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Biliary tract cancer stem cells-translational options and challenges

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World Journal of Gastroenterology 2017年第14期23卷 2470-2482页

作者： Christian Mayr Matthias Ocker Markus Ritter Martin Pichler Daniel Neureiter tobias kiesslich Department of Internal Medicine I Paracelsus Medical University Laboratory for Tumour Biology and Experimental Therapies Institute of Physiology and PathophysiologyParacelsus Medical University Tanslational Medicine Oncology Department of Gastroenterology CBF CharitéUniversity Medicine Berlin Laboratory for Tumour Biology and Experimental Therapies(TREAT) Laboratory for Functional and Molecular Membrane PhysiologyParacelsus Medical University Department for Radon Therapy Research Ludwig Boltzmann Cluster for Arthritis and RehabilitationInstitute of Physiology and PathophysiologyParacelsus Medical University Research Unit for Non-coding RNA and genome editing in cancer Division of OncologyDepartment of Internal MedicineMedical University of Graz Institute of Pathology Paracelsus Medical University Cancer Cluster Salzburg

Management of biliary tract cancer remains challenging. Tumors show high recurrence rates and therapeutic resistance, leading to dismal prognosis and short survival. The cancer stem cell model states that a tumor is a heterogeneous conglomerate of cells, in which a certain subpopulation of cells-the cancer stem cells-possesses stem cell properties. Cancer stem cells have high clinical relevance due to their potential contributions to development, progression and aggressiveness as well as recurrence and metastasis of malignant tumors. Consequently, reliable identification of as well as pharmacological intervention with cancer stem cells is an intensively investigated and promising research field. The involvement of cancer stem cells in biliary tract cancer is likely as a number of studies demonstrated their existence and the obvious clinical relevance of several established cancer stem cell markers in biliary tract cancer models and tissues. In the present article, we review and discuss the currently available literature addressing the role of putative cancer stem cells in biliary tract cancer as well as the connection between known contributors of biliary tract tumorigenesis such as oncogenic signaling pathways, micro-RNAs and the tumor microenvironment with cancer stem cells.

关键词： Biliary tract cancer cancer stem cells Cancer stem cell markers Tumor microenvironment Micro-RNAs

Modularization of adhesion G protein-coupled receptor(aGPCR)structure:how alternative splicing regulates synaptogenesis

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Signal Transduction and Targeted Therapy 2024年第5期9卷 1793-1795页

作者： tobias Langenhan Rudolf Schönheimer Institute of Biochemistry Division of General BiochemistryMedical FacultyLeipzig UniversityLeipzigGermany Comprehensive Cancer Center Central Germany(CCCG) Leipzig UniversityLeipzigGermany Institute of Biology Faculty of Life SciencesLeipzig UniversityLeipzigGermany

A recent report has uncovered a fascinating aspect of how neurons utilize alternative splicing of transcripts of an adhesion G protein-coupled receptor(aGPCR)gene to serve specific functions in the life of a synapse.1 The work provides significant insight into the ability of cells to support distinct biochemical and physiological operations through post-transcriptional processing of genetic information that is encoded in a single aGPCR locus.

关键词： GPCR utilize operations

Epigenetics and pancreatic cancer:Pathophysiology and novel treatment aspects

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World Journal of Gastroenterology 2014年第24期20卷 7830-7848页

作者： Daniel Neureiter Tarkan Jger Matthias Ocker tobias kiesslich Institute of Pathology Paracelsus Medical University/Salzburger Landeskliniken (SALK)5020 SalzburgAustria Department of Surgery Paracelsus Medical University/Salzburger Landeskliniken (SALK)5020 SalzburgAustria Experimental Medicine Oncology Bayer Pharma AG13342 BerlinGermany Department of Internal Medicine I Paracelsus Medical University/Salzburger Landeskliniken (SALK)5020 SalzburgAustria Institute of Physiology and Pathophysiology Paracelsus Medical University5020 SalzburgAustria

An improvement in pancreatic cancer treatment represents an urgent medical *** diagnosis and high intrinsic resistance to conventional chemotherapy has led to a dismal overall prognosis that has remained unchanged during the past *** knowledge about the molecular pathogenesis of the disease has shown that genetic alterations,such as mutations of K-ras,and especially epigenetic dysregulation of tumor-associated genes,such as silencing of the tumor suppressor p16ink4a,are hallmarks of pancreatic ***,we describe genes that are commonly affected by epigenetic dysregulation in pancreatic cancer via DNA methylation,histone acetylation or miRNA(microRNA)expression,and review the implications on pancreatic cancer biology such as epithelial-mesenchymal transition,morphological pattern formation,or cancer stem cell regulation during carcinogenesis from PanIN(pancreatic intraepithelial lesions)to invasive cancer and resistance *** drugs,such as DNA methyltransferases or histone deactylase inhibitors,have shown promising preclinical results in pancreatic cancer and are currently in early phases of clinical *** of epigenetic drugs with established cytotoxic drugs or targeted therapies are promising approaches to improve the poor response and survival rate of pancreatic cancer patients.

关键词： Pancreatic cancer Epigenetics DNA methylation Hist

How to establish endoscopic submucosal dissection in Western countries

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World Journal of Gastroenterology 2015年第40期21卷 11209-11220页

作者： Tsuneo Oyama Naohisa Yahagi Thierry Ponchon tobias kiesslich Frieder Berr Department of Endoscopy Saku Central Hospital Advanced Care Center Cancer Center Keio University School of Medicine35 ShinanomachiShinjuku-kuTokyo 160-8582Japan H?pital Edouard Herriot Specialités DigestivesPavillon HPlaced’Arsonval69437 LyonFrance Department of Medicine I University Hospital Salzburg and Institute of Physiology and PathophysiologyParacelsus Medical University

Endoscopic submucosal dissection(ESD) has been invented in Japan to provide resection for cure of early cancer in the gastrointestinal tract. Professional level of ESD requires excellent staging of early neoplasias with image enhanced endoscopy(IEE) to make correct indications for ESD,and high skills in endoscopic electrosurgical dissection. In Japan,endodiagnostic and endosurgical excellence spread through personal tutoring of skilled endoscopists by the inventors and experts in IEE and ESD. To translocate this expertise to other continents must overcome two fundamental obstacles:(1) inadequate expectations as to the complexity of IEE and ESD; and(2) lack of suitable lesions and master-mentors for ESD trainees. Leading endoscopic mucosal resection-proficient endoscopists must pioneer themselves through the long learning curve to proficient ESD experts. Major referral centers for ESD must arise in Western countries on comparable professional level as in Japan. In the second stage,the upcoming Western experts must commit themselves to teach skilled endoscopists from other referral centers,in order to spread ESD in Western countries. Respect for patients with early gastrointestinal cancer asks for best efforts to learn endoscopic categorization of early neoplasias and skills for ESD based on sustained cooperation with the masters in Japan. The strategy is discussed here.

关键词： Endoscopic submucosal dissection Early cancer Endo

Extension of Flow Behaviour and Damage Models for Cast Iron Alloys with Strain Rate Effect

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Chinese Journal of Mechanical Engineering 2024年第3期37卷 297-310页

作者： Chuang Liu Dongzhi Sun Xianfeng Zhang Florence Andrieux tobias Gersterc School of Mechanical Engineering Nanjing University of Science and TechnologyNanjing 210094China Fraunhofer Institute for Mechanics of Materials(IWM) 79108 FreiburgGermany Fraunhofer Institute for High Speed Dynamics Ernst-Mach-Institute(EMI)79104 FreiburgGermany

Cast iron alloys with low production cost and quite good mechanical properties are widely used in the automotive *** study the mechanical behavior of a typical ductile cast iron(GJS-450)with nodular graphite,uni-axial quasi-static and dynamic tensile tests at strain rates of 10^(-4),1,10,100,and 250 s^(-1)were carried *** order to investigate the influence of stress state on the deformation and fracture parameters,specimens with various geometries were used in the *** strain curves and fracture strains of the GJS-450 alloy in the strain rate range of 10^(-4)to 250 s^(-1)were obtained.A strain rate-dependent plastic flow model was proposed to describe the mechanical behavior in the corresponding strain-rate *** available damage model was extended to take the strain rate into account and calibrated based on the analysis of local fracture *** with the proposed plastic flow model and the damage model were conducted to observe the deformation and fracture *** results show that the strain rate has obviously nonlinear effects on the yield stress and fracture strain of GJS-450 *** predictions with the proposed plastic flow and damage models at various strain rates agree well with the experimental results,which illustrates that the rate-dependent plastic flow and damage models can be used to describe the mechanical behavior of cast iron alloys at elevated strain *** proposed plastic flow and damage models can be used to describe the deformation and fracture analysis of materials with similar properties.

关键词： Dynamic behavior of materials Strain rate dependency Damage model Voce model Cast iron

Differential role of Hedgehog signaling in human pancreatic(patho-)physiology:An up to date review

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World Journal of Gastrointestinal Pathophysiology 2016年第2期7卷 199-210页

作者： Eckhard Klieser Stefan Swierczynski Christian Mayr Tarkan Jager Johanna Schmidt Daniel Neureiter tobias kiesslich Romana Illig Institute of Pathology Paracelsus Medical UniversitySalzburger Landeskliniken(SALK) Department of Surgery Paracelsus Medical UniversitySalzburger Landeskliniken(SALK) Department of Internal Medicine I Paracelsus Medical UniversitySalzburger Landeskliniken(SALK) Laboratory for Tumour Biology and Experimental Therapies(TREAT) Institute of Physiology and PathophysiologyParacelsus Medical University

Since the discovery of the Hedgehog(Hh)pathway in drosophila melanogaster,our knowledge of the role of Hh in embryonic development,inflammation,and cancerogenesis in humans has dramatically increased over the last *** is the case especially concerning the pancreas,however,real therapeutic breakthroughs are missing until *** general,Hh signaling is essential for pancreatic organogenesis,development,and tissue *** the case of acute pancreatitis,Hh has a protective role,whereas in chronic pancreatitis,Hh interacts with pancreatic stellate cells,leading to destructive parenchym fibrosis and atrophy,as well as to irregular tissue remodeling with potency of initiating *** vitro and in situ analysis of Hh in pancreatic cancer revealed that the Hh pathway participates in the development of pancreatic precursor lesions and ductal adenocarcinoma including critical interactions with the tumor *** application of specific inhibitors of components of the Hh pathway is currently subject of ongoing clinical trials(phases 1 and 2).Furthermore,a combination of Hh pathway inhibitors and established chemotherapeutic drugs could also represent a promising therapeutic *** this review,we give a structured survey of the role of the Hh pathway in pancreatic development,pancreatitis,pancreatic carcinogenesis and pancreatic cancer as well as an overview of current clinical trials concerning Hh pathway inhibitors and pancreas cancer.

关键词： Pancreatic cancer Hedgehog Pancreatitis Pancreas Development

Role of histone deacetylases in pancreas: Implications for pathogenesis and therapy

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World Journal of Gastrointestinal Oncology 2015年第12期7卷 473-483页

作者： Eckhard Klieser Stefan Swierczynski Christian Mayr Johanna Schmidt Daniel Neureiter tobias kiesslich Romana Illig Institute of Pathology Paracelsus Medical UniversitySalzburger Landeskliniken (SALK) 5020 Salzburg Austria Department of Surgery Paracelsus Medical University Salzburger Landeskliniken (SALK) 5020 SalzburgAustria Department of Internal Medicine I Paracelsus Medical University Salzburger Landes- kliniken (SALK) 5020 Salzburg Austria Laboratory for Tumour Biology and Experimental Therapies (TREAT) Institute of Physiology and Pathophysiology Paracelsus Medical University

In the last years, our knowledge of the pathogenesis in acute and chronic pancreatitis(AP/CP) as well as in pancreatic cancerogenesis has significantly diversified. Nevertheless, the medicinal therapeutic options are still limited and therapeutic success and patient outcome are poor. Epigenetic deregulation of gene expression is known to contribute to development and progression of AP and CP as well as of pancreatic cancer. Therefore, the selective inhibition of aberrantly active epigenetic regulators can be an effective option for future thera-pies. Histone deacetylases(HDACs) are enzymes that remove an acetyl group from histone tails, thereby causing chromatin compaction and repression of transcri-ption. In this review we present an overview of the currently available literature addressing the role of HDACs in the pancreas and in pancreatic diseases. In pancreatic cancerogenesis, HDACs play a role in the important process of epithelial-mesenchymal-transition, ubiquitin-proteasome pathway and, hypoxia-inducible-factor-1-angiogenesis. Finally, we focus on HDACs as potential therapeutic targets by summarizing currently available histone deacetylase inhibitors.

关键词： Pancreatitis Pancreatic cancer Epigenetics Histone

Hyper spectral resolution stimulated Raman spectroscopy with amplified fs pulse bursts

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Light(Science & Applications) 2024年第3期13卷 566-576页

作者： Hongtao Hu tobias Flöry Vinzenz Stummer Audrius Pugzlys Markus Zeiler Xinhua Xie Aleksei Zheltikov Andrius Baltuška Photonics Institute Technische Universität WienGußhausstraße 27-29Vienna A-1040Austria SwissFEL Paul Scherrer InstituteVilligen PSI 5232Switzerland Institute for Quantum Science and Engineering Department of Physics and AstronomyTexas A&M UniversityCollege StationTX 77843USA

We present a novel approach for Stimulated Raman Scattering(SRS)spectroscopy in which a hyper spectral resolution and high-speed spectral acquisition are achieved by employing amplified offset-phase controlled fs-pulse *** investigate the method by solving the coupled non-linear Schrödinger equations and validate it by numerically characterizing SRS in molecular nitrogen as a model *** spectral resolution of the method is found to be determined by the inverse product of the number of pulses in the burst and the intraburst pulse *** SRS spectrum is obtained through a motion-free scanning of the offset phase that results in a sweep of the Raman-shift *** to high spectral resolution and fast motion-free scanning the technique is beneficial for a number SRS-based applications such as gas sensing and chemical analysis.

关键词： compound spectral resolution

The Structure of Gravity Funnels and Stability Considerations of Matter in SI Units

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Journal of High Energy Physics, Gravitation and Cosmology 2024年第1期10卷 71-81页

作者： tobias Bartusch Bartusch Plasma and Vacuum Kissing Germany

This article describes an extension of the theory of vortices to electromagnetic types with a start point from known fluid systems. From this, properties of gravity-generating objects (particles and black holes) can be derived, which can also describe their possible interior. This also leads to questions about stability, which are then addressed and ultimately lead to considerations of black holes and their possible internal structure. The results fit into the observable areas and can also be directly verified because they were analytically calculated in SI units.

关键词： Black Hole Dark Matter Electromagnetic Gravity Singularity Vortex