to multispectral data, clinical disease severity, angiographic findings, phantom experiments, and histological examinations from calf muscle biopsies. We were able to show that synergistic use of US/SWL-OAI is most likely to map clinical degeneration of the muscle and progressive PAD.
CRIS-Team Scopus Importer:2023-12-15
Keywords: Muscle degeneration; Muscle imaging; Optoacoustics; Peripheral artery disease; Photoacoustics

Hypermutation In Pancreatic Cancer - Humphris, Jeremy L.; Patch, Ann-Marie; Nones, Katia; Bailey, Peter J.; Johns, Amber L.; Mckay, Skye; Chang, David K.; Miller, David K.; Pajic, Marina; Kassahn, Karin S.; Quinn, Michael C. J.; Bruxner, Timothy J. C.; et al. (Gastroenterology, 2017)
Pancreatic cancer is molecularly diverse, with few effective therapies. Increased mutation burden and defective DNA repair are associated with response to immune checkpoint inhibitors in several other cancer types. We interrogated 385 pancreatic cancer genomes to define hypermutation and its causes. Mutational signatures inferring defects in DNA repair were enriched in those with the highest mutation burdens. Mismatch repair deficiency was identified in 1% of tumors harboring different mechanisms of somatic inactivation of MLH1 and MSH2. Defining mutation load in individual pancreatic cancers and the optimal assay for patient selection may inform clinical trial design for immunotherapy in pancreatic cancer.
EVALuna2:15259

Hypoxia generates a more invasive phenotype of tumour cells: An in vivo experimental setup based on the chorioallantoic membrane - Demir, Resit; Naschberger, Elisabeth; Demir, Ilknur; Melling, Nathaniel; Dimmler, Arno; Papadopoulus, Thomas; Stürzl, Michael; Klein, Peter; Hohenberger, Werner (Pathology & Oncology Research, 2009)
Of all processes involved in carcinogenesis, local invasion and the formation of metastases are the clinically most relevant but the scientifically least well understood at their molecular level. Recent experimental progress has identified that tumour hypoxia not only induces tumour angiogenesis, but also modulates the expression of several genes that have been implicated in tumour invasion and metastasis. Here we developed an in vivo model to understand a number of molecular pathways and cellular mechanisms for tumour invasion in hypoxia. For this purpose fertilized chicken eggs were incubated for 10 days in normoxic conditions. Subsequently colon carcinoma cells (SW-480) were placed on the chorioallantoic membrane. During the following 6 days the eggs were incubated either in normoxic conditions or in stepwise decreasing hypoxic conditions. SW-480 colon carcinoma cells did not invade the epithelial layer in normoxic conditions. In contrast an invasion through the epithelial layer in to the mesoderm was already seen after 3 days when incubated in hypoxic conditions. The chorioallantoic membrane assay described in this paper allows investigating tumour invasion and its cellular mechanisms under defined hypoxic conditions. © 2008 Arányi Lajos Foundation.
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Keywords: Chorioallantoic membrane; Hypoxia; Tumor progression; Tumour invasion

Identification and validation of a multivariable prediction model based on blood plasma and serum metabolomics for the distinction of chronic pancreatitis subjects from non-pancreas disease control subjects - Adam, M. Gordian; Beyer, Georg; Christiansen, Nicole; Kamlage, Beate; Pilarsky, Christian; Distler, Marius; Fahlbusch, Tim; Chromik, Ansgar; Klein, Fritz; Bahra, Marcus; Uhl, Waldemar; Grützmann, Robert; et al. (Gut, 2021)
Objective Chronic pancreatitis (CP) is a fibroinflammatory syndrome leading to organ dysfunction, chronic pain, an increased risk for pancreatic cancer and considerable morbidity. Due to a lack of specific biomarkers, diagnosis is based on symptoms and specific but insensitive imaging features, preventing an early diagnosis and appropriate management. Design We conducted a type 3 study for multivariable prediction for individual prognosis according to the TRIPOD guidelines. A signature to distinguish CP from controls (n=160) was identified using gas chromatography-mass spectrometry and liquid chromatography-tandem mass spectrometry on ethylenediaminetetraacetic acid (EDTA)-plasma and validated in independent cohorts. Results A Naive Bayes algorithm identified eight metabolites of six ontology classes. After algorithm training and computation of optimal cut-offs, classification according to the metabolic signature detected CP with an area under the curve (AUC) of 0.85 ((95% CI 0.79 to 0.91). External validation in two independent cohorts (total n=502) resulted in similar accuracy for detection of CP compared with non-pancreatic controls in EDTA-plasma (AUC 0.85 (95% CI 0.81 to 0.89)) and serum (AUC 0.87 (95% CI 0.81 to 0.95)). Conclusions This is the first study that identifies and independently validates a metabolomic signature in plasma and serum for the diagnosis of CP in large, prospective cohorts. The results could provide the basis for the development of the first routine laboratory test for CP.
CRIS-Team WoS Importer:2021-11-05

Identification of Genes Associated with Liver Metastasis in Pancreatic Cancer Reveals PCSK6 as a Crucial Mediator - He, Hang; Zhang, Shuman; Yang, Hai; Xu, Pengyan; Kutschick, Isabella; Pfeffer, Sina; Britzen-Laurent, Nathalie; Grützmann, Robert; Fu, Deliang; Pilarsky, Christian (Cancers, 2023)
Liver metastasis occurs frequently in patients with pancreatic cancer. We analyzed the molecular profiling in liver metastatic lesions aiming to uncover novel genes responsible for tumor progression. Bioinformatics analysis was applied to identify genes directing liver metastasis. CRISPR/Cas9 technology was used to knock out the candidate gene. Proliferation assays, colony formation assays, cell cycle analysis, migration assays, wound healing assays, Immunofluorescence analysis, and the tumor xenograft model of intrasplenic injection were adopted to evaluate the effects of PCSK6 inactivation on cell growth, migration and liver metastasis. GSEA and Western blot were used to investigate the corresponding signaling pathway. PCSK6 was one of the obtained liver-metastasis-related genes in pancreatic cancer. PCSK6 inactivation inhibited cell growth and cell migration, due to G0/G1 cell cycle arrest and the remodeling of cell–cell junctions or the cell skeleton, respectively. PCSK6 inactivation led to fewer counts and lower outgrowth rates of liver metastatic niches in vivo. The Raf-MEK1/2-ERK1/2 axis was repressed by PCSK6 inactivation. Accordingly, we found PCSK6 inactivation could inhibit cell growth, cell migration, and liver metastasis, and explored the role of the Raf-MEK1/2-ERK1/2 axis in PCSK6 inactivation. PCSK6-targeted therapy might represent a novel approach for combatting liver metastasis in pancreatic cancer.
CRIS-Team Scopus Importer:2023-01-20
Keywords: CRISPR/Cas9; ERK; liver metastasis; PCSK6

Identification of interleukin-1 and platelet-derived growth factor-B as major mitogens for the spindle cells of Kaposi's sarcoma: a combined in vitro and in vivo analysis. - Stürzl, Michael; Brandstetter, H; Zietz, Christian; Eisenburg, B; Raivich, G; Gearing, D P; Brockmeyer, Norbert H.; Hofschneider, Peter Hans (Oncogene, 1995)
By means of a combined in vitro and in vivo analysis we provide evidence that IL-1 beta and PDGF-B, but not OSM (oncostatin M) or IL-6, are major mitogens for the spindle cells of Kaposi's sarcoma (KS) in vivo. PDGF-B and IL-1 beta stimulated proliferation of cultivated KS spindle cells in vitro. Analysis of gene expression in vivo revealed that both factors as well as the PDGF beta-receptor are present in KS lesions. By contrast, IL-6 had no effect and OSM inhibited proliferation of cultivated KS spindle cells. Again, the effect of these factors on cultivated KS spindle cells in vitro was reflected by the gene expression observed in KS lesions in vivo. Neither the expression of IL-6 receptor nor of OSM could be detected in KS lesions by in situ hybridization. Moreover, in situ hybridization revealed an identical pattern of gene expression in cultivated KS spindle cells and KS spindle cells in vivo with respect to the above-mentioned cytokines [PDGF-B, IL-1 beta, IL-1 alpha, IL-6, OSM] and their receptors [PDGF beta-receptor, gp130, IL-6 receptor, leukemia inhibitory factor (LIF) receptor]. This further supported the suitability of cultivated KS spindle cells as an in vitro model in order to determine which cytokines may activate proliferation of KS spindle cells in vivo.

Identification of Predictive Markers for Response to Neoadjuvant Chemoradiation in Rectal Carcinomas by Proteomic Isotope Coded Protein Label (ICPL) Analysis - Croner, Roland S.; Sevim, Muezeyyen; Metodiev, Metodi V.; Jo, Peter; Ghadimi, Michael; Schellerer, Vera; Brunner, Michaela; Geppert, Carol-Immanuel; Rau, Tilman; Stürzl, Michael; Naschberger, Elisabeth; Matzel, Klaus E.; et al. (International Journal of Molecular Sciences, 2016)
Neoadjuvant chemoradiation (nCRT) is an established procedure in stage union internationale contre le cancer (UICC) II/III rectal carcinomas. Around 53% of the tumours present with good tumor regression after nCRT, and 8%-15% are complete responders. Reliable selection markers would allow the identification of poor or non-responders prior to therapy. Tumor biopsies were harvested from 20 patients with rectal carcinomas, and stored in liquid nitrogen prior to therapy after obtaining patients' informed consent (Erlangen-No.3784). Patients received standardized nCRT with 5-Fluoruracil (nCRT I) or 5-Fluoruracil ± Oxaliplatin (nCRT II) according to the CAO/ARO/AIO-04 protocol. After surgery, regression grading (Dworak) of the tumors was performed during histopathological examination of the specimens. Tumors were classified as poor (Dworak 1 + 2) or good (Dworak 3 + 4) responders. Laser capture microdissection (LCM) for tumor enrichment was performed on preoperative biopsies. Differences in expressed proteins between poor and good responders to nCRT I and II were identified by proteomic analysis (Isotope Coded Protein Label, ICPL(TM)) and selected markers were validated by immunohistochemistry. Tumors of 10 patients were classified as histopathologically poor (Dworak 1 or 2) and the other 10 tumor samples as histopathologically good (Dworak 3 or 4) responders to nCRT after surgery. Sufficient material in good quality was harvested for ICPL analysis by LCM from all biopsies. We identified 140 differentially regulated proteins regarding the selection criteria and the response to nCRT. Fourteen of these proteins were synchronously up-regulated at least 1.5-fold after nCRT I or nCRT II (e.g., FLNB, TKT, PKM2, SERINB1, IGHG2). Thirty-five proteins showed a complete reciprocal regulation (up or down) after nCRT I or nCRT II and the rest was regulated either according to nCRT I or II. The protein expression of regulated proteins such as PLEC1, TKT, HADHA and TAGLN was validated successfully by immunohistochemistry. ICPL is a valid method to identify differentially expressed proteins in rectal carcinoma tissue between poor vs. good responders to nCRT. The identified protein markers may act as selection criteria for nCRT in the future, but our preliminary findings must be reproduced and validated in a prospective cohort.
EVALuna2:6749

Identification of the novel allele, HLA-A*01:234, in the mother of a German cord blood donor - Strobel, Julian; Hauck-Dlimi, Barbara; Dullinger, Katharina; Weisbach, Volker Günter; Zingsem, Jürgen (HLA, 2018)
HLA-A*01:234 was identified by next-generation sequencing and confirmed by Sanger sequencing.
EVALuna2:213430

Identification of the novel allele, HLA-C*01:136 in a German cord blood donor originating from Azerbaijan - Zingsem, Jürgen; Hauck-Dlimi, Barbara; Dullinger, Katharina; Weisbach, Volker Günter; Strobel, Julian (HLA, 2018)
HLA-C*01:136 identified by next generation sequencing and confirmed by Sanger sequencing.
EVALuna2:213431

Identifying modulators of CXC receptors 3 and 4 with tailored selectivity using multi-target docking - Schmidt, Denis; Bernat, Viachaslau; Brox, Regine; Tschammer, Nuska; Kolb, Peter (ACS Chemical Biology, 2015)
The G protein-coupled receptors of the C-X-C subfamily form a group among the chemokine receptors whose endogenous ligands are peptides with a common Cys-X-Cys motif. The CXC chemokine receptors 3 and 4 (CXCR3, CXCR4), which are investigated in this study, are linked to severe diseases such as cancer, multiple sclerosis, and HIV infections. Of particular interest, this receptor pair potentially forms a target for a polypharmacological drug treatment. Considering known ligands from public databases, such dual binders have not been identified yet. We therefore applied large-scale docking to the structure of CXCR4 and a homology model of CXCR3 with the goal to predict such dual binders, as well as compounds selective for either one of the receptors. Using signaling and biochemical assays, we showed that more than 50% of these predictions were correct in each category, yielding ligands with excellent binding efficiencies. These results highlight that docking is a suitable tool for the identification of ligands with tailored binding profiles to GPCRs, even when using homology models. More importantly, we present novel CXCR3-CXCR4 dual modulators that might pave the road to understanding the mechanisms of polypharmacological inhibition of these receptors.
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IFN-γ and TNF-α-induced GBP-1 inhibits epithelial cell proliferation through suppression of β-catenin/TCF signaling - Capaldo, C. T.; Beeman, N.; Hilgarth, R. S.; Nava, Porfirio; Louis, N. A.; Naschberger, Elisabeth; Stürzl, Michael; Parkos, C. A.; Nusrat, A. (Mucosal Immunology, 2012)
Proinflammatory cytokines induce guanylate-binding protein 1 (GBP-1) protein expression in intestinal epithelial tissues. GBP-1 has been described as influencing a number of cellular processes important for epithelial homeostasis, including cell proliferation. However, many questions remain as to the role of GBP-1 in intestinal mucosal homeostasis. We therefore sought to investigate the function of proinflammatory cytokine-induced GBP-1 during intestinal epithelial cell proliferation. Through the use of complementary GBP-1 overexpression and small interfering RNA-mediated knockdown studies, we now show that GBP-1 acts to inhibit pro-mitogenic β-catenin/T cell factor (TCF) signaling. Interestingly, proinflammatory cytokine-induced GBP-1 was found to be a potent suppressor of β-catenin protein levels and β-catenin serine 552 phosphorylation. Neither glycogen synthase kinase 3β nor proteasomal inhibition alleviated GBP-1-mediated suppression of cell proliferation or β-catenin/TCF signaling, indicating a non-canonical mechanism of β-catenin inhibition. Together, these data show that cytokine-induced GBP-1 retards cell proliferation by forming a negative feedback loop that suppresses β-catenin/TCF signaling. © 2012 Society for Mucosal Immunology.
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IFN-γ-driven intratumoral microenvironment exhibits superior prognostic effect compared with an IFN-α-driven microenvironment in patients with colon carcinoma - Grenz, Sandra; Naschberger, Elisabeth; Merkel, Susanne; Britzen-Laurent, Nathalie; Schaal, Ute; Konrad, Andreas; Aigner, Michael; Rau, Tilman; Hartmann, Arndt; Croner, Roland S.; Hohenberger, Werner; Stürzl, Michael (American Journal of Pathology, 2013)
Interferon (IFN)-α and IFN-γ are cytokines with potent immunomodulating and anti-tumor activities. It is unknown which of the two IFNs may be more potent in the regulation of an anti-tumorigenic response in colorectal carcinoma or whether both cytokines cooperate. We, therefore, established human myxovirus resistance protein A and human guanylate-binding protein-1 as markers for the differential detection of IFN-α- and IFN-γ-driven tumor micromilieus, respectively. In vitro studies with different cultures of tumor cells from colorectal carcinoma and stroma cells showed that the expression of myxovirus resistance protein A was exclusively induced by IFN-α, whereas guanylate-binding protein-1 was strongly induced by IFN-γ and only weakly by IFN-α. This expression pattern was used to distinguish cell activation caused by the two cytokines in a clinical cohort of patients with colon carcinoma (n = 378). Patients with primary tumors expressing only guanylate-binding protein-1 exhibited the highest cancer-specific 5-year survival (94.0%, P = 0.006) compared with those expressing both factors (90.3%, P = 0.006), myxovirus resistance protein A alone (83.5%, P = 0.096), or none (72.8%). Our study describes a successful proof-of-principle approach that complex cytokine interaction networks can be dissected in human tissues and demonstrates that an IFN-γ-driven tumor microenvironment exhibits a superior prognostic effect compared with an IFN-α-driven tumor microenvironment in colon carcinoma. © 2013 American Society for Investigative Pathology.
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IFN-γ drives inflammatory bowel disease pathogenesis through VE-cadherin-directed vascular barrier disruption. - Langer, Victoria; Vivi, Eugenia; Regensburger, Daniela; Winkler, Thomas; Waldner, Maximilian; Rath, Timo; Schmid, Benjamin; Skottke, Lisa; Lee, Somin; Jeon, Noo Li; Wohlfahrt, Thomas; Kramer, Viktoria; et al. (Journal of Clinical Investigation, 2019)
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder with rising incidence. Diseased tissues are heavily vascularized. Surprisingly, the pathogenic impact of the vasculature in IBD and the underlying regulatory mechanisms remain largely unknown. IFN-γ is a major cytokine in IBD pathogenesis, but in the context of the disease, it is almost exclusively its immune-modulatory and epithelial cell-directed functions that have been considered. Recent studies by our group demonstrated that IFN-γ also exerts potent effects on blood vessels. Based on these considerations, we analyzed the vessel-directed pathogenic functions of IFN-γ and found that it drives IBD pathogenesis through vascular barrier disruption. Specifically, we show that inhibition of the IFN-γ response in vessels by endothelial-specific knockout of IFN-γ receptor 2 ameliorates experimentally induced colitis in mice. IFN-γ acts pathogenic by causing a breakdown of the vascular barrier through disruption of the adherens junction protein VE-cadherin. Notably, intestinal vascular barrier dysfunction was also confirmed in human IBD patients, supporting the clinical relevance of our findings. Treatment with imatinib restored VE-cadherin/adherens junctions, inhibited vascular permeability, and significantly reduced colonic inflammation in experimental colitis. Our findings inaugurate the pathogenic impact of IFN-γ-mediated intestinal vessel activation in IBD and open new avenues for vascular-directed treatment of this disease.

IFN-γ-response mediator GBP-1 represses human cell proliferation by inhibiting the Hippo signaling transcription factor TEAD - Unterer, Bea; Wiesmann, Veit; Gunasekaran, Mekala; Sticht, Heinrich; Tenkerian, Clara; Behrens, Jürgen; Leone, Marina; Engel, Felix; Britzen-Laurent, Nathalie; Naschberger, Elisabeth; Wittenberg, Thomas; Stürzl, Michael (Biochemical Journal, 2018)
Interferon-gamma (IFN-γ) is a pleiotropic cytokine that exerts important functions in inflammation, infectious diseases, and cancer. The large GTPase human guanylate-binding protein 1 (GBP-1) is among the most strongly IFN-γ-induced cellular proteins. Previously, it has been shown that GBP-1 mediates manifold cellular responses to IFN-γ including the inhibition of proliferation, spreading, migration, and invasion and through this exerts anti-tumorigenic activity. However, the mechanisms of GBP-1 anti-tumorigenic activities remain poorly understood. Here, we elucidated the molecular mechanism of the human GBP-1-mediated suppression of proliferation by demonstrating for the first time a cross-talk between the anti-tumorigenic IFN-γ and Hippo pathways. The α9-helix of GBP-1 was found to be sufficient to inhibit proliferation. Protein-binding and molecular modeling studies revealed that the α9-helix binds to the DNA-binding domain of the Hippo signaling transcription factor TEA domain protein (TEAD) mediated by the 376VDHLFQK382 sequence at the N-terminus of the GBP-1-α9-helix. Mutation of this sequence resulted in abrogation of both TEAD interaction and suppression of proliferation. Further on, the interaction caused inhibition of TEAD transcriptional activity associated with the down-regulation of TEAD-target genes. In agreement with these results, IFN-γ treatment of the cells also impaired TEAD activity, and this effect was abrogated by siRNA-mediated inhibition of GBP-1 expression. Altogether, this demonstrated that the α9-helix is the proliferation inhibitory domain of GBP-1, which acts independent of the GTPase activity through the inhibition of the Hippo transcription factor TEAD in mediating the anti-proliferative cell response to IFN-γ.
EVALuna2:34818

IgA2 Antibodies against SARS-CoV-2 Correlate with NET Formation and Fatal Outcome in Severely Diseased COVID-19 Patients - Staats, Leonie A. N.; Pfeiffer, Hella; Knopf, Jasmin; Lindemann, Aylin; Fürst, Julia; Kremer, Andreas; Hackstein, Holger; Neurath, Markus; Munoz, Luis Enrique; Achenbach, Susanne; Leppkes, Moritz; Herrmann, Martin; et al. (Cells, 2020)
Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to an adaptive immune response in the host and the formation of anti-SARS-CoV-2 specific antibodies. While IgG responses against SARS-CoV-2 have been characterized quite well, less is known about IgA. IgA2 activates immune cells and induces inflammation and neutrophil extracellular trap (NET) formation which may contribute to organ injury and fatal outcome in SARS-CoV-2-infected patients. SARS-CoV-2 spike protein specific antibody levels were measured in plasma samples of 15 noninfected controls and 82 SARS-CoV-2-infected patients with no or mild symptoms, moderate symptoms (hospitalization) or severe disease (intensive care unit, ICU). Antibody levels were compared to levels of C-reactive protein (CRP) and circulating extracellular DNA (ecDNA) as markers for general inflammation and NET formation, respectively. While levels of SARS-CoV-2-specific IgG were similar in all patient groups, IgA2 antibodies were restricted to severe disease and showed the strongest discrimination between nonfatal and fatal outcome in patients with severe SARS-CoV-2 infection. While anti-SARS-CoV-2 IgG and IgA2 levels correlated with CRP levels in severely diseased patients, only anti-SARS-CoV-2 IgA2 correlated with ecDNA. These data suggest that the formation of anti-SARS-CoV-2 IgA2 during SARS-CoV-2 infection is a marker for more severe disease related to NET formation and poor outcome.
CRIS-Team WoS Importer:2021-01-15

IL-23 is centrally involved in mediating molecular resistance to anti-TNF therapy in Crohn's disease patients - Schmitt, H.; Billmeier, Ulrike; Dieterich, Walburga; Rath, T.; Sonnewald, Sophia; Reid, Stephen; Hirschmann, S.; Hildner, Kai; Waldner, Maximilian; Mudter, J.; Hartmann, Arndt; Grützmann, Robert; et al. (2018)
EVALuna2:34077

IL-2 decreased PU.1 and PD-1 expression in NK-cells in NSCLC patients - Hohenberger, Katja; Trufa, Denis; Geppert, Carol-Immanuel; Rieker, Ralf; Sirbu, Horia; Neurath-Finotto, Susetta (JOURNAL OF IMMUNOLOGY, 2021)
CRIS-Team WoS Importer:2021-12-03

IL-3 orchestrates ulcerative colitis pathogenesis by controlling the development and the recruitment of splenic reservoir neutrophils - Benard, Alan; Mittelstädt, Anke; Klösch, Bettina; Glanz, Karolina; Müller, Jan; Schoen, Janina; Nüse, Björn; Brunner, Maximilian; Naschberger, Elisabeth; Stürzl, Michael; Mattner, Jochen; Munoz, Luis Enrique; et al. (Cell Reports, 2023)
Inflammatory bowel diseases (IBDs) are a global health issue with an increasing incidence. Although the pathogenesis of IBDs has been investigated intensively, the etiology of IBDs remains enigmatic. Here, we report that interleukin-3 (Il-3)-deficient mice are more susceptible and exhibit increased intestinal inflammation during the early stage of experimental colitis. IL-3 is locally expressed in the colon by cells harboring a mesenchymal stem cell phenotype and protects by promoting the early recruitment of splenic neutrophils with high microbicidal capability into the colon. Mechanistically, IL-3-dependent neutrophil recruitment involves CCL5+ PD-1high LAG-3high T cells, STAT5, and CCL20 and is sustained by extramedullary splenic hematopoiesis. During acute colitis, Il-3−/− show, however, increased resistance to the disease as well as reduced intestinal inflammation. Altogether, this study deepens our understanding of IBD pathogenesis, identifies IL-3 as an orchestrator of intestinal inflammation, and reveals the spleen as an emergency reservoir for neutrophils during colonic inflammation.
CRIS-Team Scopus Importer:2023-06-23
Keywords: CCL5; colitis; CP: Immunology; interleukin-3; neutrophils; spleen

IL-3 protects from colitis by recruiting splenic reservoir neutrophils - Benard, A.; Kloesch, B.; Kutschick, I.; Grützmann, Robert; Weber, Georg (EUROPEAN JOURNAL OF IMMUNOLOGY, 2019)
CRIS-Team WoS Importer:2019-11-05

IL-9 Producing Tumor-Infiltrating Lymphocytes and Treg Subsets Drive Immune Escape of Tumor Cells in Non-Small Cell Lung Cancer - Heim, Lisanne; Yang, Zuqin; Tausche, Patrick; Hohenberger, Katja; Chiriac, Mircea-Teodor; Kölle, Julia; Geppert, Carol-Immanuel; Kachler, Katerina; Miksch, Sarah; Graser, Anna; Friedrich, Juliane; Kharwadkar, Rakshin; et al. (Frontiers in Immunology, 2022)
Although lung cancer is the leading cause of cancer deaths worldwide, the mechanisms how lung cancer cells evade the immune system remain incompletely understood. Here, we discovered IL-9-dependent signaling mechanisms that drive immune evasion in non-small cell lung cancer (NSCLC). We found increased IL-9 and IL-21 production by T cells in the tumoral region of the lung of patients with NSCLC, suggesting the presence of Th9 cells in the lung tumor microenvironment. Moreover, we noted IL-9 producing Tregs in NSCLC. IL-9 target cells in NSCLC consisted of IL-9R+ tumor cells and tumor-infiltrating lymphocytes. In two murine experimental models of NSCLC, and in vitro, IL-9 prevented cell death and controlled growth of lung adenocarcinoma cells. Targeted deletion of IL-9 resulted in successful lung tumor rejection in vivo associated with an induction of IL-21 and reduction of Treg cells. Finally, anti-IL-9 antibody immunotherapy resulted in suppression of tumor development even in established experimental NSCLC and was associated with reduced IL-10 production in the lung. In conclusion, our findings indicate that IL-9 drives immune escape of lung tumor cells via effects on tumor cell survival and tumor infiltrating T cells. Thus, strategies blocking IL-9 emerge as a new approach for clinical therapy of lung cancer.
CRIS-Team Scopus Importer:2022-05-20
Keywords: IL-9; immune escape; NSCLC; TIL; tumor immunotherapy

Immature platelets do not reliably predict platelet recovery in patients with intensive chemotherapy or stem cell transplantation - Meintker, Lisa; Fritsch, Juliana; Ringwald, J.; Krause, Stefan (Vox Sanguinis, 2017)
It has been reported that immature platelets may indicate imminent platelet (PLT) recovery following intensive chemotherapy and/or haematopoietic stem cell transplantation with the perspective to withhold unnecessary transfusions. The objective of our prospective study was to test immature PLTs as measured by two haematology analysers to predict PLT recovery.This study monitored 51 courses of severe thrombocytopenia after chemotherapy in 35 adult haematology/oncology patients starting at a PLT count <70 × 10(9) /l until PLT recovery (>20 × 10(9) /l) or discharge from hospital. Immature platelets as measured by immature platelet fraction (IPF) (Sysmex XE-5000) and retPLT (Abbott CD-Sapphire) as well as reticulocyte and leucocyte count were evaluated regarding their usefulness to predict PLT recovery. Furthermore, the influence of platelet concentrate (PC) transfusions upon IPF and retPLT was assessed.With beginning of thrombocytopenia, most patients demonstrated elevated IPF% (median 8·6%) and retPLT% (median 6·8%). These elevated values significantly dropped after transfusions of PCs. IPF and retPLT values during nadir and at imminent PLT recovery were largely overlapping and receiver operating characteristics analysis demonstrated poor separation between both clinical situations. A reasonable cut-off could not be established to prospectively predict imminent PLT recovery for either of the parameters investigated.Measurements of IPF and retPLT lack predictive power regarding imminent PLT recovery in patients with severe thrombocytopenia following intensive chemotherapy. Decisions regarding prophylactic PC transfusions should not be based on these parameters.
EVALuna2:25760

Immediate changes of angiosome perfusion during tibial angioplasty - Rother, Ulrich; Krenz, Katrin; Lang, Werner; Horch, Raymund E.; Schmid, Axel; Heinz, Marco; Meyer, Alexander; Regus, Susanne (Journal of Vascular Surgery, 2017)
In recent years, a controversial discussion about the clinical relevance of the angiosome concept during tibial angioplasty has developed. Therefore, we conducted a prospective study to evaluate the angiosome concept on the level of microcirculation during tibial vascular interventions.Thirty patients with isolated tibial angioplasty were examined prospectively. Macrocirculation was evaluated by measurement of the ankle-brachial index (ABI). For the assessment of microcirculation, a combined method of laser Doppler flowmetry and tissue spectrometry (O2C; LEA Medizintechnik GmbH, Giessen, Germany) was applied. Microcirculatory parameters were measured continuously during the procedures. Measuring points were located over different angiosomes of the index foot; a control probe was placed on the contralateral leg.Cumulated microcirculation parameters (sO2, flow) as well as the ABI showed a significant improvement postinterventionally (ABI, P < .001; sO2, P < .001; flow, P < .001). Assessment of the separate angiosomes of the index leg and the comparison of the directly revascularized (DR) and indirectly revascularized (IR) angiosomes showed no significant difference concerning the microperfusion postinterventionally (DR - IR: sO2, P = .399; flow, P = .909) as well as during angioplasty. Even a further subdivision of the collective into patients with diabetes (sO2, P = .445; flow, P =.758) and renal insufficiency (sO2, P = .246; flow, P = .691) could not demonstrate a superiority of the direct revascularization at the level of microcirculation in these patients (comparison DR - IR).There is a significant overall improvement in tissue perfusion of the foot immediately after tibial angioplasty. The effect shown in this study, however, was found to be global and was not restricted to certain borders, such as defined by angiosomes.
EVALuna2:14616

Immune Phenotypes and Target Antigens of Clonally Expanded Bone Marrow T Cells in Treatment-Naïve Multiple Myeloma - Welters, Carlotta; Lammoglia Cobo, María Fernanda; Stein, Christian Alexander; Hsu, Meng Tung; Ben Hamza, Amin; Penter, Livius; Chen, Xiaojing; Buccitelli, Christopher; Popp, Oliver; Mertins, Philipp; Dietze, Kerstin; Bullinger, Lars; et al. (Cancer Immunology Research, 2022)
Multiple myeloma is a hematologic malignancy of monoclonal plasma cells that accumulate in the bone marrow. Despite their clinical and pathophysiologic relevance, the roles of bone marrow-infiltrating T cells in treatment-naïve patients are incompletely understood. We investigated whether clonally expanded T cells (i) were detectable in multiple myeloma bone marrow, (ii) showed characteristic immune phenotypes, and (iii) whether dominant clones recognized antigens selectively presented on multiple myeloma cells. Single-cell index sorting and T-cell receptor (TCR) αβ sequencing of bone marrow T cells from 13 treatment-naïve patients showed dominant clonal expansion within CD8+ cytolytic effector compartments, and only a minority of expanded T-cell clones expressed the classic immune-checkpoint molecules PD-1, CTLA-4, or TIM-3. To identify their molecular targets, TCRs of 68 dominant bone marrow clones from five selected patients were reexpressed and incubated with multiple myeloma and non-multiple myeloma cells from corresponding patients. Only 1 of 68 TCRs recognized antigen presented on multiple myeloma cells. This TCR was HLA-C-restricted, self-peptide-specific and could be activated by multiple myeloma cells of multiple patients. The remaining dominant T-cell clones did not recognize multiple myeloma cells and were, in part, specific for antigens associated with chronic viral infections. In conclusion, we showed that dominant bone marrow T-cell clones in treatment-naïve patients rarely recognize antigens presented on multiple myeloma cells and exhibit low expression of classic immune-checkpoint molecules. Our data provide experimental context for experiences from clinical immune-checkpoint inhibition trials and will inform future T cell-dependent therapeutic strategies.
CRIS-Team Scopus Importer:2022-11-25

Immunohistochemical panel for the diagnosis of Hirschsprung's disease using antibodies to MAP2, calretinin, GLUT1 and S100 - Bachmann, Leonhard; Besendörfer, Manuel; Carbon, Roman; Lux, Philipp; Agaimy, Abbas; Hartmann, Arndt; Rau, Tilman (Histopathology, 2015)
The diagnosis of Hirschsprung's disease is currently based on the identification of aganglionosis and the presence of an increase in acetylcholinesterase-positive hypertrophic nerve fibres in the large bowel submucosa. However, acetylcholinesterase staining is laborious and requires a skilled technician. The aim of this study was to identify a method for diagnosing Hirschsprung's disease reliably using an immunohistochemical panel of recently proposed markers.Sixty-nine specimens from 37 patients were evaluated. MAP2 and calretinin antibodies were shown to stain ganglia reliably in the submucosal and myenteric plexuses of normal tissue. By contrast, reduced staining of ganglia was observed in patients with Hirschsprung's disease. Staining for GLUT1 and S100 was used to evaluate the number and thickness of nerve fibres. Gain of GLUT1 and S100 expression was in contrast to the loss of calretinin and MAP2. Hypertrophic submucosal nerve fibres in Hirschsprung's disease develop a perineurium with a ring-like GLUT1 staining pattern similar in size and intensity to that observed in deeper subserosal tissue.The diagnosis of Hirschsprung's disease using immunohistochemical panels could be as accurate as with conventional frozen section techniques. In particular, the use of a combination of markers for ganglia and hypertrophic nerve fibres highlighting a prominent perineurium in Hirschsprung's disease could be an alternative method.
EVALuna2:6718

Immunophenotypes and Targets of clonally expanded T Cells in the Bone Marrow of Patients with acquired Aplastic Anemia - Ben Hamza, A.; Welters, C.; Bruggemann, M.; Dietze, K.; Bullinger, L.; Brummendorf, T. H.; Winkler, Thomas; Strobel, Joachim; Hackstein, Holger; Dornmair, K.; Beier, F.; Hansmann, L. (ONCOLOGY RESEARCH AND TREATMENT, 2022)
CRIS-Team WoS Importer:2022-11-18