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Role of circulating tumor cell spheroids in drug resistance

Cancer Drug Resistance 2019年第3期2卷 762-772页

作者： gerhard Hamilton Barbara Rath Department of Surgery Medical University of ViennaVienna A-1090Austria

Cancer cell spheroids are used for drug screening as these three-dimensional(3D)assemblies recapitulate tumors more realistic than the widely employed 2D in vitro *** drug diffusion and gradients of oxygen and nutrients in spheroids represent avascular tumor regions containing quiescent and hypoxic tumor cells with high drug *** tumor cells(CTCs)effect metastatic spread and are present in high numbers in malignant diseases such as small-cell lung cancer(SCLC)and in other cancer patients with high tumor *** are heterogeneous and only a small fraction of these cells survive in the circulation and cause distal *** may circulate as single cells but small CTC clusters or CTC spheroids have been detected in cancer patients and demonstrated to possess increased metastatic *** our lab we have obtained 9 permanent SCLC CTC cell lines(BHGc7,BHGc10,BHGc16,BHGc26,BHGc27,BHGc50,BHGc59,BHGc71,and UHGc5)of distinct patients exhibiting similar characteristics and spontaneous formation of large spheroids,termed *** aggregates were shown to exhibit high drug resistance compared to the corresponding single cell *** increased metastatic capability of small circulating tumor clusters/spheroids may be explained by their role as putative precursors of tumorospheres eventually trapped in *** drug penetration and the presence of hypoxic/quiescent cells can readily account for the global drug resistance of advanced SCLC which has resulted in clinical failure of a wide range of chemotherapeutics and low ***,we have detected such tumorospheres in non-small-cell lung cancer(NSCLC)patients progressing under EGFR-directed tyrosine kinase inhibitor therapy which had undergone NSCLC-SCLC transformation.

关键词： Cancer spheroid circulating tumor cells small cell lung cancer non-small-cell lung cancer transformation dormancy

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Serum bile acid profiling reflects enterohepatic detoxification state and intestinal barrier function in inflammatory bowel disease

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World Journal of Gastroenterology 2009年第25期15卷 3134-3141页

作者： Carsten Gnewuch gerhard Liebisch Thomas Langmann Benjamin Dieplinger Thomas Mueller Meinhard Haltmayer Hans Dieplinger Alexandra Zahn Wolfgang Stremmel gerhard Rogler Gerd Schmitz Institute of Clinical Chemistry and Laboratory Medicine Regensburg University Medical Center Institute of Human Genetics University of Regensburg Department of Laboratory Medicine Konventhospital Barmherzige Brueder Linz Division of Genetic Epidemiology Department of Medical GeneticsClinical and Molecular PharmacologyInnsbruck Medical University Department of Gastro-enterology University Hospital Heidelberg Department of Internal Medicine I Regensburg University Medical Center

AIM： To determine free and conjugated serum bile acid （BA） levels in inflammatory bowel disease （IBD） subgroups with defined clinical manifestations. METHODS： Comprehensive serum BA profiling was performed in 358 IBD patients and 310 healthy con- trols by liquid chromatography coupled to electrospray ionization tandem mass spectrometry. RESULTS： Serum levels of hyodeoxycholic acid, the CYP3A4-mediated detoxification product of the second- ary BA lithocholic acid （LCA）, was increased significantly in Crohn＇s disease （CD） and ulcerative colitis （UC）, while most other serum BA species were decreased signifi- cantly. Total BA, total BA conjugate, and total BA glyco- conjugate levels were decreased only in CD, whereas total unconjugated BA levels were decreased only in UC. In UC patients with hepatobiliary manifestations, the conjugated primary BAs glycocholic acid, taurocholic acid, and glycochenodeoxycholic acid were as signifi- cantly increased as the secondary BAs LCA, ursodeoxy- cholic acid, and tauroursodeoxycholic acid compared to UC patients without hepatobiliary manifestations. Finally, we found that in ileocecal resected CD patients, the unconjugated primary BAs, cholic acid and chenode- oxycholic acid, were increased significantly compared to controls and patients without surgical interventions. CONCLUSION： Serum BA profiling in IBD patients that indicates impaired intestinal barrier function and increased detoxification is suitable for advanced diag- nostic characterization and differentiation of IBD sub- groups with defined clinical manifestations.

关键词： Bile acids Liquid chromatography Tandem mass spectrometry Inflammatory bowel disease Crohn's disease Ulcerative colitis

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Impact of endoscopy-based research on quality of life in healthy volunteers

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World Journal of Gastroenterology 2010年第4期16卷 467-473页

作者： Alexander Link gerhard Treiber Brigitte Peters Thomas Wex Peter Malfertheiner Department of Gastroenterology Hepatology and Infectious Diseases Otto-von-Guericke University Leipziger St.44 39120 Magdeburg Germany Department of Internal Medicine Division of Gastroenterology Baylor Research Institute Baylor UniversityMedical Center 3500 Gaston Ave (H-250) Dallas TX 75246United States Department of Gastroenterology Oncology and General Internal Medicine Zollernalb Clinic Tuebinger St.30 72336 Balingen Germany Institute for Biometry and Medical Informatics Otto-von-Guericke University Leipziger St. 44 39120 Magde-burg Germany Department of Gastroenterology Hepatology and Infectious Diseases Otto-von-Guericke University Leipziger St.44 39120 MagdeburgGermany

AIM:To study the impact of an endoscopy-based long-term study on the quality of life in healthy volunteers(HV).METHODS:Ten HV were included into a long-term prospective endoscopy-based placebo-controlled trial with 15 endoscopic examinations per person in 5 different drug *** completed short form-36(SF-36) and visual analog scale-based questionnaires(VAS) for different abdominal symptoms at days 0,7 and 14 of each drug *** wereperformed according to short-and long-term changes and compared to the control ***:All HV completed the study with duration of more than 6 *** quality of life score was comparable to a general *** of the SF-36 questionnaires showed no significant changes in physical,mental and total scores,either in a short-term perspective due to different medications,or to potentially endoscopic procedure-associated long-term cumulative *** to SF-36,VAS revealed no significant changes in total scores for pathological abdominal symptoms and remained unchanged over the time course and when compared to the control ***:This study demonstrates that quality of life in HV is not significantly affected by a longterm endoscopy-based study with multiple endoscopic procedures.

关键词： Endoscopy research Ethics Healthy volunteers Quality of life

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Upper limits for chlorophyll a changes with brine volume in sea ice during the austral spring in the Weddell Sea,Antarctica

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Acta Oceanologica Sinica 2016年第2期35卷 68-75页

作者： LI Zhijun LI Runling WANG Zipan HAAS Christian DIECKMANN gerhard State Key Laboratory of Coastal and Offshore Engineering Dalian University of Technology Dalian 116024 China Second Institute of Oceanography State Oceanic Administration Hangzhou 310012 China Department of Earth and Space Science and Engineering York University Toronto M3J1P3 Canada Alfred Wegener Institute Helmholtz Centre for Polar and Marine Research Bremerhaven D-27570 Germany

During the winter and spring of 2006, we investigated the sea ice physics and marine biology in the northwest Weddell Sea, Antarctica aboard R/V Polarstern. We determined the texture of each ice core and 71 ice crystal thin sections from 27 ice cores. We analyzed 393 ice cores, their temperatures, 348 block density and salinity samples,and 311 chlorophyll a（Chl a） and phaeophytin samples along the cruise route during the investigation. Based on the vertical distributions of 302 groups of data for the ice porosity and Chl a content in the ice at the same position, we obtained new evidence that ice physical parameters influence the Chl a content in ice. We collected snow and ice thickness data, and established the effects of the snow and ice thickness on the Chl a blooms under the ice, as well as the relationships between the activity of ice algae cells and the brine volume in ice according to the principle of environmental control of the ecological balance. We determined the upper limits for Chl a in the brine volume of granular and columnar ice in the Antarctica, thereby demonstrating the effects of ice crystals on brine drainage, and the contributions of the physical properties of sea ice to Chl a blooms near the ice bottom and on the ice-water interface in the austral spring. Moreover, we found that the physical properties of sea ice affect ice algae and they are key control elements that modulate marine phytoplankton blooms in the ice-covered waters around Antarctica.

关键词： Antarctic brine volume chlorophyll a ice crystal mode sea ice

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Bionic Photovoltaic Panels Bio-Inspired by Green Leaves

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Journal of Bionic Engineering 2010年第3期7卷 284-293页

作者： MatthiasZhr Dennis Friedrich Tania Y.Kloth gerhard Goldmann Helmut Tributsch Technische Fachhochschule Berlin Helmholtz-Zentrum

In strong solar light, silicon solar panels can heat up by 70℃ and, thereby, loose approximately one third of their efficiencyfor electricity generation. Leaf structures of plants on the other hand, have developed a series of technological adaptations,which allow them to limit their temperature to 40-45℃ in full sunlight, even if water evaporation is suppressed. This is accomplishedby several strategies such as limitation of leaf size, optimization of aerodynamics in wind, limitation of absorbedsolar energy only to the useful fraction of radiation and by efficient thermal emission. Optical and infrared thermographicmeasurements under a solar simulator and in a streaming channel were used to investigate the corresponding properties of leavesand to identify suitable bionic model systems. Experiments started with the serrated structure of ordinary green leaves distributedover typical twig structures and finally identified the Australian palm tree Licuala ramsayi as a more useful bionic model. Itcombines a large area for solar energy harvesting with optimized aerodynamic properties for cooling and is able to restructureitself as a protection against strong winds. The bionic models, which were constructed and built, are analyzed and discussed.

关键词： bionics photovoltaic panel green leaves heat control Licuala ramsayi

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Lithocholic acid induction of the FGF19 promoter in intestinal cells is mediated by PXR

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World Journal of Gastroenterology 2007年第31期13卷 4230-4235页

作者： Wolfgang Wistuba Carsten Gnewuch gerhard Liebisch Gerd Schmitz Thomas Langmann Institute of Clinical Chemistry and Laboratory Medicine University of Regensburg Regensburg 93053 Germany

To study the effect of the toxic secondary bile acid lithocholic acid （LCA） on the expression of fibroblast growth factor 19 （FGF19） in intestinal cells and to characterize the pregnane-X-receptor （PXR） response of the FGF19 promoter region. METHODS： The intestinal cell line LS174T was stimulated with various concentrations of chenodeoxy- cholic acid and lithocholic acid for several time points. FGF19 mRNA levels were determined with quantitative realtime RT-PCR. FGF19 deletion promoter constructs were generated and the LCA response was analzyed in reporter assays. Co-transfections with PXR and RXR were carried out to study FGF19 regulation by these factors, RESULTS： LCA and CDCA strongly up-regulate FGF19 mRNA expression in LS174T cells in a time and dose dependent manner. Using reporter gene assays with several deletion constructs we found that the LCA responsive element in the human FGF19 promoter maps to the proximal regulatory region containing two poten- tial binding sites for PXR. Overexpression of PXR and its dimerization partner retinoid X receptor （RXR） and stimulation with LCA or the potent PXR ligand rifampicin leads to a significant induction of FGF19 promoter activ- ity in intestinal cells. CONCLUSION： LCA induced feedback inhibition of bile acid synthesis in the liver is likely to be regulated by PXR inducing intestinal FGF19 expression.

关键词： Pregnane X receptor Detoxification Fibroblast growth factor 19 Lithocholic acid

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Numerical Modelling of Seismic Site Effects Incorporating Non-linearity and Groundwater Level Changes

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Journal of Earth Science 2010年第6期21卷 931-940页

作者： Dominik Ehret Joachim Rohn Dieter Hannich Carlos Grandas gerhard Huber Department of Applied Geology University of Erlangen-Nuremberg Department of Applied Geology University (TH) of Karlsruhe Institute of Soil and Rock Mechanics University (TH) of Karlsruhe

In the past decades, the necessity for detailed earthquake microzonation studies was recognized worldwide. Therefore, different approaches were established and applied. Unfortunately, the majority of these approaches are not based on pre-existing field data but require extensive seismic measurements and investigations. Furthermore, these approaches incorporate non-linearity inadequately and cannot take groundwater level changes into account. For this purpose, notably numerical models are most suitable. These models require a good knowledge of the local geological conditions （especially of the uppermost unconsolidated units）, information about the geotechnical parameters of these units, and a hydrogeological model of the investigated area. Most of this information can be obtained from geotechnical investigations and surveys that have already been carried out in most densely populated areas. In a case study for Bucharest City, non-linear analyses were performed using software that is based on the visco-hypoplastic constitutive law. The results indicate that groundwater level changes have an important influence on duration and amplitude of ground response and thus should be considered for seismic microzonation studies. This approach ean be used to display site effects and to identify different microzones taking different earthquake magnitudes and groundwater levels into account.

关键词： microzonation site effect visco-hypoplasticity non-linearity Bucharest Romania.

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Budesonide induces complete remission in autoimmune hepatitis

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World Journal of Gastroenterology 2006年第9期12卷 1362-1366页

作者： Antal Csepregi Christoph R(o|¨)cken gerhard Treiber Peter Malfertheiner Department of Gastroenterology Hepatology and Infectious DiseasesOtto-von-Guericke UniversityLeipziger Str 4439120 MagdeburgGermany Institute of Pathology Otto-von-Guericke University Leipziger Str 4439120 MagdeburgGermany

AIM： Prednisone and azathioprine represent the standard treatment for autoimmune hepatitis （AIH）. However, only 65% of the patients enter complete histological remission. Recently, budesonide （BUD） was reported to be a promising alternative. In this study we assessed the efficacy and safety of BUD in AIH. METHODS： Eighteen patients （12 women, 6 men; mean age 45.4±21 years） with AIH were treated with BUD （Budenofalk） 3 mg thrice daily and followed up for at least 24 wk. Seven patients also had features of primary biliary cirrhosis （n = 5） or primary sclerosing cholangitis （n = 2）. Advanced liver fibrosis or cirrhosis was present in RESULTS： Fifteen （83%） patients had a complete clinical and biochemical remission. Ten patients, including five with acute hepatitis, were given BUD as first-line therapy, of which seven enter remission. Three patients, two with liver cirrhosis, did not improve. All patients with second-line therapy experienced long-term remission. A histological remission was also seen in three patients. Clinically relevant BUD-induced side effects were recorded only in patients with liver cirrhosis （n = 4）. CONCLUSION： BUD is effective in remission induction in the majority of our patients with AIH. Side effects and treatment failure was mainly observed in patients with liver cirrhosis.

关键词： Budesonide Autoimmune hepatitis Complete remission Adverse events

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Mucosal healing and deep remission: What does it mean?

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World Journal of Gastroenterology 2013年第43期19卷 7552-7560页

作者： gerhard Rogler Stephan Vavricka Alain Schoepfer Peter L Lakatos Division of Gastroenterology and Hepatology Department of Internal MedicineUniversity Hospital Zürich8091 ZürichSwitzerland Zurich Center for Integrative Human Physiology University of Zurich8006 ZürichSwitzerland Gastroenterology Triemli Spital8063 ZürichSwitzerland Division of Gastroenterology and Hepatology Centre Hospitalier Universitaire Vaudois et Université de Lausanne1011 LausanneSwitzerland Division of Gastroenterology and Hepatology 1st Department of MedicineSemmelweis UniversityH1083 BudapestHungary

The use of specific terms under different meanings and varying definitions has always been a source of confusion in *** we point our efforts towards an evidence based medicine for inflammatory bowel diseases(IBD)the same is true:Terms such as"mucosal healing"or"deep remission"as endpoints in clinical trials or treatment goals in daily patient care may contribute to misconceptions if meanings change over time or definitions are *** appears to be useful to first have a look at the development of terms and their definitions,to assess their intrinsic and context-independent problems and then to analyze the different relevance in present-day clinical studies and *** purpose of such an attempt would be to gain clearer insights into the true impact of the clinical findings behind the *** may also lead to a better defined use of those terms for future *** terms"mucosal healing"and"deep remission"have been introduced in recent years as new therapeutic targets in the treatment of IBD *** clinical trials,cohort studies or inception cohorts provided data that the long term disease course is better,when mucosal healing is ***,it is still unclear whether continued or increased therapeutic measures will aid or improve mucosal healing for patients in clinical *** trials are under way to answer this *** should be paid to clearly address what levels of IBD activity are looked *** the present review article authors aim to summarize the current evidence available on mucosal healing and deep remission and try to highlight their value and position in the everyday decision making for gastroenterologists.

关键词： Inflammatory bowel disease Mucosal healing Deep remission Treatment targets Clinical activity

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Physics-based algorithm to simulate tree dynamics under wind load

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International Journal of Agricultural and Biological Engineering 2020年第2期13卷 26-32页

作者： Lifeng Xu Zhongzhu Yang Weilong Ding gerhard Buck-Sorlin College of Computer Science&Technology Zhejiang University of TechnologyHangzhou 310026China IRHS INRAEAGROCAMPUS OUESTUniversitéd'AngersSFR 4207 QUASAV42 rue Georges Morel49071 BeaucouzécedexFrance

Rapid development in the different computer science fields during the recent decades has facilitated the creation of new applications in the area of dynamic simulation of plant *** these new applications,simulation of trees swaying in the wind is of great importance,as those computer graphics related areas,e.g.,computer games,tree cultivation and forest management simulations,help a lot in revealing the mechanisms of tree dynamics under wind ***,it is a big challenge to balance the effect of visualization in real time and calculation efficiency for any simulation algorithm.A physics-based algorithm to simulate tree dynamics under wind load was proposed in this study.A mechanistic model simulating the bending of a cantilever beam was used within the algorithm to simulate deformation of stems,and the algorithm was integrated with a landscape model in which different types of trees were constructed with an L-system-based *** results show that realistic dynamic effects can be achieved with reasonably high computational efficiency.

关键词： physics-based algorithm tree model L-system Cantilever beam

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