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Tumor heterogeneity in VHL drives metastasis in clear cell renal cell carcinoma

Signal Transduction and Targeted Therapy 2023年第5期8卷 2329-2344页

作者： Junhui Hu Ping Tan moe Ishihara nicholas ABayley Shiruyeh Schokrpur Jeremy GReynoso Yangjun Zhang Raymond JLim Camelia Dumitras Lu Yang Steven mDubinett Parmjit SJat Jacques Van Snick Jiaoti Huang Arnold IChin Robert mPrins Thomas GGraeber Hua Xu Lily Wu Department of molecular and medical Pharmacology David Geffen School of MedicineUniversity of California Los AngelesLos AngelesCA90095USA Department of Urology West China HospitalChengduChina Department of Hematology and Oncology University of California San DiegoSan DiegoCA92103USA Department of Neurosurgery David Geffen School of MedicineUniversity of California Los AngelesLos AngelesCA90095USA Department of Biological Repositories Department of UrologyZhongnan Hospital of Wuhan UniversityWuhanChina Department of medicine David Geffen School of MedicineUniversity of California Los AngelesLos AngelesCA90095USA Jonsson Comprehensive Cancer Center David Geffen School of Medicine at UCLAUniversity of California Los AngelesLos AngelesCA90095USA mRC Prion Unit at UCL Institute of Prion Diseases33 Cleveland StreetLondonW1W 7FFUK Ludwig Institute for Cancer Research Ltd BrusselsBelgium Department of Pathology Duke UniversityDurhamNCUSA Department of Urology David Geffen School of MedicineUniversity of California Los AngelesLos AngelesCA90095USA Cancer Precision Diagnosis and Treatment and Translational medicine Hubei Engineering Research Center WuhanChina

Loss of function of the von Hippel-Lindau(VHL)tumor suppressor gene is a hallmark of clear cell renal cell carcinoma(ccRCC).The importance of heterogeneity in the loss of this tumor suppressor has been under *** study the impact of intratumoral VHL heterogeneity observed in human ccRCC,we engineered VHL gene deletion in four RCC models,including a new primary tumor cell line derived from an aggressive metastatic *** VHL gene-deleted(VHL-KO)cells underwent epithelial-to-mesenchymal transition(EmT)and exhibited increased motility but diminished proliferation and tumorigenicity compared to the parental VHL-expressing(VHL+)*** tumors with either VHL+or VHL-KO cells alone exhibit minimal metastatic *** tumors displayed rampant lung metastases,highlighting a novel cooperative metastatic *** poorly proliferative VHL-KO cells stimulated the proliferation,EmT,and motility of neighboring VHL+***(POSTN),a soluble protein overexpressed and secreted by VHL non-expressing(VHL−)cells,promoted metastasis by enhancing the motility of VHL-WT cells and facilitating tumor cell vascular *** deletion or antibody blockade of POSTN dramatically suppressed lung metastases in our preclinical *** work supports a new strategy to halt the progression of ccRCC by disrupting the critical metastatic crosstalk between heterogeneous cell populations within a tumor.

关键词： VHL metastasis motility

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Combinations of chronic conditions,functional limitations and geriatric syndromes associated with periodontal disease

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Family medicine and Community Health 2022年第3期10卷 20-26页

作者： Hussam m Alqahtani Siran m Koroukian Kurt Stange Nabil F Bissada nicholas K Schiltz Department of Population and Quantitative Health Sciences Case Western Reserve University School of MedicineClevelandOhioUSA Department of Preventive Dental Science King Saud bin Abdulaziz University for Health SciencesRiyadhSaudi Arabia Center for Community Health Integration Case Comprehensive Cancer CenterClevelandOhioUSA Department of Periodontics Case Western Reserve University School of Dental MedicineClevelandOhioUSA

Objective To identify complex multimorbid conditions,including chronic conditions,functional limitations and geriatric syndromes,associated with the presence and severity of periodontal disease(PD),after accounting for a series of demographic and behavioural *** This cross-sectional study used secondary data from a nationally representative sample,classification and regression tree analysis and random forest identified combinations of specific conditions constituting complex multimorbidity associated with the presence and severity of *** US National Health and Nutritional Examination Survey(2013-2014).Participants Individuals 60 years of age or older who completed a periodontal *** Among 937 participants aged 60 and over,the prevalence of PD was 72.6%.PD was associated with sociodemographic factors and limitations in instrumental activities of daily *** sex and non-white race were the two most critical predictors of stage III/IV *** important factors included age,education level and the federal poverty *** Rather than chronic conditions or geriatric syndromes,PD was associated with sociodemographic factors and functional *** for the co-occurrence of sociodemographic and functional limitations will help recognise older adults who are at an increased vulnerability to the severity of PD.

关键词： periodontal limitations functional

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在SRC-I工艺流程中利用物理溶剂法脱除酸性气的最优化条件

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煤炭转化 1983年第3期 16-26页

作者： David m.nicholas,汪幼芝美国国际煤精炼公司

一、前言物理溶剂法在合成燃料生产中用来脱除气体的酸性组份（主要是H2S和CO2）,起着重要的作用。当需要处理的气体具有较高的酸性气体分压（>100 psia）,含有多种硫化物,并且所含CO2的量比H2S多时,采用物理溶剂法最为有利。物理溶剂... 详细信息

一、前言物理溶剂法在合成燃料生产中用来脱除气体的酸性组份（主要是H2S和CO2）,起着重要的作用。当需要处理的气体具有较高的酸性气体分压（>100 psia）,含有多种硫化物,并且所含CO2的量比H2S多时,采用物理溶剂法最为有利。物理溶剂法不涉及化学反应,它只是取决于气体中的酸性组份在溶剂中的溶解度。一般说来,物理溶剂的作

关键词：物理溶剂进料贫液酸性气天然气吸收塔废气处理设备脱除闪蒸气 SRC-I 富液解吸塔

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获得性免疫缺陷综合征患者的寡克隆免疫球蛋白

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宁夏医科大学学报 1986年第2期 93-94页

作者： nicholas m. Papadopoulos 王湘仪

用高分辩电泳法对获得性免疫缺陷综合征(acquired immunodeficiency syadrome,AIDS)患者的血清标本作了分析。发现27例Kaposi氏肉瘤患者中的24例和15例条件致病性感染(opportu nist infection,OI)中的2例的血清,单克隆和寡克隆免疫球蛋... 详细信息

用高分辩电泳法对获得性免疫缺陷综合征(acquired immunodeficiency syadrome,AIDS)患者的血清标本作了分析。发现27例Kaposi氏肉瘤患者中的24例和15例条件致病性感染(opportu nist infection,OI)中的2例的血清,单克隆和寡克隆免疫球蛋白(oligoclonal immunoglobulins)的出现率高。单克隆蛋白带的存在与患者是否有过OI无关。这些发现说明,伴有Kaposi氏肉瘤的AIDS患者中单克隆或寡克隆B—细胞活化的发生率要高得多。从而提示,在AIDS患者的B—细胞和内皮细胞恶性或假恶性增殖当中,相似的机制可能起着作用。获得性免疫缺陷综合征(AIDS)是近来报道的一种病,它由严重的条件致病性感染(opportunistinfection,OI)、Kaposi氏肉瘤(KS)的发生,淋巴腺肿瘤和细胞免疫体系的基本功能丧失等组成。最近已经报道了这些病人多克隆B—淋巴细胞活化作用和B-细胞免疫调节异常。我们用高分辩电泳法证明了那些存在KS的AIDS患者,除了有以前报道过的多克隆B—细胞活化作用之外,单克隆或寡克隆B—细胞还有变化。

关键词：获得性免疫缺陷综合征 KS 单克隆艾滋病病毒病寡克隆 AIDS 免疫球蛋白患者

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Stem cell-based therapy for human diseases

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Signal Transduction and Targeted Therapy 2022年第9期7卷 3242-3282页

作者： Duc m.Hoang Phuong T.Pham Trung Q.Bach Anh T.L.Ngo Quyen T.Nguyen Trang T.K.Phan Giang H.Nguyen Phuong T.T.Le Van T.Hoang nicholas R.Forsyth michael Heke Liem Thanh Nguyen Department of Research and Development Vinmec Research Institute of Stem Cell and Gene TechnologyVinmec Healthcare SystemHanoiVietnam Department of Cellular Therapy Vinmec High.Tech CenterVinmec Healthcare SsystemHanoiVietnam Institute for Science&Technology in medicine Keele UniversityKeeleUK a Department of Biology Stanford UniversityStanfordCAUSA

Recent advancements in stem cell technology open a new door for patients suffering from diseases and disorders that have yet to be *** cell-based therapy,including human pluripotent stem cells(hPsCs)and multipotent mesenchymal stem cells(mSCs),has recently emerged as a key player in regenerative *** are defined as self-renewable cell types conferring the ability to differentiate into various cellular phenotypes of the human body,including three germ *** are multipotent progenitor cells possessing self-renewal ability(limited in vitro)and differentiation potential into mesenchymal lineages,according to the International Society for Cell and Gene Therapy(ISCT).This review provides an update on recent clinical applications using either hPSCs or mSCs derived from bone marrow(Bm),adipose tissue(AT),or the umbilical cord(UC)for the treatment of human diseases,including neurological disorders,pulmonary dysfunctions,metabolic/endocrine-related diseases,reproductive disorders,skin burns,and cardiovascular ***,we discuss our own clinical trial experiences on targeted therapies using msCs in a clinical setting,and we propose and discuss the mSC tissue origin concept and how mSC origin may contribute to the role of mSCs in downstream applications,with the ultimate objective of facilitating translational research in regenerative medicine into clinical *** mechanisms discussed here support the proposed hypothesis that Bm-mSCs are potentially good candidates for brain and spinal cord injury treatment,AT-mSCs are potentially good candidates for reproductive disorder treatment and skin regeneration,and UC-msCs are potentially good candidates for pulmonary disease and acute respiratory distress svndrometreatment.

关键词： diseases distress treatment

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Leveraging mathematical models of disease dynamics and machine learning to improve development of novel malaria interventions

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Infectious Diseases of Poverty 2022年第3期11卷 37-53页

作者： monica Golumbeanu Guo-Jing Yang Flavia Camponovo Erin m.Stuckey nicholas Hamon mathias mondy Sarah Rees Nakul Chitnis Ewan Cameron melissa A.Penny Swiss Tropical and Public Health Institute AllschwilSwitzerland Key Laboratory of Tropical Translational medicine of ministry of Education and School of Tropical medicine and Laboratory medicine The First and Second Affiliated Hospital of Hainan Medical UniversityHainan Medical UniversityHaikouHainanPeople’s Republic of China University of Basel BaselSwitzerland Center for Communicable Disease Dynamics Department of EpidemiologyHarvard T.H.Chan School of Public HealthBostonMA02115USA The Bill&melinda Gates Foundation SeattleWAUSA Innovative Vector Control Consortium LiverpoolUK malaria Atlas Project Big Data InstituteUniversity of OxfordOxfordUK Curtin University PerthAustralia Telethon Kids Institute Perth Children’s HospitalPerthAustralia

Background:Substantial research is underway to develop next-generation interventions that address current malaria control *** there is limited testing in their early development,it is difficult to predefine intervention properties such as efficacy that achieve target health goals,and therefore challenging to prioritize selection of novel candidate ***,we present a quantitative approach to guide intervention development using mathematical models of malaria dynamics coupled with machine *** analysis identifies requirements of efficacy,coverage,and duration of effect for five novel malaria interventions to achieve targeted reductions in malaria ***:A mathematical model of malaria transmission dynamics is used to simulate deployment and predict potential impact of new malaria interventions by considering operational,health-system,population,and disease *** method relies on consultation with product development stakeholders to define the putative space of novel intervention *** couple the disease model with machine learning to search this multi-dimensional space and efficiently identify optimal intervention properties that achieve specified health ***:We apply our approach to five malaria interventions under *** for malaria prevalence reduction,we identify and quantify key determinants of intervention impact along with their minimal properties required to achieve the desired health *** coverage is generally identified as the largest driver of impact,higher efficacy,longer protection duration or multiple deployments per year are needed to increase prevalence *** show that interventions on multiple parasite or vector targets,as well as combinations the new interventions with drug treatment,lead to significant burden reductions and lower efficacy or duration ***:Our approach uses disease dynamic models and machine learning to support

关键词： Infectious diseases malaria Novel interventions mathematical modelling machine learning

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Lineage relationship of CD8^＋ T cell subsets is revealed by progressive changes in the epigenetic landscape

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Cellular & molecular Immunology 2016年第4期13卷 502-513页

作者： Joseph G. Crompton manikandan Narayanan Suresh Cuddapah Rahul Roychoudhuri Yun Ji Wenjing Yang Shashank J. Patel madhusudhanan Sukumar Douglas C. Palmer Weiqun Peng Ena Wang Francesco m. marincola Christopher A. Klebanoff Keji Zhao John S. Tsang Luca Gatt-inoni nicholas P. Restifo Surgery Branch National Cancer Institute National Institutes of Health Bethesda MD 20892 USA Cambridge Institute for medical Research University of Cam bridge Cambridge CB20XY UK Systems Genomics and Bioinformatics Unit Laboratory of Systems Biology National Institute of Allergy and Infectious Diseases National Institutes of Health Bethesda MD 20892 USA Department of Environmental medicine New York University School of Medicine Tuxedo NY 10987 USA Experimental Transplantation and Immunology Branch National Cancer Institute National Institutes of Health Bethesda MD 20892 USA Department of Physics The George Washington University Washington DC 20052 USA Research Branch Sidra Medical and Research Centre Doha Qatar Infectious Disease and Immunogenetics Section Department of Transfusion Medicine Clinical Center National Institutes of Health Bethesda MD 20892 USA Clinical Investigator Development Program NCI/NIH Bethesda MD 20892 USA Systems Biology Center National Heart Lung and Blood Institute National Institutes of Health Bethesda MD 20892 USA. Lombardi Comprehensive Cancer Center Georgetown University Washington. DC 20007. United States. Bethesda. MD 20892. USA.

To better elucidate epigenetic mechanisms that correlate with the dynamic gene expression program observed upon T-cell differentiation, we investigated the genomic landscape of histone modifications in naive and memory CD8＋ T cells. Using a ChlP-Seq approach coupled with global gene expression profiling, we generated genome-wide histone H3 lysine 4 （H3K4me3） and H3 lysine 27 （H3K27me3） trimethylation maps in naive, T memory stem cells, central memory cells, and effector memory cells in order to gain insight into how histone architecture is remodeled during T cell differentiation. We show that H3K4me3 histone modifications are associated with activation of genes, while H3K27me3 is negatively correlated with gene expression at canonical loci and enhancers associated with T-cell metabolism, effector function, and memory. Our results also reveal histone modifications and gene expression signatures that distinguish the recently identified T memory stem cells from other CD8＋ T-cell subsets. Taken together, our results suggest that CD8＋ lymphocytes undergo chromatin remodeling in a progressive fashion. These findings have major implications for our understanding of peripheral T-cell ontogeny and the formation of immunological memory.

关键词： TRANSCRIPTION FACTOR STEm-CELLS mEmORY EFFECTOR DIFFERENTIATION BET FATE LYmPHOCYTES mAINTENANCE GENERATION

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Emerging mechanisms for exercise effects on muscle wasting and anabolic resistance

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Sports medicine and Health Science 2020年第4期2卷 175-176页

作者： J.William Deaver nicholas P.Greene Cachexia Research Laboratory Exercise Science Research CenterDepartment of HealthHuman Performance and RecreationUniversity of ArkansasFayettevilleARUSA muscle Biology Laboratory Department of Health and KinesiologyTexas A&M UniversityCollege StationTXUSA

Introduction At the 2018 Annual meeting of the American College of Sports medicine,presentations were given by *** ***,James ***,and James ***,at a symposium titled“Emerging mechanisms for Exercise Effects on muscle Wasting and Anabolic Resistance”.Inspired by the presentations at this symposium,the following reviews have been crafted to examine the current understanding of muscle diseases characterized by muscle wasting and anabolic resistance,particularly their identification,development,progression,and mitigation.

关键词： resistance mechanisms muscle

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Specific bone region localization of osteolytic versus osteoblastic lesions in a patient-derived xenograft model of bone metastatic prostate cancer

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Asian Journal of Urology 2016年第4期3卷 229-239页

作者： Takeshi Hirata Seung Chol Park michelle T.muldong Christina N.Wu Tomonori Yamaguchi Amy Strasner Omer Raheem Hiromi Kumon Robert L.Sah nicholas A.Cacalano Catriona H.m.Jamieson Christopher J.Kane Koichi masuda Anna A.Kulidjian Christina A.m.Jamieson Department of Urology Okayama University Graduate School of MedicineDentistry and Pharmaceutical SciencesOkayamaJapan Department of Urology Wonkwang University School of Medicine and HospitalIksanSouth Korea moores Cancer Center University of CaliforniaSan DiegoLa JollaCAUSA Department of Urology University of CaliforniaSan DiegoLa JollaCAUSA Department of Surgery University of CaliforniaSan DiegoLa JollaCAUSA Department of medicine University of CaliforniaSan DiegoLa JollaCAUSA Department of Orthopaedic Surgery School of MedicineUniversity of CaliforniaSan DiegoLa JollaCAUSA Department of Bioengineering University of CaliforniaSan DiegoLa JollaCAUSA Department of Radiation Oncology University of California at Los AngelesLos AngelesCAUSA

Objective:Bone metastasis occurs in up to 90%of men with advanced prostate cancer and leads to fractures,severe pain and *** metastases induce a spectrum of types of bone lesions which can respond differently to therapy even within individual prostate cancer ***,the special environment of the bone makes the disease more complicated and incurable.A model in which bone lesions are reproducibly induced that mirrors the complexity seen in patients would be invaluable for pre-clinical testing of novel *** microstructural changes in the femurs of mice implanted with PCSD1,a new patient-derived xenograft from a surgical prostate cancer bone metastasis specimen,were ***:Quantitative micro-computed tomography(micro-CT)and histological analyses were performed to evaluate the effects of direct injection of PCSD1 cells or media alone(Control)into the right femurs of Rag2/gc/male ***:Bone lesions formed only in femurs of mice injected with PCSD1 *** volume(BV)was significantly decreased at the proximal and distal ends of the femurs(pmeter(pmur ***:PCSD1 cells reproducibly induced bone loss leading to osteolytic lesions at the ends of the femur,and,in contrast,induced aberrant bone formation leading to osteoblastic lesions along the femur ***,the interaction of PCSD1 cells with different bone region-specific microenvironments specified the type of bone *** approach can be used to determine if different bone regions support more therapy resistant tumor growth,thus,requiring novel treatments.

关键词： Bone metastatic prostate cancer Patient-derived xenograft microenvironment microstructural CT Osteolytic lesions Osteoblastic lesions

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高功率激光二极管端面抽运复合晶体激光器的研究

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中国激光 2005年第3期32卷 297-300页

作者：李志刚熊政军黄维玲陈涛 nicholas moore G.C.Lim 华中科技大学激光工程技术研究院 Singapore Institute of manufacturing Technology 638075 Singapore

在高功率激光二极管抽运固体激光器中,热效应已成为获得高输出功率和高光束质量的最大阻碍因素.用有限元方法研究了高功率激光二极管端面抽运Nd∶YVO4激光器中热透镜分布规律,提出了用复合晶体消除热透镜效应的方法.研究表明在端面抽运... 详细信息

在高功率激光二极管抽运固体激光器中,热效应已成为获得高输出功率和高光束质量的最大阻碍因素.用有限元方法研究了高功率激光二极管端面抽运Nd∶YVO4激光器中热透镜分布规律,提出了用复合晶体消除热透镜效应的方法.研究表明在端面抽运的传统单一Nd∶YVO4晶体激光器中,由于抽运功率密度很高,热透镜效应非常严重,由端面变形而造成的热透镜效应约占整个热透镜效应的50%;而采用复合晶体能够很好地消除由端面变形而造成的热透镜效应,同时得到很好的冷却效果,获得比采用传统单一晶体高出许多的基模输出功率和更好的光束质量.实验证明,采用复合结构晶体在23 W的抽运功率水平下得到了11 W的基模输出功率,光束质量因子m2 <1 5,光光转换效率达到48%.

关键词：激光技术激光二极管端面抽运热透镜有限元 Nd:YVO4晶体复合晶体

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