Araştırma Çıktıları
Permanent URI for this communityhttps://hdl.handle.net/11443/931
Browse
7 results
Search Results
Item Targeting nNOS ameliorates the severe neuropathic pain due to chronic pancreatitis(ELSEVIER, 2019-01-01) Demir, Ihsan Ekin; Heinrich, Tobias; Carty, Dominique G.; Saricaoglu, Omer Cemil; Klauss, Sarah; Teller, Steffen; Kehl, Timo; Reyes, Carmen Mota; Tieftrunk, Elke; Lazarou, Maria; Bahceci, Dorukhan H.; Gokcek, Betul; Ucurum, Bahar E.; Maak, Matthias; Diakopoulos, Kalliope N.; Lesina, Marina; Schemann, Michael; Erkane, Mert; Krueger, Achim; Algul, Hana; Friess, Helmut; Ceyhan, Guralp O.Background: Pain due to pancreatic cancer/PCa or chronic pancreatitis/CP, is notoriously resistant to the strongest pain medications. Here, we aimed at deciphering the specific molecular mediators of pain at surgical-stage pancreatic disease and to discover novel translational targets. Methods: We performed a systematic, quantitative analysis of the neurotransmitter/neuroenzmye profile within intrapancreatic nerves of CP and PCa patients. Ex vivo neuronal cultures treated with human pancreatic extracts, conditional genetically engineered knockout mouse models of PCa and CP, and the cerulein-induced CP model were employed to explore the therapeutic potential of the identified targets. Findings: We identified a unique enrichment of neuronal nitric-oxide-synthase (nNOS) in the pancreatic nerves of CP patients with increasing pain severity. Employment of ex vivo neuronal cultures treated with pancreatic tissue extracts of CP patients, and brain-derived-neurotrophic-factor-deficient (BDNF+/-) mice revealed neuronal enrichment of nNOS to be a consequence of BDNI loss in the progressively destroyed pancreatic tissue. Mechanistically, nNOS upregulation in sensory neurons was induced by tryptase secreted from perineural mast cells. In a head-to-head comparison of several genetically induced, painless mouse models of PCa (KPC, KC mice) or CP (Ptf1a-CreItem Patterns and Relevance of Langerhans Islet Invasion in Pancreatic Cancer(MDPI, 2021-01-01) Goess, Ruediger; Mutgan, Ayse Ceren; Calisan, Umut; Erdogan, Yusuf Ceyhun; Ren, Lei; Jager, Carsten; Safak, Okan; Stupakov, Pavel; Istvanffy, Rouzanna; Friess, Helmut; Ceyhan, Guralp O.; Demir, Ihsan EkinSimple Summary The pathogenesis of pancreatic cancer-associated diabetes mellitus is poorly understood. We analyzed tumor infiltration into Langerhans islets and characterized it systematically for the first time, identifying four different main patterns of islet invasion. In a cohort of 68 pancreatic ductal adenocarcinoma (PDAC) patients, these islet invasion patterns were not related to occurrence of diabetes mellitus. However, severe islet invasion was associated with worsened overall survival. Background: Pancreatic cancer-associated diabetes mellitus (PC-DM) is present in most patients with pancreatic cancer, but its pathogenesis remains poorly understood. Therefore, we aimed to characterize tumor infiltration in Langerhans islets in pancreatic cancer and determine its clinical relevance. Methods: Langerhans islet invasion was systematically analyzed in 68 patients with pancreatic ductal adenocarcinoma (PDAC) using histopathological examination and 3D in vitro migration assays were performed to assess chemoattraction of pancreatic cancer cells to islet cells. Results: Langerhans islet invasion was present in all patients. We found four different patterns of islet invasion: (Type I) peri-insular invasion with tumor cells directly touching the boundary, but not penetrating the isletItem Drain use in pancreatic surgery: Results from an international survey among experts in the field(MOSBY-ELSEVIER, 2022-01-01) Pergolini, Ilaria; Schorn, Stephan; Goess, Ruediger; Novotny, Alexander R.; Ceyhan, Guralp O.; Friess, Helmut; Demir, Ihsan Ekin; Surg, Collaborators Int PancreaticBackground: Drain use in pancreatic surgery remains controversial. This survey sought to evaluate habits, experiences, and opinions of experts in the field on the use of drains to provide interesting insights for pancreatic surgeons worldwide. Methods: An online survey designed via Google Forms was sent in December 2020 to experienced surgeons of the International Study Group for Pancreatic Surgery. Results: Forty-two surgeons (42/63, 67\%) completed the survey. During their career, 74\% (31/42) performed personally >500 pancreatic resectionsItem Diabetes and Weight Loss Are Associated With Malignancies in Patients With Intraductal Papillary Mucinous Neoplasms(ELSEVIER SCIENCE INC, 2021-01-01) Pergolini, Ilaria; Jaeger, Carsten; Safak, Okan; Goess, Ruediger; Novotny, Alexander; Ceyhan, Guralp O.; Friess, Helmut; Demir, Ihsan EkinBACKGROUND \& AIMS: The role of diabetes in intraductal papillary mucinous neoplasms (IPMNs) is not known. We investigated the prevalence of diabetes among patients with resected IPMNs and the association between diabetes, clinical and morphological features, and high-grade dysplasia or invasive cancer. METHODS: We collected clinical, pathology, laboratory, and demographic data from 134 patients who underwent pancreatic resection for IPMN from a referral center in Germany. We identified 50 patients with diabetes (37\%). RESULTS: Higher proportions of patients with diabetes were male and older, but did not have increased body mass index, compared to patients without diabetes. Diabetes was significantly associated with main-duct involvement (odds ratio {[}OR], 2.827Item Organoids to Study Intestinal Nutrient Transport, Drug Uptake and Metabolism - Update to the Human Model and Expansion of Applications(FRONTIERS MEDIA SA, 2020-01-01) Zietek, Tamara; Giesbertz, Pieter; Ewers, Maren; Reichart, Florian; Weinmueller, Michael; Urbauer, Elisabeth; Haller, Dirk; Demir, Ihsan Ekin; Ceyhan, Guralp O.; Kessler, Horst; Rath, EvaIntestinal transport and sensing processes and their interconnection to metabolism are relevant to pathologies such as malabsorption syndromes, inflammatory diseases, obesity and type 2 diabetes. Constituting a highly selective barrier, intestinal epithelial cells absorb, metabolize, and release nutrients into the circulation, hence serving as gatekeeper of nutrient availability and metabolic health for the whole organism. Next to nutrient transport and sensing functions, intestinal transporters including peptide transporter 1 (PEPT1) are involved in the absorption of drugs and prodrugs, including certain inhibitors of angiotensin-converting enzyme, protease inhibitors, antivirals, and peptidomimetics like beta-lactam antibiotics. Here, we verify the applicability of 3D organoids forin vitroinvestigation of intestinal biochemical processes related to transport and metabolism of nutrients and drugs. Establishing a variety of methodologies including illustration of transporter-mediated nutrient and drug uptake and metabolomics approaches, we highlight intestinal organoids as robust and reliable tool in this field of research. Currently usedin vitromodels to study intestinal nutrient absorption, drug transport and enterocyte metabolism, such as Caco-2 cells or rodent explant models are of limited value due to their cancer and non-human origin, respectively. Particularly species differences result in poorly correlative data and findings obtained in these models cannot be extrapolated reliably to humans, as indicated by high failure rates in drug development pipelines. In contrast, human intestinal organoids represent a superior model of the intestinal epithelium and might help to implement the 3Rs (Reduction, Refinement and Replacement) principle in basic science as well as the preclinical and regulatory setup.Item Regulatory T Cells in Pancreatic Cancer: Of Mice and Men(MDPI, 2022-01-01) Reyes, Carmen Mota; Demir, Elke; Cifcibasi, Kaan; Istvanffy, Rouzanna; Friess, Helmut; Demir, Ihsan EkinSimple Summary Regulatory T cells (Treg) are a major immunosuppressive cell subset in the pancreatic tumor microenvironment. Tregs influence tumor growth by acting either directly on cancer cells or via the inhibition of effector immune cells. Treg cells form a partially redundant network with other immunosuppressive cells such as myeloid-derived suppressor cells (MDSC) that confer robustness to tumor immunosuppression and resistance to immunotherapy. The results obtained in preclinical studies, whereupon Treg depletion, MDSCs concomitantly decreased in early tumors whereas an inverse association was seen in advanced PCa, urge a comprehensive analysis of the immunosuppressive profile of PCa throughout tumorigenesis. One relevant context to analyse these compensatory mechanisms may be patients with locally advanced PCa undergoing neoadjuvant therapy (neoTx). In order to understand these dynamics and to uncover stage-specific actional strategies involving Tregs, pre-clinical models that allow the administration of neoTx to different stages of PCa may be a very useful platform. Regulatory T cells (Treg) are one of the major immunosuppressive cell subsets in the pancreatic tumor microenvironment. Tregs influence tumor growth by acting either directly on cancer cells or via the inhibition of effector immune cells. Treg cells mechanisms form a partially redundant network with other immunosuppressive cells such as myeloid-derived suppressor cells (MDSC) that confer robustness to tumor immunosuppression and resistance to immunotherapy. The results obtained in preclinical studies where after Treg depletion, MDSCs concomitantly decreased in early tumors whereas an inverse association was seen in advanced PCa, urge a comprehensive analysis of the immunosuppressive profile of PCa throughout tumorigenesis. One relevant context to analyse these complex compensatory mechanisms may be the tumors of patients who underwent neoTx. Here, we observed a parallel decrease in the numbers of both intratumoral Tregs and MDSC after neoTx even in locally advanced PCa. NeoTx also led to decreased amounts of alpha SMA(+) myofibroblastic cancer-associated fibroblasts (myCAF) and increased proportions of CD8(+) cytotoxic T lymphocytes in the tumor. In order to understand these dynamics and to uncover stage-specific actional strategies involving Tregs, pre-clinical models that allow the administration of neoTx to different stages of PCa may be a very useful platform.Item Mechanisms of T-Cell Exhaustion in Pancreatic Cancer(MDPI, 2020-01-01) Saka, Didem; Gokalp, Muazzez; Piyade, Betul; Cevik, Nedim Can; Sever, Elif Arik; Unutmaz, Derya; Ceyhan, Guralp O.; Demir, Ihsan Ekin; Asimgil, HandeT-cell exhaustion is a phenomenon that represents the dysfunctional state of T cells in chronic infections and cancer and is closely associated with poor prognosis in many cancers. The endogenous T-cell immunity and genetically edited cell therapies (CAR-T) failed to prevent tumor immune evasion. The effector T-cell activity is perturbed by an imbalance between inhibitory and stimulatory signals causing a reprogramming in metabolism and the high levels of multiple inhibitory receptors like programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), and Lymphocyte-activation gene 3 (Lag-3). Despite the efforts to neutralize inhibitory receptors by a single agent or combinatorial immune checkpoint inhibitors to boost effector function, PDAC remains unresponsive to these therapies, suggesting that multiple molecular mechanisms play a role in stimulating the exhaustion state of tumor-infiltrating T cells. Recent studies utilizing transcriptomics, mass cytometry, and epigenomics revealed a critical role of Thymocyte selection-associated high mobility group box protein (TOX) genes and TOX-associated pathways, driving T-cell exhaustion in chronic infection and cancer. Here, we will review recently defined molecular, genetic, and cellular factors that drive T-cell exhaustion in PDAC. We will also discuss the effects of available immune checkpoint inhibitors and the latest clinical trials targeting various molecular factors mediating T-cell exhaustion in PDAC.