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Signal Transduction and Targeted Therapy 2021年第8期6卷 2280-2281页

作者： Jehad Charo Bruno Gomes hoffmann-la roche ag pharmaceutical research and early development oncologyroche innovation center zurichzurichswitzerland hoffmann-la roche ag pharmaceutical research and early development oncologyroche innovation center baselbaselswitzerland

In a recent article published in Science by Hernandez-Lopez et al.chimeric antigen receptor(CAR)expressing T(CAR-T)cells with a two-step recognition system successfully discriminated between target cells expressing hi... 详细信息

关键词： CAR cancer

primiReference: a reference for analysis of primary-microRNA expression in single-nucleus sequencing data

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Journal of Genetics and Genomics 2023年第2期50卷 108-121页

作者： Amy E.Elias Thomas A.Nuñez Bianca Kun Jill A.Kreiling roche WilmingtonMA 01887USA. Department of Molecular Biology Cell Biology and BiochemistryBrown UniversityProvidenceRI02903USA Public Health Genetics University of PittsburghPittsburghPA 15260USA

Single-nucleus RNA-sequencing technology has revolutionized understanding of nuanced changes in gene expression between cell types within tissues.Unfortunately,our understanding of regulatory RNAs,such as microRNAs(miRNAs),is limited through both single-cell and single-nucleus techniques due to the short length of miRNAs in the cytoplasm and the incomplete reference of longer primary miRNA(pri-miRNA)transcripts in the nucleus.We build a custom reference to align and count pri-miRNA sequences in singlenucleus data.Using young and aged subventricular zone(SVZ)nuclei,we show differential expression of pri-miRNAs targeting genes involved in neural stem cells(NSC)differentiation in the aged SVZ.Furthermore,using wild-type and 5XFAD mouse model cortex nuclei,to validate the use of primiReference,we find cell-type-specific expression of pri-miRNAs known to be involved in Alzheimer’s disease(AD).pri-miRNAs likely contribute to NSC dysregulation with age and AD pathology.primiReference is paramount in capturing a global profile of gene expression and regulation in single-nucleus data and can provide key insights into cell-type-specific expression of pri-miRNAs,paving the way for future studies of regulation and pathway dysregulation.By looking at pri-miRNA abundance and transcriptional differences,regulation of gene expression by miRNAs in disease and aging can be further explored.

关键词： Primary-microRNA aging Subventricular zone Alzheimer’s disease Single-nucleus RNA-Seq microRNA Transcriptomics

Elimination of undifferentiated cancer cells by pluripotent stem cell inhibitors

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Journal of Molecular Cell Biology 2014年第3期8卷 267-269页

作者： Uri Ben-David1,2 Alva Biran2 Paola Scaffidi3,4,5 Christel Herold-Mende6 Markus Boehringer7 Eran Meshorer2 Nissim Benvenisty1,2 Stem Cell Unit Silberman Institute of Life Sciences The Hebrew University Jerusalem 91904 Israel Department of Genetics Silberman Institute of Life Sciences The Hebrew University Jerusalem 91904 Israel National Cancer Institute NIH Bethesda MD 20892 USA UCL Cancer Institute University College London London WC1E 6BT UK Cancer Research UK London Research Institute London WC2A 3LY UK Division of Neurosurgical Research Department of Neurosurgery University of Heidelberg Heidelberg Germany F. hoffmann-la roche ag Basel 4070 Switzerland

We have previously shown that fibroblasts resistant to SCD1 inhibition acquire the metabolic sensitivity when reprogrammed into induced PSCs, but this sensitivity is quickly lost upon differentiation (Ben-David et al., 2013). Here we demonstrate that these fibroblasts acquire the same metabolic vulnerability when they are transformed into undifferentiated stem cell-like cancer cells, but the resistance to SCD1 inhibition is conferred again once cancer cells are induced to differentiate (Figure 1I). These findings link, for the first time, the differentiation state of cancer cells with their response to inhibition of oleate synthesis, suggesting that SCD1 inhibition might be an especially effective cancer therapy for undifferentiated tumor types. This work also demonstrates that research on cellular reprogramming can yield insights into cancer biology, and validates that in vitro generated CSCs can be successfully used for screening anticancer drugs. [Supplementary material is available at Journal of Molecular Cell Biology online. We thank members of the Stem Cell Unit at the Hebrew University, and especially Tamar Golan-Lev for her assistance with the graphic design of the Figures, Ofra Yanuka for her help with SLGC culturing, and Ido Sagi and Daniel Ronen for critically reading the manuscript. N.B. is the Herbert Cohn Chair in Cancer Research. U.B.-D. and A.B. are Clore Fellows. This work was supported by a hoffmann la roche-Yissum Collaboration grant, a DKFZ-Israel Collaboration grant (#CA-146) from the Israel Ministry of Science, and the Intramural Research Program of the National Institutes of Health (NIH), NCI, Center for Cancer Research.]

关键词： THERAPY

Estimation of Time to Maximum Rate Under Adiabatic Conditions(TMR_(ad)) Using Kinetic Parameters Derived From DSC-Investigation of Thermal Behavior of 3-Methyl-4-Nitrophenol

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化学推进剂与高分子材料 2011年第1期9卷 84-96页

作者： Bertrand Roduit Patrick Folly Alexandre Sarbach Beat Berger Franz Brogli Francesco Mascarello Mischa Schwaninger Thomas Glarner Eberhard Irle Fritz Tobler Jacques Wiss Markus Luginbühl Craig Williams Pierre Reuse Francis Stoessel AKTS ag TechnoArk 13960 SidersSwitzerland Armasuisse Science and Technology Centre3602 ThunSwitzerland Ciba Schweizerhalle ag P.O.Box4002 BaselSwitzerland DSM Nutritional Products Ltd. Safety laboratory4334 SisselnSwitzerland F.hoffmann-la roche Ltd Safety laboratories4070 BaselSwitzerland Lonza ag Safety Laboratory VispRottenstr.63930 Visp Switzerland Novartis Pharma ag Novartis CampusWSJ-145.8.544002 BaselSwitzerland Syngenta Crop Protection Münchwilen ag WMU 3120.1.544333 MünchwilenSwitzerland Swiss Safety Institute Schwarzwaldallee 215WRO-1055.5.024002 BaselSwitzerland

Kinetic parameters of the decomposition of hazardous chemicals can be applied for the estimation of their thermal behavior under any temperature profile.Presented paper describes the application of the advanced kinetic approach for the determination of the thermal behavior also under adiabatic conditions occurring e.***.in batch reactors in case of cooling failure.The kinetics of the decomposition of different samples(different manufacturers and batches) of 3-methyl-4-nitrophenol were investigated by conventional DSC in non-isothermal(few heating rates varying from 0.25 to 8.0K/min) and isothermal(range of 200~260℃) modes.The kinetic parameters obtained with AKTS-Thermokinetics Software were applied for calculating reaction rate and progress under different heating rates and temperatures and verified by comparing simulated and experimental signals.After application of the heat balance to compare the amount of heat generated during reaction and its removal from the system,the knowledge of reaction rate at any temperature profiles allowed the determination of the temperature increase due to the self-heating in adiabatic and pseudo-adiabatic conditions.Applied advanced kinetic approach allowed simulation the course of the Heat-Wait-Search(HWS) mode of operation of adiabatic calorimeters.The thermal safety diagram depicting dependence of Time to Maximum Rate(TMR) on the initial temperature was calculated and compared with the results of HWS experiments carried out in the system with Ф-factor amounting to 3.2.The influence of the Ф-factor and reaction progress reached at the end of the HWS monitoring on the TMR is discussed.Presented calculations clearly indicate that even very minor reaction progress reduces the TMRad of 24h characteristic for a sample with initial reaction progress amounting to zero.Described estimation method can be verified by just one HWS-ARC,or by one correctly chosen ISO-ARC run of reasonable duration by knowing in advance the dependence of the TMR on the initial temperature for any Ф-factor.Prop

关键词： adiabatic condition methyl nitrophenol DSC Ф-factor kinetics thermal runaway,TMR

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World Journal of Gastroenterology 2014年第31期20卷 10984-10993页

作者： Claudia Roeder Sabine Jordan Julian Schulze zur Wiesch Heike Pfeiffer-Vornkahl Dietrich Hueppe Stefan Mauss Elmar Zehnter Sabine Stoll Ulrich Alshuth Ansgar W Lohse Stefan Lueth Department of Medicine Ⅰ University Hospital Hamburg Eppendorf Factum - company for statistics scientific information and communication mbH Center of Gastroenterology Wiescherstrasse 20 44623 Herne Germany Center for HIV and Hepatogastroenterology Grafenberger Allee 128a 40237 Duesseldorf Germany Center of Gastroenterology Am Oelpfad 12 44263 Dortmund Germany Virology Roche Pharma AG Emil-Barell-Stra?e 1 79639 Grenzach-Wyhlen Germany

AIM: To evaluate the safety and efficacy of pegylated interferon alfa-2a and ribavirin therapy in elderly patients with chronic hepatitis C infection.METHODS: Patients characteristics, treatment results and safety profiles of 4859 patients with hepatitis c virus(HCV) infection receiving treatment with pegylatedinterferon alfa-2a and ribavirin were retrieved from a large ongoing German multicentre non-interventional study. Recommended treatment duration was 24 wk for GT 2 and GT 3 infection and 48 wk for GT 1 and GT 4 infection. Patients were stratified according to age(latelet ratio index) was performed using pre-treatment laboratory data.RESULTS: Out of 4859 treated HCV patients 301(6.2%) were ≥ 60 years. There were more women(55.8% vs 34.2%, P aged ≥ 60 years and they presented more frequently with metabolic(17.6% vs 4.5%, P lar comorbidities(32.6% vs 6.7%, P age related difference in patients with genotype 1(23.7% vs 43.7%, P age and stage of liver disease were independent factors of SVR.CONCLUSION: Elderly HCV patients differ in clinical characteristics and treatment outcome from younger patients and demand special attention from their practitioner.

关键词： Hepatitis C virus infection Older patients Patient

Hepatitis B and D viruses replication interference: Influence of hepatitis B genotype

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World Journal of Gastroenterology 2016年第11期22卷 3165-3174页

作者： Antonio Madejón Míriam Romero ángela Hernández Araceli García-Sánchez Marta Sánchez-Carrillo Antonio Olveira Javier García-Samaniego Hepatology Section Gastroenterology Department Hospital Universitario La Paz 28046 Madrid Spain Centro de Investigación Biomédica en Red de Enfermedades Hepáticasy Digestivas (CIBERehd) 28046 Madrid Spain Instituto de Investigación del Hospital Universitario la Paz (IdiPAZ) 28046 Madrid Spain

AIM: To study the hepatitis B virus(HBV) and hepatitis D virus(HDV) replication interferences in patients with chronic hepatitis delta infected with different HBV genotypes.METHODS: We conducted a transversal study including 68 chronic hepatitis delta(CHD)(37 HIVpositive) patients and a control group of 49 chronic hepatitis B(CHB)(22 HIV-positive) patients. In addition, a dynamic follow-up was performed in 16 CHD patients. In all the samples, the surface antigen of hepatitis B(HBs ag) serum titers were analyzed with the Monolisa HBs ag Ultra system(Bio-Rad), using as quantification standard a serial dilution curve of an international HBs ag standard. Serum HBV-DNA titers were analyzed using the roche Cobas Taq Man(roche, Barcelona, Spain), and the serum HDV-RNA using an in-house real-time q RT-PCR method, with Taq Man probes. HBV genotype was determined with the line immunoassay Li PA HBV genotyping system(Innogenetics, Ghent, Belgium). In those patients negative for Li PA assay, a nested PCR method of complete HBs ag coding region, followed by sequence analysis was applied.RESULTS: No differences in the HBV-DNA levels were found in CHB patients infected with different HBV genotypes. However, in CHD patients the HBV-DNA levels were lower in those infected with HBV-A than in those with HBV-D, both in HIV negative [median(IQR): 1.25(1.00-1.35) vs 2.95(2.07-3.93) log10(copies/m L), P = 0.013] and HIV positive patients [2.63(1.24-2.69) vs 7.25(4.61-7.55) log10(copies/m L), P ag titers reflected no significant differences in CHD patients infected with HBV-A or D.CONCLUSION: Viral replication interference between HBV and HDV is HBV-genotype dependent, and more evident in patients infected with HBV-genotype A, than with HBV-D or E.

关键词： Hepatitis D virus Hepatitis B virus Delta hepatitis Replication interference Viral replication

Chronic hepatitis C:Treat or wait? Medical decision making in clinical practice

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World Journal of Gastroenterology 2012年第12期18卷 1339-1347页

作者： Claus Niederau Dietrich Hüppe Elmar Zehnter Bernd Mller Renate Heyne Stefan Christensen Rainer Pfaff Arno Theilmeier Ulrich Alshuth Stefan Mauss Katholische Kliniken Oberhausen St.Josef HospitalKlinik für Innere MedizinOberhausen 46045Germany Medical Office for Gastroenterology and Hepatology Herne 44623Germany Medical Office for Gastroenterology and Hepatology Dortmund 44263Germany Medical Office for Gastroenterology and Hepatology Berlin 10969Germany Center for Interdisciplinary Medicine Münster 48143Germany Medical Office for Gastroenterology and Hepatology Gie en 35392Germany Medical Office for Gastroenterology and Hepatology Mnchengladbach 41239Germany Pharma ag Medical Management Virology Grenzach-Wyhlen 79639Germany Center for HIV and Hepatogastroenterology Düsseldorf 40237Germany

AIM:To analyzes the decision whether patients with chronic hepatitis C virus (HCV) infection are treated or not.METHODS:This prospective cohort study included 7658 untreated patients and 6341 patients receiving pegylated interferon α2 a/ribavirin,involving 434 physicians/institutions throughout Germany (377 in private practice and 57 in hospital settings).A structured questionnaire had to be answered prior to the treatment decision,which included demographic data,information about the personal life situation of the patients,anamnesis and symptomatology of hepatitis C,virological data,laboratory data and data on concomitant diseases.A second part of the study analyzes patients treated with pegylated interferon α2a.All questionnaires included reasons against treatment mentioned by the physician.RESULTS:Overall treatment uptake was 45%.By multivariate analysis,genotype 1/4/5/6,HCV-RNA ≤ 520 000 IU/mL,normal alanine aminotransferase (ALT),platelets ≤ 142 500/μL,age > 56 years,female gender,infection length > 12.5 years,concomitant diseases,human immunodeficiency virus co-infection,liver biopsy not performed,care in private practice,asymptomatic disease,and unemployment were factors associated with reduced treatment rate.Treatment and sustained viral response rates in migrants (1/3 of cohort) were higher than in German natives although 1/3 of migrants had language problems.Treatment rate and liver biopsy were higher in clinical settings when compared to private practice and were low when ALT and HCV-RNA were low.CONCLUSION:Some reasons against treatment were medically based whereas others were related to fears,socio-economical problems,and information deficits both on the side of physicians and patients.

关键词：丙型肝炎病毒临床实践治疗慢性决策医疗 HCV