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cDc7 inhibition impairs neuroendocrine transformation in lung and prostate tumors through MYc degradation

Signal Transduction and Targeted Therapy 2024年第8期9卷 3519-3532页

作者： Alvaro Quintanal-Villalonga Kenta Kawasaki Esther Redin Fathema Uddin Swanand Rakhade Vidushi Durani Amin Sabet Moniquetta Shafer Wouter R.Karthaus Samir Zaidi Yingqian A.Zhan Parvathy Manoj Harsha Sridhar Dennis Kinyua Hong Zhong Barbara P.Mello Metamia ciampricotti Umesh K.Bhanot Irina Linkov Juan Qiu Radhika A.Patel colm Morrsey Sanjoy Mehta Jesse Barnes michael c.haffner Nichlas D.Socci Richard P.Koche Elisa de Stanchina Sonia Molina-Pinelo Sohrab Salehi Helena A.Yu Joseph M.chan charles M.Rudin Department of Medicine Thoracic Oncology ServiceMemorial Sloan Kettering Cancer CenterNew YorkNYUSA cancer Biology and Genetics Program Sloan Kettering InstituteMemorial Sloan Kettering Cancer CenterNew YorkNYUSA Vagelos college of Physicians and Surgeons Columbia UniversityNew YorkNYUSA Weill cornell Graduate School of Medical Sciences Weill Cornell MedicineNew YorkNYUA Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer CenterNew YorkNYUSA center for Epigenetics Research Memorial Sloan Kettering Cancer CenterNew YorkNYUSA Pathology core Facilty Department of Pathology and Laboratory MedicineMSKCCNew YorkNYUSA Antitumor Assessment core Memorial Sloan Kettering Cancer CenterNew YorkNYUSA Divisionsof Human Biology and clinical Research Fred Hutchinon Cancer CenterSeattleWAUSA Deparmentof Urology University of WashingtonSeattleWAUSA Gene Editing&Screening core Facility Memorial Sloan Kettering cancer center New YorkNYUSA Department of Laboratory Medicine and Pathology University of WashingtonSeattleWAUSA Bioinfomatics coreFacility Memorial Soan Kettering Cancer CenterNew YorkNYUSA Institute of Biomedicine of Seille(Bis) HURCSCUniversidad de SevillaSevilleSpain computational Oncology Department of Epidemiology and BiostatisticsMemorial Sloan Kettering Cancer CenterNew YorkNYUSA Well cornell Medical college New York NYUSA Present address:Swiss Institute for Experimental cancer Research(ISREc) School of Life SciencesEPFLLausanneSwitzerland

Neuroendocrine(NE)transformation is a mechanism of resistance to targeted therapy in lung and prostate adenocarcinomas leading to poor *** to date,even if patients at high risk of transformation can be identified by the occurrence of Tumor Protein P53(TP53)and Retinoblastoma Transcriptional corepressor 1(RB1)mutations in their tumors,no therapeutic strategies are available to prevent or delay histological *** of the cell cycle kinase cell Division cycle 7(cDc7)occurred in tumors during the initial steps of NE transformation,already after TP53/RB1 co-inactivation,leading to induced sensitivity to the cDc7 inhibitor ***7 inhibition suppressed NE transdifferentiation and extended response to targeted therapy in in vivo models of NE transformation by inducing the proteasome-mediated degradation of the MYc Proto-Oncogen(MYc),implicated in stemness and histological *** overexpression of a degradation-resistant MYc isoform reestablished the NE transformation phenotype observed on targeted therapy,even in the presence of ***7 inhibition also markedly extended response to standard cytotoxics(cisplatin,irinotecan)in lung and prostate small cell carcinoma *** results nominate cDc7 inhibition as a therapeutic strategy to constrain lineage plasticity,as well as to effectively treat NE tumors de novo or after *** simurosertib clinical efficacy trials are ongoing,this concept could be readily translated for patients at risk oftransformation.

关键词： tumors markedly transformation

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If this is true, what does it imply? How end-user antibody validation facilitates insights into biology and disease

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Asian Journal of Urology 2019年第1期6卷 10-25页

作者： Karen S.Sfanos Srinivasan Yegnasubramanian William G.Nelson Tamara L.Lotan Ibrahim Kulac Jessica L.Hicks Qizhi Zheng charles J.Bieberich michael c.haffner Angelo M.De Marzo Department of Pathology Johns Hopkins University School of MedicineBaltimoreMDUSA Department of Oncology The Johns Hopkins University School of MedicineBaltimoreMDUSA Department of Pathology Koc Universitesi Tip FakultesiIstanbulTurkey Department of Biological Sciences University of Maryland Baltimore CountyBaltimoreMDUSA

Antibodies are employed ubiquitously in biomedical sciences,including for diagnostics and *** of the most important uses is for immunohistochemical(IHc)staining,a process that has been improving and evolving over *** is useful when properly employed,yet misuse of the method is widespread and contributes to the“reproducibility crisis”in *** report some of the common problems encountered with IHc assays,and direct readers to a wealth of literature documenting and providing some solutions to this *** also describe a series of vignettes that include our approach to analytical validation of antibodies and IHc assays that have facilitated a number of biological insights into prostate cancer and the refutation of a controversial association of a viral etiology in *** postulate that a great deal of the problem with lack of accuracy in IHc assays stems from the lack of awareness by researchers for the critical necessity for end-users to validate IHc antibodies and assays in their laboratories,regardless of manufacturer claims or past *** suggest that one reason for the pervasive lack of end-user validation for research antibodies is that researchers fail to realize that there are two general classes of antibodies employed in ***,there are antibodies that are“clinical grade”reagents used by pathologists to help render diagnoses that influence patient *** diagnostic antibodies,which tend to be highly validated prior to clinical implementation,are in the vast minority(e.g.class of antibodies are“research grade”antibodies(now numbering>3800000),which are often not extensively validated prior to *** increased awareness of the problem,both the United States,National Institutes of Health and some journals are requiring investigators to provide evidence of specificity of their antibody-based assays.

关键词： Prostate cancer Antibodies Immunohistochemistry

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格列美脲与匹格列酮对2型糖尿病患者颈动脉内膜中层厚度影响的比较研究：随机试验

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美国医学会杂志（中文版） 2007年第2期26卷 77-85页

作者： Theodore Mazzone Peter M. Meyer Steven B. Feinstein michael H. Davidson George T. Kondos Ralph B. D＇Agostino Alfonsp Perez Jean-claude Provost StevenM. haffner 胡与（译）李呈亿（校） Department of Medicine Section of Endocrinology Diabetes and Metabolism Department of Medicine Section of Endocrinology and Section of Cardiology University of Illinois college of Medicine. chicago Departments of Preventive Medicine University of Illinois college of Medicine and Medicine Section of Cardiology Rush University Medical center Chicago Department of Mathematics Statistics and Consulting Unit Boston University Boston Mass Takeda Global Research and Developmerit Inc Lincolnshire lll Takeda Global Research Synarc Paris Franoe Department of Medicine Uni- versity of Texas Health Sdence Center at San Antonio 不详

背景：颈动脉内膜中层厚度（carotid artery intima—media thickness，cIMT）是冠状动脉粥样硬化的一种标志物，可以独立地预测心血管事件的发生。2型糖尿病患者心血管事件有所增加。尽管相对短期的研究显示，噻唑烷二酮类药物（例如... 详细信息

背景：颈动脉内膜中层厚度（carotid artery intima—media thickness，cIMT）是冠状动脉粥样硬化的一种标志物，可以独立地预测心血管事件的发生。2型糖尿病患者心血管事件有所增加。尽管相对短期的研究显示，噻唑烷二酮类药物（例如匹格列酮）可以减缓cIMT的进展，但是长期研究结果目前尚不明确。目的：与格列美脲比较，评估匹格列酮对2型糖尿病患者颈总动脉cIMT变化的影响。设计、地点及参试者：2003年10月至2006年5月于芝加哥城区28家临床单位收治的2型糖尿病患者中进行随机、双盲、对照、多中心试验。治疗期为72周（随访1周）。在每个中心由一位超声检查操作者采集cIMT影像，由一位不了解治疗分组情况的判读者应用自动边缘检测技术进行判读。462例2型糖尿病成人患者（平均年龄，60[SD，8．1]岁；平均体重指数，32[SD，5．1]；平均病程7．7[SD，7．2]年；平均糖化血红蛋白值[HbA1c]，7．4％[SD，1．0％]）或者为新近确诊，或者为目前已接受饮食／锻炼、磺酰脲类、二甲双胍、胰岛素或联合治疗的患者。干预：盐酸匹格列酮（15—45 mg／d）和作为有效比较的格列美脲（1—4mg／d）。主要观测指标：与基线比较，最后随访时左右两侧颈总动脉后壁平均cIMT的绝对变化。结果：与格列美脲比较，各时点（24、48、72周）匹格列酮组cIMT的平均变化较小。72周时，匹格列酮组与格列美脲组比较，平均cIMT进展一级终点较小（分别为-0.001mm和＋0．012mm；差别为-0．013mm；95％可信区间，-0．024至-0．002；P=0．02）。与格列美脲比较，匹格列酮还可减缓最大cIMT进展（72周时分别为0．002mm和0．026mm；差别为-0．024mm；95％可信区间，-0．042至-0．006；P=0．008）。在根据年龄、性别、收缩压、DM病程、体重指数、Hb1c。值以及他汀类药物使用预先确定的各亚组间，匹格列酮对平均cIMT的有益效应相似。结论：与格列美脲比较，在为期18个月的治疗期间，匹格列酮减缓了2型糖尿病患者cIMT的进展。

关键词：颈动脉内膜中层厚度 2型糖尿病患者匹格列酮格列美脲随机试验冠状动脉粥样硬化噻唑烷二酮类药物糖化血红蛋白值

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罗格列酮持续有效降低c反应蛋白水平

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药品评价 2010年第1期7卷 39-39页

作者： Kahn SE haffner SM Viberti G

研究者对ADOPT研究随访观察4年发现，与格列本脲和二甲双胍相比，罗格列酮分别降低糖尿病患者c反应蛋白（cRP）水平47．6％和30．5％，且独立于胰岛素敏感性、HbA1c水平及体重增加之外。说明罗格列酮可持续有效降低cRP水平，而格列本脲... 详细信息

研究者对ADOPT研究随访观察4年发现，与格列本脲和二甲双胍相比，罗格列酮分别降低糖尿病患者c反应蛋白（cRP）水平47．6％和30．5％，且独立于胰岛素敏感性、HbA1c水平及体重增加之外。说明罗格列酮可持续有效降低cRP水平，而格列本脲和二甲双胍对cRP的影响与患者体重变化相关。

关键词： c反应蛋白蛋白水平罗格列酮持续有效胰岛素敏感性二甲双胍格列本脲 HbA1c

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