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JOURNAL OF SPINAL CORD MEDICINE 2021年第SUPPL 1期44卷 S278-S324页

作者： [Anonymous] Department of Medicine Division of Physical Medicine and Rehabilitation University of Toronto Toronto ON CA KITE - Toronto Rehabilitation Institute University Health Network Toronto ON CA Institute for Health Policy Management and Evaluation University of Toronto Toronto ON CA Rehabilitation Sciences Institute University of Toronto Toronto ON CA Institute of Medical Sciences University of Toronto Toronto ON CA. Rehabilitation Sciences Institute University of Toronto ON CA KITE Research Institute-Toronto Rehab-University Health Network Toronto ON CA Physical Therapy Department University of Toronto ON CA Praxis Spinal Cord Institute Vancouver BC Université de Montréal (École de réadaptation) Montreal QC CA Institut de réadaptation Gingras-Linsay-de-Montréal Montreal QC CA Division of Physical Medicine & Rehabilitation Department of Medicine Faculty of Medicine & Dentistry University of Alberta Edmonton AB CA University of Calgary Calgary AB CA Alberta Health Services Centre for Family Medicine Kitchener ON CA McMaster University Department of Family Medicine Hamilton ON CA Dept. of Physical Therapy University of Toronto Toronto ON CA KITE-University Health Network Toronto ON CA Praxis Spinal Cord Institute Vancouver BC CA Center for Interdisciplinary Research in Rehabilitation and Social Integration (CIRRIS) Quebec City QC CA Dept. of Rehabilitation Laval University Quebec City QC CA Institute of Health Policy Management and Evaluation University of Toronto Toronto ON CA School of Rehabilitation Science University of Saskatchewan Saskatoon SK CA Ontario Neurotrauma Foundation Toronto ON CA Canadian Spinal Research Organization Toronto ON CA CIUSSS du Centre-Sud-de-l ‘Île-de-Montréal (Installation Gingras-Lindsay) Montréal QC CA École de réadaptation Université de Montréal Montréal QC CA First Steps Wellness Centre Regina SK CA Stan Cassidy Centre for Rehabilitation Horizon Health Network Fredericton NB CA Departmen

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Isocitrate dehydrogenase 1 primes group-3 medulloblastomas for cuproptosis

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Cancer Cell 2025年第6期43卷 1159-1174.e8页

作者： Dang, Derek Deogharkar, Akash McKolay, John Smith, Kyle S. Panwalkar, Pooja Hoffman, Simon Tian, Wentao Ji, Sunjong Azambuja, Ana P. Natarajan, Siva Kumar Lum, Joanna Bayliss, Jill Manzeck, Katie Sweha, Stefan R. Hamanishi, Erin Pun, Matthew Patel, Diya Rau, Sagar Animasahun, Olamide Achreja, Abhinav Ogrodzinski, Martin P. Diessl, Jutta Cotter, Jennifer Hawes, Debra Yang, Fusheng Doherty, Robert Franson, Andrea T. Hanaford, Allison R. Eberhart, Charles G. Raabe, Eric H. Orr, Brent A. Wechsler-Reya, Robert J. Chen, Brandon Lyssiotis, Costas A. Shah, Yatrik M. Lunt, Sophia Y. Banerjee, Ruma Judkins, Alexander R. Prensner, John R. Koschmann, Carl Waszak, Sebastian M. Nagrath, Deepak Simoes-Costa, Marcos Northcott, Paul A. Venneti, Sriram Laboratory of Brain Tumor Metabolism and Epigenetics Department of Pathology University of Michigan Ann Arbor MI United States Department of Developmental Neurobiology Neurobiology and Brain Tumor Program St. Jude Children's Research Hospital Memphis TN United States Center of Excellence in Neuro-Oncology Sciences St. Jude Children's Research Hospital Memphis TN United States Department of Pediatrics Michigan Medicine Ann Arbor MI United States Department of Pathology Boston Children's Hospital Boston MA United States Department of Systems Biology Harvard Medical School Boston MA United States Cancer Biology and Genetics Program Memorial Sloan Kettering Cancer Center New York NY United States Department of Chemical Engineering University of Michigan Ann Arbor MI United States Laboratory for Systems Biology of Human Diseases University of Michigan Ann Arbor MI United States Biointerfaces Institute University of Michigan Ann Arbor MI United States Department of Biomedical Engineering University of Michigan Ann Arbor MI United States Rogel Cancer Center University of Michigan Ann Arbor MI United States Department of Biochemistry and Molecular Biology Michigan State University East Lansing MI United States Department of Biological Chemistry University of Michigan Medical School Ann Arbor 48109 MI United States Department of Pathology and Laboratory Medicine Children's Hospital Los Angeles Los Angeles CA United States Keck School of Medicine University of Southern California Los Angeles CA United States Department of Pathology Johns Hopkins School of Medicine Baltimore MD United States Division of Neuropathology Department of Pathology School of Medicine Johns Hopkins University Baltimore MD United States Sidney Kimmel Comprehensive Cancer Center School of Medicine Johns Hopkins University Baltimore MD United States Division of Pediatric Oncology Department of Oncology School of Medicine Johns Hopkins University Baltimore MD United

MYC-driven group-3 medulloblastomas (MBs) are malignant pediatric brain cancers without cures. To define actionable metabolic dependencies, we identify upregulation of dihydrolipoyl transacetylase (DLAT), the E2-subunit of pyruvate dehydrogenase complex (PDC) in a subset of group-3 MB with poor prognosis. DLAT is induced by c-MYC and targeting DLAT lowers TCA cycle metabolism and glutathione synthesis. We also note upregulation of isocitrate dehydrogenase 1 (IDH1) gene expression in group-3 MB patient tumors and suppression of IDH1 epigenetically reduces c-MYC and downstream DLAT levels in multiple c-MYC amplified cancers. DLAT is a central regulator of cuproptosis (copper-dependent cell death) induced by the copper ionophore elesclomol. DLAT expression in group-3 MB cells correlates with increased sensitivity to cuproptosis. Elesclomol is brain-penetrant and suppresses tumor growth in vivo in multiple group-3 MB animal models. Our data uncover an IDH1/c-MYC dependent vulnerability that regulates DLAT levels and can be targeted to kill group-3 MB by cuproptosis. © 2025 Elsevier Inc.

关键词： cancer metabolism cell death copper cuproptosis elesclomol epigenetics pediatric brain tumor protein lipoylation

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Conserved cell-type specific signature of resilience to Alzheimer’s disease nominates role for excitatory cortical neurons

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Alzheimer's & Dementia 2022年第S4期18卷

作者： Maria Telpoukhovskaia Niran Hadad Brianna Gurdon Miko Dai Andrew R Ouellette Sarah Neuner Amy R Dunn Shania L Hansen Yiyang Wu Logan Dumitrescu Kristen MS O'Connell Eric B Dammer Nicholas T. Seyfried Sukalp Muzumdar Jesse Gillis Paul Robson Jigang Zhang Timothy J. Hohman Vivek M. Philip Vilas Menon Catherine C. Kaczorowski The Jackson Laboratory Bar Harbor ME USA The University of Maine Orono ME USA University of Maine Graduate School of Biomedical Science and Engineering Orono ME USA Department of Genetics and Genomic Sciences Icahn School of Medicine at Mount Sinai New York NY USA Vanderbilt Memory & Alzheimer’s Center Nashville TN USA Vanderbilt Memory and Alzheimer’s Center Nashville TN USA Vanderbilt Memory and Alzheimer’s Center Vanderbilt University Medical Center Nashville TN USA Emory University School of Medicine Atlanta GA USA Cold Spring Harbor Cold Spring Harbor NY USA University of Toronto Toronto ON Canada The Jackson Laboratory for Genomic Medicine Farmington CT USA Vanderbilt Memory & Alzheimer’s Center Vanderbilt University Medical Center Nashville TN USA Department of Neurology Vanderbilt University Medical Center Nashville TN USA Columbia University Irving Medical Center New York NY USA Tufts University School of Medicine Boston MA USA

Background Alzheimer’s disease (AD), the leading cause of dementia, affects millions of people worldwide. With no disease-modifying medication currently available, the human toll and economic costs are rising rapidly. Under current standards, a patient is diagnosed with AD when both cognitive decline and pathology (amyloid plaques and neurofibrillary tangles) are present. Remarkably, some individuals who have AD pathology remain cognitively normal. Uncovering factors that lead to “cognitive resilience” to AD is a promising path to create new targets for therapies. However, technical challenges discovering novel human resilience factors limit testing, validation, and nomination of novel drugs for AD. Method In this study, we use single-nuclear transcriptional profiles of postmortem cortex from human individuals with high AD pathology who were either cognitively normal (resilient) or cognitively impaired (susceptible) at time of death, as well as mouse strains that parallel these differences in cognition with high amyloid. Result Our cross-species discovery approach highlights a novel role for excitatory layer 4/5 cortical neurons in promoting cognitive resilience to AD, and nominates several resilience genes that include ATP1A1 , GABRB1 , PTK2 , and ROCK2 . Nominated resilience genes were tested for replication in orthogonal data sets and confirmed to be correlated with cognitive resilience. Additionally, we identified several potential mechanisms of resilience, including regulation of membrane potential, axonal and dendritic growth, and general increase of protein cycle, potentially of membrane proteins. Conclusion Because our discovery of resilience-associated genes in layer 4/5 cortical neurons originates from an integrated human and mouse transcriptomic space from susceptible and resilient individuals, we are positioned to test causality and perform mechanistic, validation, and pre-clinical studies in our human-relevant AD-BXD mouse panel.

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Nanoparticle Shape: The Influence of Nanoparticle Shape on Protein Corona Formation (Small 25/2020)

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Small 2020年第25期16卷

作者： Rahul Madathiparambil Visalakshan Laura E. González García Mercy R. Benzigar Arthur Ghazaryan Johanna Simon Agnieszka Mierczynska-Vasilev Thomas D. Michl Ajayan Vinu Volker Mailänder Svenja Morsbach Katharina Landfester Krasimir Vasilev Future Industries Institute School of Engineering University of South Australia Mawson Lakes Adelaide SA 5095 Australia Global Innovative Centre for Advanced Nanomaterials Faculty of Engineering and Built Environment The University of Newcastle Callaghan NSW 2308 Australia Graduate School of Biomedical Engineering The University of New South Wales Sydney NSW 2052 Australia Physical Chemistry of Polymers Max Planck Institute for Polymer Research Ackermannweg 10 Mainz 55128 Germany The Australian Wine Research Institute Waite Precinct Hartley Grove cnr Paratoo Road Urrbrae (Adelaide) SA 5064 PO Box 197 Glen Osmond SA 5064 Australia Department of Dermatology University Medical Center of the Johannes Gutenberg-University Mainz Langenbeckstr. 1 Mainz 55131 Germany

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Survey of Infection Surveillance, Prophylaxis, and Vaccination Practices after Autologous Genetically Modified Cellular Therapies

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Transplantation and Cellular Therapy 2024年第2期30卷 S235-S235页

作者： John, Tami, MD Marón, Gabriela M., MD, MSc Abraham, Allistair, MD Bertaina, Alice, MD, PhD Bhoopalan, Senthil Velan, MBBS, PhD Bidgoli, Alan, DO Bonfim, Carmem, MD, PhD Coleman, Zane DeZern, Amy E., MD Li, Jingjing Oved, Joseph H., M.D. M.A. Pavel-Dinu, Mara Purtill, Duncan, MBBS, FRCPA, FRACP Ruggeri, Annalisa, MD Russell, Athena Wynn, Robert F, MRCP, MD, FRCPath Boelens, Jaap-Jan, MD, PhD Prockop, Susan E., MD Sharma, Akshay, MBBS Division of Hematology Oncology Stem Cell Transplantation and Regenerative Medicine Stanford Stanford CA St. Jude Children's Research Hospital Memphis TN Center for Cancer and Immunology Research Division of Blood and Marrow Transplantation Children's National Hospital Washington DC Department of Pediatrics/ Division of Hematology Oncology Stem Cell Transplantation and Regenerative Medicine Stanford University School of Medicine Stanford CA Department of Bone Marrow Transplantation and Cellular Therapy St. Jude Children's Research Hospital Memphis TN Emory University Atlanta GA Pediatric Blood and Marrow Transplantation Service Federal University of Paraná Curitiba Brazil St Jude Children's Research Hospital Memphis TN Department of Oncology The Johns Hopkins University School of Medicine Baltimore MD Graduate School of Biomedical Engineering University of New South Whales Sydney NSW Australia Stem Cell Transplantation and Cellular Therapy MSK Kids Memorial Sloan Kettering Cancer Center New York NY Stanford University Stanford CA Department of Haematology Fiona Stanley Hospital Perth Australia Department of Pediatric Hematology and Oncology IRCCS Bambino Gesù Children's Hospital Rome Italy Center for Cellular Immunotherapies Philadelphia PA Royal Manchester Children's Hospital Manchester United Kingdom Transplantation and Cellular Therapy MSK Kids Memorial Sloan Kettering Cancer Center New York NY Pediatrics Boston Children's Hospital Boston MA

IntroductionGenetically modified cellular therapies (GMCT) using autologous hematopoietic stem cells are under investigation for various inherited disorders including inborn errors of immunity (IEI) and non-IEI indications. Disease and conditioning related defects in immunity vary across indications for GMCT and contribute to appropriate variations in practice. Nonetheless, evidence-based guidance for infection prevention is lacking. We sought to understand current practices around GMCTs from clinicians participating in GMCT clinical trials. MethodsWe identified individuals potentially experienced with GMCTs based on clinical trial participation on ***. After obtaining IRB approval electronic surveys were distributed via email. ResultsWe approached 94 individuals in 11 countries. Seven of 21 responses for IEI and 19 of 25 for non-IEI from 6 countries (IEI: 3, non-IEI: 5) reported based on clinical experience with GMCTs. Figure 1 SurveillanceAll IEI GMCT respondents (n=7) reported standardized viral surveillance including weekly cytomegalovirus (CMV) monitoring (n=7), and regular Epstein-Barr virus (EBV) (n=6) and adenovirus (ADV) (n=5) monitoring. Some respondents also reported regular aspergillus antigen surveillance (n=4) and following IgG levels (n=5). Of the non-IEI GMCT respondents (n=19), CMV, EBV, and ADV were followed by 13, 12, and 9, respectively. Aspergillus antigen surveillance was not common practice (n=5). IgG levels were followed by 10 respondents. Table 1 ProphylaxisFor IEI GMCT, all respondents reported use of Pneumocystis jirovecii (PJP) and fungal prophylaxis (ppx). Four reported using CMV ppx, 4 herpes simplex virus (HSV) ppx, and 3 varicella zoster virus (VZV) ppx. For non-IEI GCMT, use of ppx for PJP (n=18), fungus (n=15), and HSV (n=17) was common. Standard CMV and VZV ppx was infrequent. Encapsulated bacteria ppx was used by 11 respondents primarily for hemoglobinopathies (n=10). Table 2 Preferred agent, and duration of ppx and

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Author Correction: The lactate receptor HCAR1 drives the recruitment of immunosuppressive PMN-MDSCs in colorectal cancer

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Nature immunology 2025年第4期26卷 635页

作者： Jiacheng He Xiaolei Chai Qiansen Zhang Yang Wang Yijie Wang Xinyu Yang Jingbo Wu Bo Feng Jing Sun Weiwei Rui Shuyin Ze Yuanyuan Fu Yumiao Zhao Ying Zhang Yao Zhang Meizhen Liu Chuang Liu Meifu She Xiangfei Hu Xueyun Ma Huaiyu Yang Dawei Li Senlin Zhao Guichao Li Zhen Zhang Zhonghui Tian Yanlin Ma Lingyan Cao Bo Yi Dali Li Ruth Nussinov Charis Eng Timothy A Chan Eytan Ruppin J Silvio Gutkind Feixiong Cheng Mingyao Liu Weiqiang Lu Shanghai Key Laboratory of Regulatory Biology Institute of Biomedical Sciences and School of Life Sciences East China Normal University Shanghai China. Department of Urology and Department of Pathology The Fifth People's Hospital of Shanghai Fudan University Shanghai China. Department of General Surgery and Department of Pathology Ruijin Hospital Shanghai Jiaotong University School of Medicine Shanghai China. Research Center for Complexity Sciences Hangzhou Normal University Hangzhou China. Department of Colorectal Surgery Department of Radiation Oncology Fudan University Shanghai Cancer Center Shanghai China. School of Life Sciences Fudan University Shanghai China. Hainan Provincial Key Laboratory for Human Reproductive Medicine and Genetic Research Hainan Provincial Clinical Research Center for Thalassemia Department of Reproductive Medicine Key Laboratory of Reproductive Health Diseases Research and Translation (Hainan Medical University) Ministry of Education The First Affiliated Hospital of Hainan Medical University Haikou China. Shanghai Ninth People's Hospital Shanghai Jiao Tong University School of Medicine College of Stomatology Shanghai Jiao Tong University Shanghai China. Department of Gastrointestinal Surgery The Third Xiangya Hospital Central South University Changsha China. Computational Structural Biology Section Basic Science Program Frederick National Laboratory for Cancer Research National Cancer Institute at Frederick Frederick MD USA. Department of Human Molecular Genetics and Biochemistry Sackler School of Medicine Tel Aviv University Tel Aviv Israel. Genomic Medicine Institute Lerner Research Institute Cleveland Clinic Cleveland OH USA. Department of Molecular Medicine Cleveland Clinic Lerner College of Medicine Case Western Reserve University Cleveland OH USA. Case Comprehensive Cancer Center Case Western Reserve University School of Medicine Cleveland OH USA. Center for Immunotherapy and Precision Immuno-Oncology Cleveland Clini

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Visible supercontinuum generation from a tunable mid-infrared laser 17

Visible supercontinuum generation from a tunable mid-infrare...

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Nonlinear Frequency Generation and Conversion: Materials and Devices XVII 2018

作者： Marble, Christopher B. O'Connor, Sean P. Nodurft, Dawson T. Yakovlev, Vladislav V. Wharmby, Andrew W. Texas A and M University Departments of Biomedical Engineering and Physics and Astronom 4242 TAMU College StationTX77843 United States Consortium Research Fellows Program 4214 King Street Virginia22302 United States Engility Corporation 4241 Woodcock Dr. Ste. B-100 San AntonioTX78228 United States 711th Human Performance Wing Airman Systems Direct. Bioeffects Division 4141 Petroleum Rd JBSA Fort Sam HoustonTX78234 United States

ISBN: (数字)9781510615182

ISBN: (纸本)9781510615175

Calcium fluoride, BK7 and fused silica are common optical materials used in lenses and windows. In this report, we discuss supercontinuum generation using tunable femtosecond mid-IR laser pulses with wavelengths ranging from 2.7 μm to 7.0 μm and pulse energies between 3 and 18 microjoules. We observed harmonic generation in fused silica and BK7, but not supercontinuum generation. Other borosilicate targets generated supercontinuum in both visible and near infrared regions of the spectrum. The visible supercontinuum was, in some instances, strong enough to be observed directly by the human eye. These results contribute to ongoing work being done to refine eye safety standards for femtosecond lasers. © 2018 SPIE.

关键词： Calcium fluoride

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Mucormycosis infection in patients with COVID-19: A systematic review

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Health science reports 2022年第2期5卷 e529页

作者： SeyedAhmad SeyedAlinaghi Amirali Karimi Alireza Barzegary Zahra Pashaei Amir Masoud Afsahi Sanam Alilou Nazanin Janfaza Alireza Shojaei Fatemeh Afroughi Parsa Mohammadi Yasna Soleimani Newsha Nazarian Ava Amiri Marcarious M Tantuoyir Shahram Oliaei Esmaeil Mehraeen Omid Dadras Iranian Research Center for HIV/AIDS Iranian Institute for Reduction of High-Risk Behaviors Tehran University of Medical Sciences Tehran Iran. School of Medicine Tehran University of Medical Sciences Tehran Iran. School of Medicine Islamic Azad University Tehran Iran. Department of Radiology School of Medicine University of California San Diego (UCSD) San Diego California USA. Internal Medicine Department Imam Khomeini Hospital Complex School of Medicine Tehran University of Medical Sciences Tehran Iran. Pars Hospital Iran University of Medical Sciences Tehran Iran. Biomedical Engineering Unit University of Ghana Medical Center (UGMC) Accra Ghana. HBOT Research Center Golestan Hospital Islamic Republic of Iran Navy and AJA Medical University Tehran Iran. Department of Health Information Technology Ardebil University of Medical Sciences Ardebil Iran. Department of Global Health and Socioepidemiology Graduate School of Medicine Kyoto University Kyoto Japan.

INTRODUCTION:Several reports previously described mucormycosis co-infection in patients with COVID-19. As mucormycosis and COVID-19 co-infection might adversely affect patients' outcomes, we aimed to systematically review the related evidence and the subsequent outcomes. METHODS:We conducted a systematic review of relevant articles searching the keywords in the online databases of PubMed, Scopus, Embase, Cochrane, and Web of Science. All the records from the start of the pandemic until June 12th, 2021 underwent title/abstract and then full-text screening process, and the eligible studies were included. We did not include any language or time restrictions for the included studies. RESULTS:We found 31 eligible studies reporting 144 total cases of COVID-19 and mucormycosis co-infection. The nose, cranial sinuses, and orbital cavity were the most commonly involved organs, although the cerebrum, lungs, and heart were also involved in the studies. Pre-existing diabetes mellitus (DM), as well as corticosteroid use, were the most commonly identified risk factors, but other underlying conditions and immunomodulatory drug use were also present in several cases. Aspergillus was the most commonly reported micro-organism that caused further co-infections in patients with concurrent COVID-19 and mucormycosis. As most of the studies were case reports, no reliable estimate of the mortality rate could be made, but overall, 33.6% of the studied cases died. CONCLUSION:Early diagnosis of mucormycosis co-infection in COVID-19 patients and selecting the right treatment plan could be a challenge for physicians. Patients with underlying co-morbidities, immunocompromised patients, and those receiving corticosteroids are at higher risk of developing mucormycosis co-infection and it is crucial to have an eye examination for early signs and symptoms suggesting a fungal infection in these patients.

关键词： COVID‐19 SARS‐CoV‐2 black fungus mucormycosis

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Personalized brain network models for assessing structure-function relationships

arXiv

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arXiv 2018年

作者： Bansal, Kanika Nakuci, Johan Muldoon, Sarah Feldt Mathematics Department University at Buffalo SUNY BuffaloNY14260 Human Sciences US Army Research Laboratory Aberdeen Proving GroundsMD21005 Department of Biomedical Engineering Columbia University New YorkNY10027 Neuroscience Program University at Buffalo SUNY BuffaloNY14260 CDSE Program University at Buffalo SUNY BuffaloNY1260

Many recent efforts in computational modeling of macro-scale brain dynamics have begun to take a datadriven approach by incorporating structural and/or functional information derived from subject data. Here, we discuss recent work using personalized brain network models to study structure-function relationships in human brains. We describe the steps necessary to build such models and show how this computational approach can provide previously unobtainable information through the ability to perform virtual experiments. Finally, we present examples of how personalized brain network models can be used to gain insight into the effects of local stimulation and improve surgical outcomes in epilepsy. Copyright © 2018, The Authors. All rights reserved.

关键词： Virtual reality

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Comprehensive functional annotation of susceptibility variants identifies genetic heterogeneity between lung adenocarcinoma and squamous cell carcinoma

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Frontiers of Medicine 2021年第2期15卷 275-291页

作者： Na Qin Yuancheng Li Cheng Wang Meng Zhu Juncheng Dai Tongtong Hong Demetrius Albanes Stephen Lam Adonina Tardon Chu Chen Gary Goodman Stig EBojesen Maria Teresa Landi Mattias Johansson Angela Risch H-Erich Wichmann Heike Bickeboller Gadi Rennert Susanne Arnold Paul Brennan John KField Sanjay Shete Loic Le Marchand Olle Melander Hans Brunnstrom Geoffrey Liu Rayjean JHung Angeline Andrew Lambertus AKiemeney Shan Zienolddiny Kjell Grankvist Mikael Johansson Neil Caporaso Penella Woll Philip Lazarus Matthew BSchabath Melinda CAldrich Victoria LStevens Guangfu Jin David CChristiani Zhibin Hu Christopher IAmos Hongxia Ma Hongbing Shen Department of Epidemiology Center for Global HealthSchool of Public HealthNanjing Medical UniversityNanjing 211166China State Key Laboratory of Reproductive Medicine Center for Global HealthNanjing Medical UniversityNanjing 211166China Department of Bioinformatics School of Biomedical Engineering and InformaticsNanjing Medical UniversityNanjing 211166China Jiangsu Key Lab of Cancer Biomarkers Prevention and TreatmentCollaborative Innovation Center for Cancer MedicineNanjing Medical UniversityNanjing 211166China China International Cooperation Center for Environment and Human Health School of Public HealthNanjing Medical UniversityNanjing 211166China Division of Cancer Epidemiology and Genetics National Cancer InstituteBethesdaMD 20892-9304USA Department of Integrative Oncology British Columbia Cancer AgencyVancouverBC V5Z 1L3Canada Faculty of Medicine University of Oviedo and CIBERESPOviedo 33006Spain Program in Epidemiology Public Health Sciences DivisionFred Hutchinson Cancer Research CenterSeattleWA 98109-1024USA Public Health Sciences Division Swedish Cancer InstituteSeattleWA 98026USA Department of Clinical Biochemistry Copenhagen University HospitalCopenhagen DK-1017Denmark National Cancer Institute BethesdaMD 20892-9304USA Genetic Epidemiology Group International Agency for Research on CancerLyon 69372France Cancer Center Cluster Salzburg at PLUS Department of Molecular BiologyUniversity of SalzburgHeidelberg 5020Austria Institute of Medical Informatics Biometry and EpidemiologyChair of EpidemiologyLudwig Maximilians UniversityMunichBavaria 80539Germany Department of Genetic Epidemiology University Medical Center GoettingenGoettingen 37075Germany Technion Faculty of Medicine Carmel Medical CenterHaifa 3448516Israel Markey Cancer Center University of KentuckyLexingtonKY 40506-0054USA Department of Molecular and Clinical Cancer Medicine Roy Castle Lung Cancer Research ProgrammeThe University of Liverpool Institute of Translational MedicineLiverpool L697Z

Although genome-wide association studies have identified more than eighty genetic variants associated with non-small cell lung cancer(NSCLC)risk,biological mechanisms of these variants remain largely *** integrating a large-scale genotype data of 15581 lung adenocarcinoma(AD)cases,8350 squamous cell carcinoma(SqCC)cases,and 27355 controls,as well as multiple transcriptome and epigenomic databases,we conducted histology-specific meta-analyses and functional annotations of both reported and novel susceptibility *** identified 3064 credible risk variants for NSCLC,which were overrepresented in enhancer-like and promoter-like histone modification peaks as well as DNase I hypersensitive *** factor enrichment analysis revealed that USF1 was AD-specific while CREB1 was *** annotation and genebased analysis implicated 894 target genes,including 274 specifics for AD and 123 for SqCC,which were overrepresented in somatic driver genes(ER=1.95,P=0.005).Pathway enrichment analysis and Gene-Set Enrichment Analysis revealed that AD genes were primarily involved in immune-related pathways,while SqCC genes were homologous recombination deficiency *** results illustrate the molecular basis of both wellstudied and new susceptibility loci of NSCLC,providing not only novel insights into the genetic heterogeneity between AD and SqCC but also a set of plausible gene targets for post-GWAS functional experiments.

关键词： lung cancer genome-wide association study function annotation immune homologous recombination repair deficiency genetic heterogeneity

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