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ROS1 in Squamous Non-Small Cell Lung Cancer—Combined Immunotherapy (PD1/CTLA4) or Targeted Therapy?

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Journal of Cancer Therapy 2020年第6期11卷 365-370页

作者： Alexander Yakobson Tal Mor Levitas Dina Laila C. Roisman Daniel Levin Wafeek Alguayn Sara Morgenstern Keren Rouvinov nir peled Waleed Kian The Legacy Heritage Oncology Center & Dr. Larry Norton Institute Soroka Medical Center & Ben-Gurion University Beer-Sheva Israel Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel Faculty of Health Sciences Ben-Gurion University of the Negev Beer-Sheva Israel Rabin Medical Center Beilinson Campus Petah Tikva Israel

ROS1 oncogenic fusion is reported to be 1% - 2% of non-small cell lung cancers (NSCLCs) of the adenocarcinoma subgroup. Meanwhile, there are no records of squamous cell cancer patients with tumors harboring ROS1 fusions. The Foundation Medicine database indicates a frequency of ROS1 rearrangements is 0.2% among squamous NSCLC. Crizotinib is known to be very effective in these patients. Here we present a non-smoker patient who had pure squamous NSCLC that was treated by combinational immunotherapy under a clinical trial and progressed after 2 cycles. Surprisingly, comprehensive genomic profiling detected a rare oncogenic EZR-ROS1 fusion, and the patient was treated by crizotinib with a significant response within 6 weeks. To date, the patient has been on therapy for 42 months and has achieved a complete metabolic response.

关键词： ROS1 Crizotinib Squamous Cell Lung Cancer Immunotherapy Non-Small Cell Lung Cancer

Better Selection Model for EML4-ALK Fusion Gene Test in Patients with Non-Small-Cell Lung Cancer

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Journal of Cancer Therapy 2013年第8期4卷 54-58页

作者： Dekel Shlomi Amir Onn Maya Gottfried Jair Bar Haim Biran Maya Ilouze Addie Dvir Hovav Nechushtan Lior Soussan-Gutman nir peled Oncology Department Meir Medical Center Kfar Saba Israel Oncotest-TEVA Teva Pharmaceutical Industries LTD. Shoham Israel Pulmonary-Oncology Unit Chaim Sheba Medical Center Tel Hashomer Israel Sharett Institute of Oncology Hadassah He- brew University Medical Center Jerusalem Israel.

Background: In the last decade, the search for gene mutations in lung cancer has been constantly growing. EGFR, KRAS mutations and, recently, the EML4-ALK fusion can guide the selection of treatment for patients who carry a specific mutation. Methods: During 2010-2011, EML4-ALK fusion test has been performed in Israel, mostly for wild type EGFR non-squamous NSCLC patients based on fluorescent in-situ hybridization (FISH) technique to detect EML4-ALK rearrangements. Results: Between January 2010 and December 2011, 3341 patients were diagnosed with lung cancer in Israel. Of the 2997 patients with NSCLC 687 had squamous cell carcinoma and 2310 had non-squamous NSCLC. This study focused on available 125 non-squamous NSCLC cases in which analysis for EML4-ALK rearrangement was available. All were negative for EGFR mutation. Nineteen (15.2%) were found positive for the fusion, a figure 2 - 10 times higher compared with previously reported findings. The EML4-ALK fusion was significantly more prevalent in younger male patients (52.1 vs. 61.3 years, p = 0.049), in whom every additional year reduced the chance to find the fusion by 7% [CI = 0.93 (0.88 - 0.99), p = 0.03]. Conclusions: A stepwise approach based on histology and prior EGFR analysis to detect EML4-ALK fusion is highly efficient with a related increased yield of detection. We recommend testing patients with non-squamous cell lung carcinoma after ruling out an EGFR mutation. The chance to find the ALK fusion is significantly greater in younger men.

关键词： Lung Cancer EML4-ALK Gene Mutation EGFR Histology

帕博利珠单抗单药治疗PD-L1阳性伴脑转移的非小细胞肺癌患者的疗效：KEYNOTE-001、010、024和042研究的汇总分析

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中国肺癌杂志 2022年第9期25卷 701-712页

作者： Aaron S. MANSFIELD Roy S. HERBST Gilberto de CASTRO Jr. Rina HUI nir peled Dong-Wan KIM Silvia NOVELLO Miyako SATOUCHI Yi-Long WU Edward B.GARON Martin RECK Andrew G.ROBINSON Ayman SAMKaRI Bilal PIPERDI Victoria EBIANA Jianxin LIN Tony S.K.MOK 黎扬斯 Division of Medical Oncology Mayo Clinic Yale Comprehensive Cancer Center Yale University School of Medicine Instituto do Cancer do Estado de S?o Paulo Westmead Hospital and the University of Sydney Soroka Cancer Center Ben Gurion University Seoul National University Hospital Seoul National University College of Medicine Azienda Ospedaliero-Universitaria San Luigi Gonzaga University of Turin Hyogo Cancer Center Guangdong Lung Cancer Institute Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences David Geffen School of Medicine at the University of California Los Angeles Lung Clinic Grosshansdorf Airway Research Center North German Center of Lung Research Cancer Centre of Southeastern Ontario at Kingston General Hospital Merck & Co. Inc. State Key Laboratory of Translational Oncology Chinese University of Hong Kong 广东省人民医院广东省人民医院肿瘤医院广东省肺癌研究所

背景与目的我们回顾性评估了程序性死亡配体1（programmed death ligand 1, PD-L1）阳性非小细胞肺癌（non-small cell lung cancer, NSCLC）患者的预后，以比较基线（即入组时）脑转移与帕博利珠单抗及化疗的疗效关系。方法我们汇总... 详细信息

背景与目的我们回顾性评估了程序性死亡配体1（programmed death ligand 1, PD-L1）阳性非小细胞肺癌（non-small cell lung cancer, NSCLC）患者的预后，以比较基线（即入组时）脑转移与帕博利珠单抗及化疗的疗效关系。方法我们汇总分析了KEYNOTE-001（NCT01295827）、KEYNOTE-010（NCT01905657）、KEYNOTE-024（NCT02142738）和KEYNOTE-042（NCT02220894）研究中既往接受过治疗或未接受过的PD-L1阳性[肿瘤细胞阳性比例评分（tumor proportion score, TPS）≥1%]的晚期或转移性NSCLC患者的数据。患者接受帕博利珠单抗（2 mg/kg,10 mg/kg，或每3周200 mg或每2周10 mg/kg）治疗；而化疗是除KEYNOTE-001外所有研究的对照组。所有研究都纳入了既往接受过治疗的稳定脑转移的患者。结果共计纳入3,170例患者，基线时，293例（9.2%）患者伴有脑转移，而2,877例（90.8%）是无脑转移患者；数据截止时，中位（范围）随访时间为12.9（0.1-43.7）个月。与化疗相比，帕博利珠单抗可改善基线伴有脑转移及无脑转移患者的总生存期：PD-L1 TPS≥50%[分别为0.67（95%CI:0.44-1.02）和0.66（95%CI:0.58-0.76）]和PD-L1 TPS≥1%[分别为0.83（95%CI:0.62-1.10）和0.78（95%CI:0.71-0.85）]。无论是否有脑转移，与化疗相比，接受帕博利珠单抗治疗患者的无进展生存期更长，客观缓解率更高，缓解持续时间更长。在脑转移患者中，帕博利珠单抗与化疗的治疗相关不良事件发生率分别为66.3%和84.4%，在无脑转移患者中分别为67.2%和88.3%。结论对于既往未接受治疗或接受过治疗的PD-L1阳性晚期/转移性NSCLC患者，无论基线时是否存在治疗后稳定的脑转移，帕博利珠单抗单药治疗显示出明显的疗效改善，且与化疗相比，不良事件更少。

关键词：帕博利珠单抗脑转移化疗非小细胞肺癌 PD-L1

Dynamic metabolite QTL analyses provide novel biochemical insights into kernel development and nutritional quality improvement in common wheat

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Plant Communications 2024年第5期5卷 42-56页

作者： Bo Yin Jingqi Jia Xu Sun Xin Hu Min Ao Wei Liu Zhitao Tian Hongbo Liu Dongqin Li Wenfei Tian Yuanfeng Hao Xianchun Xia nir Sade Yariv Brotman Alisdair RFernie Jie Chen Zhonghu He Wei Chen National Key Laboratory of Crop Genetic Improvement and National Center of Plant Gene Research(Wuhan) Huazhong Agricultural UniversityWuhan 430070China Hubei Hongshan Laboratory Wuhan 430070China National Wheat Improvement Center Institute of Crop SciencesChinese Academy of Agricultural SciencesBeijingChina School of Plant Sciences and Food Security The Institute for Cereal Crops ImprovementTel Aviv UniversityTel Aviv 69978Israel Max Planck Institute of Molecular Plant Physiology 14476 Potsdam-GolmGermany Yazhouwan National Laboratory Sanya 572025China

Despite recent advances in crop metabolomics,the genetic control and molecular basis of the wheat kernel metabolome at different developmental stages remain largely ***,we performed widely tar-geted metabolite profiling of kernels from three developmental stages(grain-filling kernels[FKs],mature kernels[MKs],and germinating kernels[GKs])using a population of 159 recombinant inbred *** de-tected 625 annotated metabolites and mapped 3173,3143,and 2644 metabolite quantitative trait loci(mQTLs)in FKs,MKs,and GKs,*** 52 mQTLs were mapped at all three stages,indicating the high stage specificity of the wheat kernel *** candidate genes were functionally vali-dated by in vitro enzymatic reactions and/or transgenic approaches in wheat,three of which mediated the tricin metabolic ***ﬂux efficiencies within the tricin pathway were evaluated,and su-perior candidate haplotypes were identified,comprehensively delineating the tricin metabolism pathway in ***,additional wheat metabolic pathways were re-constructed by updating them to incorporate the 177 candidate genes identified in this *** work provides new information on variations in the wheat kernel metabolome and important molecular resources for improvement of wheat nutritional quality.

关键词： mQTL wheat kernel development gene validation nutritional quality wheat

Interval to surgery after neoadjuvant treatment for colorectal cancer

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World Journal of Gastroenterology 2014年第15期20卷 4256-4262页

作者： nir Wasserberg Department of Surgery B Rabin Medical CenterBeilinson CampusPetach Tikva and Sackler School of MedicineTel Aviv University69978 Tel AvivIsrael

The current standard treatment of low-lying locally advanced rectal cancer consists of chemoradiation followed by radical *** interval between chemoradiation and surgery varied for many years until the1999 Lyon R90-01 trial which compared the effects of a short(2-wk)and long(6-wk)*** showed a better clinical tumor response(71.7%vs 53.1%)and higher rate of positive and pathologic tumor regression(26%vs 10.3%)after the longer ***,a 6-wk interval between chemoradiation and surgery was set to balance the oncological results with the surgical ***,several recent retrospective studies reported that prolonging the interval beyond 8or even 12 wk may lead to significantly higher rates of tumor downstaging and pathologic complete *** in turn,according to some reports,may improve overall and disease-free survival,without increasing the surgical difficulty or *** work reviews the data on the effect of different intervals,derived mostly from retrospective analyses using a wide variation of treatment *** randomized trials are currently ongoing.

关键词： Rectal cancer Chemoradiation therapy Neoadjuvant Surgery Interval to surgery Colorectal cancer

The nature and sources of international variation in formal institutions related to initial coin offerings:preliminary findings and a research agenda

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Financial Innovation 2023年第1期9卷 281-318页

作者： nir Kshetri The University of North Carolina at Greensboro GreensboroUSA

As prior researchers have suggested,a firm’s success in an international market depends on how well its strategy fits the nonmarket environment,such as formal *** paper examines the determinants of formal institutions around new areas of economic ***,we propose a framework for understanding how the quality of formal institutions in promoting entrepreneurship drives the focus of such institutions concerning initial coin offering(ICO),which is emerging as a popular fundraising *** paper uses inductive analysis to examine how nonmarket factors—such as a jurisdiction’s tax haven nature,regulators’perceptions of ICOs as threats to national or political interests,and trade and industry associations—might moderate the relationship between the quality of institutions and the focus of such institutions regarding *** of this study’s key findings is that an economy’s quality of entrepreneurship-related institutions,perceived threats to national/political interests,and tax haven nature lead to different policy ***,regulators assign different importance when promoting crypto-entrepreneurship and dealing with associated *** focusing mainly on promoting crypto-ventures have taken measures to enrich the blockchain ecosystem and provided tax and non-tax incentives to attract such *** focusing mainly on dealing with crypto-venture risks rely on a regulatory sandbox and close regulatory monitoring of such ventures.

关键词： Blockchain Cryptocurrencies Crypto-ventures Initial coin offerings Regulatory sandboxes Tax havens

Inhibition of FLT3:A Prototype for Molecular Targeted Therapy in Acute Myeloid Leukemia

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Engineering 2021年第10期7卷 1354-1368页

作者： Meira Yisraeli Salman Jacob M.Rowe nir Weigert Department of Hematology Shaare Zedek Medical CenterJerusalem 9103102Israel Department of Hematology and Bone Marrow Transplantation Rambam Medical CenterHaifa 3109601Israel Technion—Israel Institute of Technology Haifa 3200003Israel

Modern therapy of acute myeloid leukemia(AML)began in 1973 with the first report of the successful combination of daunorubicin and cytarabine,which led to complete remission in approximately 45%of *** AML diagnosis was dependent on morphology,aided initially only by *** acute lymphoblastic leukemia(ALL),immunophenotyping offered little in the diagnosis of AML,at least during the 1970s and *** advent of reliable cytogenetics changed the entire prognostic outlook of *** karyotypic analysis,different groups of AML could be classified and stratified for various *** mutational profiling was a major advance in further categorizing AML patients,aided by the immunophenotypic identification of antigenic markers on the *** these advances were occurring as the understanding of the importance of the tumor burden—known as minimal residual disease(MRD)—became crucial for the management of AML *** efficacy of MRD has rapidly progressed in the past decade,from a specificity of 103 with immunophenotyping to 104 with polymerase chain reaction(PCR),which is only appropriate for some patients with AML,and finally to 105 or even 106 cells with the extraordinary sensitivity of next-generation sequencing(NGS).All of these advances have promoted the concept of personalized medicine,which has led to the advent of targeted agents that can accurately be used for specific diagnostic *** can be predicted and measured *** targeted agents have now become a cornerstone in the management of AML,increasing effi-cacy and dramatically reducing *** focus of this review is on one of the most well-studied targeted agents in AML:the FMS-like tyrosine kinase 3(FLT3)inhibitors,which have impacted the prognostication and therapeutics of *** review selectively discusses the FLT3 inhibitors in detail,as a model for the other burgeoning targeted agents that have already been approved,as well as tho

关键词： AML Targeted therapy FLT3 inhibitors Midostaurin Gilteritinib Quizartinib Sorafenib

DMRT1 at the border between mitosis and meiosis

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Asian Journal of Andrology 2011年第2期13卷 189-190页

作者： Jeremy Don Uri nir Haim Breitbart The Mina and Everard Goodman Faculty of LifeSciences Bar-Ilan University Ramat-Gan 52900 Israel

In males, sperm production begins at puberty and lasts throughout reproduct-ire life. This implies that a population of germ stem cells/progenitors must be main- tained, amplified and differentiate throughout life to enable the continuous supply of sperm. Spermatogenesis is indeed divided into three phases： a proliferative phase, a meiotic phase and a postmeiotic spermio- genic phase. In the proliferative phase, undifferentiated spermatogonia stem cells are divided to maintain the principle undiffer- entiated stern cell population on the one hand, and on the other hand to amplify and differentiate a fraction of the spermatogonia into primary spermatocytes.

关键词： Production Productivity Products Cells Lymphocytes Semen Political systems Stems Gametes Spermatozoa

Systems-based approaches to study immunometabolism

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Cellular & Molecular Immunology 2022年第3期19卷 409-420页

作者： Vinee Purohit Allon Wagner nir Yosef Vijay K.Kuchroo Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases Brigham and Women’s HospitalHarvard Medical SchoolBostonMA02115USA Broad Institute of MIT and Harvard CambridgeMA02141USA Department of Electrical Engineering and Computer Science University of CaliforniaBerkeleyCA94720USA Center for Computational Biology University of CaliforniaBerkeleyCA94720USA

Technical advances at the interface of biology and computation,such as single-cell RNA-sequencing(scRNA-seq),reveal new layers of complexity in cellular *** emerging area of investigation using the systems biology approach is the study of the metabolism of immune *** diverse spectra of immune cell phenotypes,sparsity of immune cell numbers in vivo,limitations in the number of metabolites identified,dynamic nature of cellular metabolism and metabolic fluxes,tissue specificity,and high dependence on the local milieu make investigations in immunometabolism challenging,especially at the single-cell *** this review,we define the systemic nature of immunometabolism,summarize cell-and system-based approaches,and introduce mathematical modeling approaches for systems interrogation of metabolic changes in immune *** close the review by discussing the applications and shortcomings of metabolic modeling *** systems-oriented studies of metabolism expected to become a mainstay of immunological research,an understanding of current approaches toward systems immunometabolism will help investigators make the best use of current resources and push the boundaries of the discipline.

关键词： Immunometabolism Metabolic techniques GSMM Metabolic modeling Systems biology