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257 results on '"Memorial Sloan Kettering Cancer Center (MSKCC)"'

1. Personalized cancer therapy prioritization based on driver alteration co-occurrence patterns

Author: Pedram Razavi, Patrick Aloy, Maurizio Scaltriti, Lidia Mateo, Miquel Duran-Frigola, Joaquín Arribas, Meritxell Bellet, Sarat Chandarlapaty, Marta Palafox, Albert Gris-Oliver, Violeta Serra, Institut Català de la Salut, [Mateo L, Duran-Frigola M] Joint IRB-BSC-CRG Program in Computational Biology, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Catalonia, Spain. [Gris-Oliver A, Palafox M] Experimental Therapeutics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Scaltriti M] Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA. Department of Pathology, MSKC C, New York, NY 10065, USA. [Razavi P] Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA. Breast Medicine Service, Department of Medicine, MSKCC and Weill-Cornell Medical College, New York, NY 10065, USA. [Arribas J] Growth Factors Laboratory, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Spain. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain. CIBERONC, Barcelona, Spain. [Bellet M] Breast Cancer Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Serra V] Experimental Therapeutics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. CIBERONC, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Genomic profiling, Databases, Factual, Oncologia, Computer science, Method, lcsh:Medicine, Genome, Translational Research, Biomedical, Drug-response biomarkers, 0302 clinical medicine, Survival data, terapéutica::medicina de precisión [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Neoplasms, Profiling (information science), Medicina personalitzada, Precision Medicine, Genetics (clinical), Otros calificadores::/terapia [Otros calificadores], 0303 health sciences, Càncer - Tractament, Disease Management, Precision oncology, Genomics, 3. Good health, Gene Expression Regulation, Neoplastic, Identification (information), Treatment Outcome, 030220 oncology & carcinogenesis, Biomarker (medicine), Molecular Medicine, Càncer -- Tractament, Therapeutics::Precision Medicine [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Algorithms, Prioritization, lcsh:QH426-470, Systems biology, Clinical Decision-Making, Cancer therapy, Antineoplastic Agents, Computational biology, neoplasias [ENFERMEDADES], 03 medical and health sciences, In vivo, Biomarkers, Tumor, medicine, Genetics, Humans, Tumor growth, Progression-free survival, Molecular Biology, 030304 developmental biology, lcsh:R, Co-occurrence, Reproducibility of Results, Cancer, Oncogenes, Other subheadings::/therapy [Other subheadings], Models, Theoretical, medicine.disease, Human genetics, Clinical trial, Neoplasms [DISEASES], lcsh:Genetics, Genòmica, Drug Resistance, Neoplasm, Driver co-occurrence networks
Abstract: Molecular profiling of personal cancer genomes, and the identification of actionable vulnerabilities and drug-response biomarkers, are the basis of precision oncology. Tumors often present several driver alterations that might be connected by cross-talk and feedback mechanisms, making it difficult to mark single oncogenic variations as reliable predictors of therapeutic outcome. In the current work, we uncover and exploit driver alteration co-occurrence patterns from a recently published in vivo screening in patient-derived xenografts (PDXs), including 187 tumors and 53 drugs. For each treatment, we compare the mutational profiles of sensitive and resistant PDXs to statistically define Driver Co-Occurrence (DCO) networks, which capture both genomic structure and putative oncogenic synergy. We then use the DCO networks to train classifiers that can prioritize, among the available options, the best possible treatment for each tumor based on its oncogenomic profile. In a cross-validation setting, our drug-response models are able to correctly predict 66% of sensitive and 77% of resistant drug-tumor pairs, based on tumor growth variation. Perhaps more interesting, our models are applicable to several tumor types and drug classes for which no biomarker has yet been described. Additionally, we experimentally validated the performance of our models on 15 new tumor samples engrafted in mice, achieving an overall accuracy of 75%. Finally, we adapted our strategy to derive drug-response models from continuous clinical outcome measures, such as progression free survival, which better represent the data acquired during routine clinical practice and in clinical trials. We believe that the computational framework presented here could be incorporated into the design of adaptive clinical trials, revealing unexpected connections between oncogenic alterations and increasing the clinical impact of genomic profiling.
Published: 2020

2. Emerging and Evolving Concepts in Cancer Immunotherapy Imaging

Author: Laurent Dercle, Shawn Sun, Romain-David Seban, Ahmed Mekki, Roger Sun, Lambros Tselikas, Sophie Hans, Alice Bernard-Tessier, Fadila Mihoubi Bouvier, Nicolas Aide, Laetitia Vercellino, Alexia Rivas, Antoine Girard, Fatima-Zohra Mokrane, Guillaume Manson, Roch Houot, Egesta Lopci, Randy Yeh, Samy Ammari, Lawrence H. Schwartz, Columbia University Medical Center (CUMC), Columbia University [New York], Institut Curie [Paris], Hôpital Raymond Poincaré [AP-HP], Radiothérapie Moléculaire et Innovation Thérapeutique (RaMo-IT), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, TheraPanacea [Paris], Institut Gustave Roussy (IGR), Département d'imagerie médicale [Gustave Roussy], CHU Henri Mondor [Créteil], Département d’Innovation Thérapeutique et essais précoces [Gustave Roussy] (DITEP), AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers (ANTICIPE), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM), Hopital Saint-Louis [AP-HP] (AP-HP), Centre Eugène Marquis (CRLCC), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Microenvironment and B-cells: Immunopathology,Cell Differentiation, and Cancer (MOBIDIC), Université de Rennes (UR)-Etablissement français du sang [Rennes] (EFS Bretagne)-Institut National de la Santé et de la Recherche Médicale (INSERM), Humanitas Clinical and Research Center [Rozzano, Milan, Italy], Memorial Sloan Kettering Cancer Center (MSKCC), Fondation ARC pour la recherche médicale (international mobility grant and grant SIGN’IC20161236437), INSERM, and Fondation Bettencourt Schueller, pending U.S. patent (no. 16630031), and Fondazione AIRC
Subjects: [SDV]Life Sciences [q-bio], CLINICAL BENEFIT, NIVOLUMAB, MELANOMA, ASSOCIATION, HYPERPROGRESSIVE DISEASE, GUIDELINES, Neoplasms, Positron-Emission Tomography, Disease Progression, Humans, Immunologic Factors, CRITERIA, Radiology, Nuclear Medicine and imaging, Immunotherapy, IMMUNE-RELATED RESPONSE, ADVERSE EVENTS, INHIBITORS
Abstract: International audience; Criteria based on measurements of lesion diameter at CT have guided treatment with historical therapies due to the strong association between tumor size and survival. Clinical experience with immune checkpoint modulators shows that editing immune system function can be effective in various solid tumors. Equally, novel immune-related phenomena accompany this novel therapeutic paradigm. These effects of immunotherapy challenge the association of tumor size with response or progression and include risks and adverse events that present new demands for imaging to guide treatment decisions. Emerging and evolving approaches to immunotherapy highlight further key issues for imaging evaluation, such as dissociated response following local administration of immune checkpoint modulators, pseudoprogression due to immune infiltration in the tumor environment, and premature death due to hyperprogression. Research that may offer tools for radiologists to meet these challenges is reviewed. Different modalities are discussed, including immuno-PET, as well as new applications of CT, MRI, and fluorodeoxyglucose PET, such as radiomics and imaging of hematopoietic tissues or anthropometric characteristics. Multilevel integration of imaging and other biomarkers may improve clinical guidance for immunotherapies and provide theranostic opportunities.
Published: 2023
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3. Nivolumab and Relatlimab in Patients With Advanced Melanoma That Had Progressed on Anti–Programmed Death-1/Programmed Death Ligand 1 Therapy: Results From the Phase I/IIa RELATIVITY-020 Trial

Author: Paolo Antonio Ascierto, Evan J. Lipson, Reinhard Dummer, James Larkin, Georgina V. Long, Rachel E. Sanborn, Vanna Chiarion-Sileni, Brigitte Dréno, Stéphane Dalle, Dirk Schadendorf, Margaret K. Callahan, Marta Nyakas, Victoria Atkinson, Carlos Alberto Gomez-Roca, Naoya Yamazaki, Hussein A. Tawbi, Naomey Sarkis, Deepti Warad, Sonia Dolfi, Priyam Mitra, Satyendra Suryawanshi, Jean-Jacques Grob, University of Zurich, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale [Naples, Italy] (INT-FGP), Johns Hopkins University (JHU), Universität Zürich [Zürich] = University of Zurich (UZH), The institute of cancer research [London], The University of Sydney, Providence Cancer Center, Veneto Institute of Oncology IOV-IRCCS [Padua, Italy], Immunology and New Concepts in ImmunoTherapy (INCIT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), Memorial Sloan Kettering Cancer Center (MSKCC), Oslo University Hospital [Oslo], Greenslopes Private Hospital [QLD, Australia] (GPH), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), National Cancer Center Research Institute [Tokyo], The University of Texas M.D. Anderson Cancer Center [Houston], Bristol-Myers Squibb [Princeton], Service de dermatologie, vénéreologie et cancérologie cutanée [Hôpital de la Timone - APHM], and Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)
Subjects: Cancer Research, Oncology, [SDV]Life Sciences [q-bio], Medizin, 10177 Dermatology Clinic, 610 Medicine & health, 2730 Oncology, 1306 Cancer Research
Abstract: PURPOSE Nivolumab and relatlimab activity in advanced melanoma with prior progression on anti–programmed death-1/programmed death ligand 1 (PD-(L)1)-containing regimens is under investigation. RELATIVITY-047 demonstrated significantly improved progression-free survival (PFS) for nivolumab and relatlimab over nivolumab in previously untreated advanced melanoma. METHODS The phase I/IIa, open-label RELATIVITY-020 trial part D assessed efficacy and safety of nivolumab and relatlimab in advanced melanoma with progression during, or within 3 months of, 1 (D1) or ≥ 1 (D2) anti–PD-(L)1-containing regimens. Safety was a primary end point. Objective response rate (coprimary end point) and PFS by blinded independent central review (BICR) were assessed. RESULTS Five hundred eighteen patients (D1 = 354; D2 = 164) received nivolumab and relatlimab. Among evaluable patients, the objective response rate by BICR was 12.0% (95% CI, 8.8 to 15.8) in D1 (n = 351) and 9.2% (95% CI, 5.2 to 14.7) in D2 (n = 163). Responses appeared to be enriched among patients with tumors expressing programmed death ligand 1 or lymphocyte activation gene 3; however, responses were observed regardless of programmed death ligand 1 and lymphocyte activation gene 3 expression (1%). The median duration of response was not reached (95% CI, 12.9 to not reached) in D1 and 12.8 months (95% CI, 6.9 to 12.9) in D2. The median PFS by BICR was 2.1 months (95% CI, 1.9 to 3.5) in D1 and 3.2 months (95% CI, 1.9 to 3.6) in D2; the 6-month PFS rate was 29.1% (95% CI, 24.2 to 34.1) and 27.7% (95% CI, 20.5 to 35.4), respectively. The grade 3-4 treatment-related adverse event incidence was 15.0% in D1 and 12.8% in D2. One case of grade 3 myocarditis and no treatment-related deaths occurred across part D. CONCLUSION Nivolumab and relatlimab had a manageable safety profile and demonstrated durable clinical activity in a proportion of patients with heavily pretreated advanced melanoma with prior progression on anti–PD-(L)1-containing regimens. [Media: see text]
Published: 2023
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4. Utility of (18)fluoro-deoxyglucose positron emission tomography for prognosis and response assessments in a phase 2 study of romidepsin in patients with relapsed or refractory peripheral T-cell lymphoma

Author: Lauren Pinter-Brown, Steven M. Horwitz, John Balser, Bertrand Coiffier, Andrei R. Shustov, Jean Nichols, Barbara Balser, Matthew Greenwood, F. Morschhauser, Henry Miles Prince, Lubomir Sokol, Francine M. Foss, Swaminathan P. Iyer, Dolores Caballero, Barbara Pro, Memorial Sloan Kettering Cancer Center (MSKCC), Hospices Civils de Lyon (HCL), Yale Cancer Center, Yale University School of Medicine, Peter Mac Callum Cancer Centre, H. Lee Moffitt Cancer Center and Research Institute, Royal North Shore Hospital (RNSH), Universidad de Salamanca, Groupe de Recherche sur les formes Injectables et les Technologies Associées - ULR 7365 (GRITA), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille, Harbor UCLA Medical Center [Torrance, Ca.], Houston Methodist Hospital [Houston, TX, USA], University of Washington [Seattle], University of Liverpool, Jefferson University Hospitals, Université de Lille, CHU Lille, Groupe de Recherche sur les formes Injectables et les Technologies Associées (GRITA) - EA 7365, Memorial Sloan Kettering Cancer Center [MSKCC], Hospices Civils de Lyon, Departement de Neurologie [HCL], Royal North Shore Hospital [RNSH], Groupe de Recherche sur les formes Injectables et les Technologies Associées - ULR 7365 [GRITA], Yale School of Medicine [New Haven, Connecticut] (YSM), and Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)
Subjects: 0303 health sciences, medicine.diagnostic_test, business.industry, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Phases of clinical research, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, 3. Good health, Romidepsin, 03 medical and health sciences, 0302 clinical medicine, Oncology, Refractory, Positron emission tomography, 030220 oncology & carcinogenesis, medicine, Clinical endpoint, Radiation treatment planning, Nuclear medicine, business, Prospective cohort study, Survival rate, 030304 developmental biology, medicine.drug
Abstract: International audience; BACKGROUND: For patients with peripheral T-cell lymphoma (PTCL), the value of (18)fluoro-deoxyglucose positron emission tomography (FDG-PET) scans for assessing prognosis and response to treatment remains unclear. The utility of FDG-PET, in addition to conventional radiology, was examined as a planned exploratory end point in the pivotal phase 2 trial of romidepsin for the treatment of relapsed/refractory PTCL.PATIENTS AND METHODS: Patients received romidepsin at a dose of 14 mg/m(2) on days 1, 8, and 15 of 28-day cycles. The primary end point was the rate of confirmed/unconfirmed complete response (CR/CRu) as assessed by International Workshop Criteria (IWC) using conventional radiology. For the exploratory PET end point, patients with at least baseline FDG-PET scans were assessed by IWC + PET criteria.RESULTS: Of 130 patients, 110 had baseline FDG-PET scans, and 105 were PET positive at baseline. The use of IWC + PET criteria increased the objective response rate to 30% compared with 26% by conventional radiology. Durations of response were well differentiated by both conventional radiology response criteria [CR/CRu versus partial response (PR), P = 0.0001] and PET status (negative versus positive, P < 0.0001). Patients who achieved CR/CRu had prolonged progression-free survival (PFS, median 25.9 months) compared with other response groups (P = 0.0007). Patients who achieved PR or stable disease (SD) had similar PFS (median 7.2 and 6.3 months, respectively, P = 0.6427). When grouping PR and SD patients by PET status, patients with PET-negative versus PET-positive disease had a median PFS of 18.2 versus 7.1 months (P = 0.0923).CONCLUSIONS: Routine use of FDG-PET does not obviate conventional staging, but may aid in determining prognosis and refine response assessments for patients with PTCL, particularly for those who do not achieve CR/CRu by conventional staging. The optimal way to incorporate FDG-PET scans for patients with PTCL remains to be determined.TRIAL REGISTRATION: NCT00426764.
Published: 2015
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5. Inactivation of AMPK Leads to Attenuation of Antigen Presentation and Immune Evasion in Lung Adenocarcinoma

Author: Emmy W. Verschuren, Pekka Paivinen, Sushil Tripathi, Ashwini S. Nagaraj, Eva Domenech-Moreno, Tomi P. Mäkelä, Kari Vaahtomeri, Iris P. L. Wong, Sarang S. Talwelkar, Marc Foretz, Benoit Viollet, Yan Yan, Yajing Gao, Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Memorial Sloan Kettering Cancer Center (MSKCC), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), FORETZ, Marc, University of Helsinki, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)
Subjects: congenital, hereditary, and neonatal diseases and abnormalities, Cancer Research, Lung Neoplasms, medicine.medical_treatment, Antigen presentation, STK11, Adenocarcinoma of Lung, AMP-Activated Protein Kinases, Biology, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease_cause, Mice, 03 medical and health sciences, 0302 clinical medicine, Immune system, Carcinoma, Non-Small-Cell Lung, Tumor Microenvironment, medicine, Animals, Humans, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], skin and connective tissue diseases, [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Immune Evasion, 030304 developmental biology, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Antigen Presentation, 0303 health sciences, AMPK, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Immunotherapy, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Oncology, 030220 oncology & carcinogenesis, Cancer research, KRAS, Carcinogenesis, CD8
Abstract: Purpose: Mutations in STK11 (LKB1) occur in 17% of lung adenocarcinoma (LUAD) and drive a suppressive (cold) tumor immune microenvironment (TIME) and resistance to immunotherapy. The mechanisms underpinning the establishment and maintenance of a cold TIME in LKB1-mutant LUAD remain poorly understood. In this study, we investigated the role of the LKB1 substrate AMPK in immune evasion in human non—small cell lung cancer (NSCLC) and mouse models and explored the mechanisms involved. Experimental Design: We addressed the role of AMPK in immune evasion in NSCLC by correlating AMPK phosphorylation and immune-suppressive signatures and by deleting AMPKα1 (Prkaa1) and AMPKα2 (Prkaa2) in a KrasG12D-driven LUAD. Furthermore, we dissected the molecular mechanisms involved in immune evasion by comparing gene-expression signatures, AMPK activity, and immune infiltration in mouse and human LUAD and gain or loss-of-function experiments with LKB1- or AMPK-deficient cell lines. Results: Inactivation of both AMPKα1 and AMPKα2 together with Kras activation accelerated tumorigenesis and led to tumors with reduced infiltration of CD8+/CD4+ T cells and gene signatures associated with a suppressive TIME. These signatures recapitulate those in Lkb1-deleted murine LUAD and in LKB1-deficient human NSCLC. Interestingly, a similar signature is noted in human NSCLC with low AMPK activity. In mechanistic studies, we find that compromised LKB1 and AMPK activity leads to attenuated antigen presentation in both LUAD mouse models and human NSCLC. Conclusions: The results provide evidence that the immune evasion noted in LKB1-inactivated lung cancer is due to subsequent inactivation of AMPK and attenuation of antigen presentation.
Published: 2022
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6. Phase 1/2 study of intratumoral G100 (TLR4 agonist) with or without pembrolizumab in follicular lymphoma

Author: Ahmad S. Halwani, Carlos Panizo, Iris Isufi, Alex F. Herrera, Craig Y. Okada, Elizabeth H. Cull, Bela Kis, Jorge M. Chaves, Nancy L. Bartlett, Weiyun Ai, Luis de la Cruz-Merino, Locke J. Bryan, Roch Houot, Kim Linton, Javier Briones, Ian Chau, Gottfried R. von Keudell, Hailing Lu, Adam Yakovich, Michael Chen, ter Meulen JH, Sergey Yurasov, Frank J. Hsu, Christopher R. Flowers, University of Utah, Clínica Universidad de Navarra [Pamplona], Universidad de Navarra [Pamplona] (UNAV), Yale University School of Medicine, H. Lee Moffitt Cancer Center and Research Institute, North-West University [Potchefstroom] (NWU), University of California [San Francisco] (UCSF), University of California, University of Sevilla, Augusta University, University System of Georgia (USG), CHU Pontchaillou [Rennes], Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Manchester University NHS Foundation Trust (MFT), Memorial Sloan Kettering Cancer Center (MSKCC), The University of Texas M.D. Anderson Cancer Center [Houston], Emory University [Atlanta, GA], Immune Design Corp., Yale School of Medicine [New Haven, Connecticut] (YSM), University of California [San Francisco] (UC San Francisco), University of California (UC), Universidad de Sevilla / University of Sevilla, and Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: 0303 health sciences, Cancer Research, [SDV.CAN]Life Sciences [q-bio]/Cancer, Hematology, Antibodies, Monoclonal, Humanized, 3. Good health, Toll-Like Receptor 4, 03 medical and health sciences, 0302 clinical medicine, follicular lymphoma, Oncology, glucopyranosyl lipid A, 030220 oncology & carcinogenesis, Antineoplastic Combined Chemotherapy Protocols, Humans, TLR4, immunotherapy, pembrolizumab, Lymphoma, Follicular, 030304 developmental biology
Abstract: International audience; Intratumoral injection of G100, a toll-like receptor 4 (TLR4) agonist, was shown pre-clinically to stimulate anti-tumor immune responses and tumor regression. This open-label, multicenter, phase 1/2 trial evaluated the safety, tolerability, and preliminary efficacy of intratumoral G100 injections following localized low-dose radiation in patients with follicular lymphoma (ClinicalTrials.gov #NCT02501473). The study was comprised of a G100 dose escalation (5 or 10 mu g/dose, or 20 mu g/dose for large tumors); a randomized component comparing G100 to G100 plus pembrolizumab; and G100 20 mu g/dose expansion. Adverse events grade >= 3 were uncommon in patients treated with G100, and no unexpected toxicities were observed when combined with pembrolizumab. G100 20 mu g (n = 18) resulted in an overall response rate of 33.3% and abscopal tumor regression in 72.2% of patients. This early-phase study provides a foundation for combining an intratumoral TLR4 agonist with agents to produce immune-mediated responses in follicular lymphoma with limited added toxicity.
Published: 2021
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7. Consensus guidelines for the definition of time-to-event end points in image-guided tumor ablation

Author: Puijk, Robbert, Ahmed, Muneeb, Adam, Andreas, Arai, Yasuaki, Arellano, Ronald, de Baère, Thierry, Bale, Reto, Bellera, Carine, Binkert, Christoph, Brace, Christopher, Breen, David, Brountzos, Elias, Callstrom, Matthew, Carrafiello, Gianpaolo, Chapiro, Julius, de Cobelli, Francesco, Coupé, Veerle, Crocetti, Laura, Denys, Alban, Dupuy, Damian, Erinjeri, Joseph, Filippiadis, Dimitris, Gangi, Afshin, Gervais, Debra, Gillams, Alice, Greene, Tissy, Guiu, Boris, Helmberger, Thomas, Iezzi, Roberto, Kang, Tae Wook, Kelekis, Alexis, Kim, Hyun, Kröncke, Thomas, Kwan, Sharon, Lee, Min Woo, Lee, Fred, Lee, Edward, Liang, Ping, Lissenberg-Witte, Birgit, Lu, David, Madoff, David, Mauri, Giovanni, Meloni, Maria Franca, Morgan, Robert, Nadolski, Gregory, Narayanan, Govindarajan, Newton, Isabel, Nikolic, Boris, Orsi, Franco, Pereira, Philippe, Pua, Uei, Rhim, Hyunchul, Ricke, Jens, Rilling, William, Salem, Riad, Scheffer, Hester, Sofocleous, Constantinos, Solbiati, Luigi, Solomon, Stephen, Soulen, Michael, Sze, Daniel, Uberoi, Raman, Vogl, Thomas, Wang, David, Wood, Bradford, Goldberg, S Nahum, Meijerink, Martijn, Goldberg, S. Nahum, Amsterdam UMC - Amsterdam University Medical Center, Harvard Medical School [Boston] (HMS), Guy's and St Thomas' Hospital [London], National Cancer Center Hospital (NCCJ), Department of radiology (Massachusetts General Hospital), Massachusetts General Hospital [Boston], Institut Gustave Roussy (IGR), Imagerie thérapeutique (radiologie interventionnelle), Département d'imagerie médicale [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Institut Bergonié [Bordeaux], UNICANCER, Kantonsspital Winterthur (KSW), University of Wisconsin School of Medicine and Public Health, University Hospital Southampton NHS Foundation Trust, National and Kapodistrian University of Athens (NKUA), Mayo Clinic [Rochester], Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Yale University [New Haven], IRCCS Ospedale San Raffaele [Milan, Italy], Vrije Universiteit Medical Centre (VUMC), Vrije Universiteit Amsterdam [Amsterdam] (VU), University of Pisa - Università di Pisa, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Warren Alpert Medical School of Brown University, Memorial Sloan Kettering Cancer Center (MSKCC), L'Institut hospitalo-universitaire de Strasbourg (IHU Strasbourg), Institut National de Recherche en Informatique et en Automatique (Inria)-l'Institut de Recherche contre les Cancers de l'Appareil Digestif (IRCAD)-Les Hôpitaux Universitaires de Strasbourg (HUS)-La Fédération des Crédits Mutuels Centre Est (FCMCE)-L'Association pour la Recherche contre le Cancer (ARC)-La société Karl STORZ, The London Clinic cancer, Society of Interventional Oncology (SIO), Service de radiologie et d'Imagerie médicale diagnostique et thérapeutique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein (UKSH), and Kiel University
Subjects: Ablation Techniques, medicine.medical_specialty, Consensus, [SDV]Life Sciences [q-bio], MESH: Societies, Medical, MEDLINE, Outcome (game theory), Session (web analytics), Quality of life (healthcare), Humans, Neoplasms, Reproducibility of Results, Societies, Medical, Medical, medicine, MESH: Neoplasms, Radiology, Nuclear Medicine and imaging, Medical physics, ddc:610, MESH: Consensus, License, MESH: Humans, Health economics, business.industry, MESH: Ablation Techniques, Opinion leadership, MESH: Reproducibility of Results, Clinical trial, business, Societies
Abstract: International audience; There is currently no consensus regarding preferred clinical outcome measures following image-guided tumor ablation or clear definitions of oncologic end points. This consensus document proposes standardized definitions for a broad range of oncologic outcome measures with recommendations on how to uniformly document, analyze, and report outcomes. The initiative was coordinated by the Society of Interventional Oncology in collaboration with the Definition for the Assessment of Time-to-Event End Points in Cancer Trials, or DATECAN, group. According to predefined criteria, based on experience with clinical trials, an international panel of 62 experts convened. Recommendations were developed using the validated three-step modified Delphi consensus method. Consensus was reached on when to assess outcomes per patient, per session, or per tumor; on starting and ending time and survival time definitions; and on time-to-event end points. Although no consensus was reached on the preferred classification system to report complications, quality of life, and health economics issues, the panel did agree on using the most recent version of a validated patient-reported outcome questionnaire. This article provides a framework of key opinion leader recommendations with the intent to facilitate a clear interpretation of results and standardize worldwide communication. Widespread adoption will improve reproducibility, allow for accurate comparisons, and avoid misinterpretations in the field of interventional oncology research. Published under a CC BY 4.0 license. Online supplemental material is available for this article. See also the editorial by Liddell in this issue.
Published: 2021
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8. Stochastic motion and transcriptional dynamics of pairs of distal DNA loci on a compacted chromosome

Author: David B. Brückner, Hongtao Chen, Lev Barinov, Benjamin Zoller, Thomas Gregor, Institute of Science and Technology [Klosterneuburg, Austria] (IST Austria), ShanghaiTech University [Shanghai], Princeton University, Memorial Sloan Kettering Cancer Center (MSKCC), Physique des fonctions biologiques / Physics of Biological Functions, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), This work was supported in part by the U.S. National Science Foundation, through the Center for the Physics of Biological Function (PHY-1734030), and by National Institutes of Health Grants R01GM097275, U01DA047730, and U01DK127429. D.B.B. was supported by the NOMIS foundation as a NOMIS Fellow and by an EMBO Postdoctoral Fellowship (ALTF 343-2022). H.C. was supported by the Charles H. Revson Biomedical Science Fellowship., Department of Physics, Princeton University (DPPU), Lewis-Sigler Institute for Integrative Genomics, and This work was supported in part by theU.S. National Science Foundation, through the Center forthe Physics of Biological Function (PHY-1734030), andby National Institutes of Health Grants R01GM097275,U01DA047730, and U01DK127429. D.B.B. was sup-ported by the NOMIS foundation as a NOMIS Fellowand by an EMBO Postdoctoral Fellowship (ALTF 343-2022). H.C. was supported by the Charles H. RevsonBiomedical Science Fellowship.
Subjects: [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics
Abstract: International audience; Chromosomes in the eukaryotic nucleus are highly compacted. However, for many functional processes, including transcription initiation, the 3D pair-wise motion of distal chromosomal elements, such as enhancers and promoters, is essential and necessitates dynamic fluidity. Therefore, the interplay of chromosome organization and dynamics is crucial for gene regulation. Here, we use a live imaging assay to simultaneously measure the positions of pairs of enhancers and promoters and their transcriptional output in the developing fly embryo while systematically varying the genomic separation between these two DNA loci. Our analysis reveals a combination of a compact globular organization and fast subdiffusive dynamics. These combined features cause an anomalous scaling of polymer relaxation times with genomic separation and lead to long-ranged correlations compared to existing polymer models. This scaling implies that encounter times of DNA loci are much less dependent on genomic separation than predicted by existing polymer models, with potentially significant consequences for eukaryotic gene expression.
Published: 2023
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9. In vivo inactivation of RAD51-mediated homologous recombination leads to premature aging, but not to tumorigenesis

Author: Gabriel Matos-Rodrigues, Vilma Barroca, Ali-Akbar Muhammad, Awatef Allouch, Stephane Koundrioukoff, Daniel Lewandowski, Emmanuelle Despras, Josée Guirouilh-Barbat, Lucien Frappart, Patricia Kannouche, Pauline Dupaigne, Eric Le Cam, Jean-Luc Perfettini, Paul-Henri Romeo, Michelle Debatisse, Maria Jasin, Gabriel Livera, Emmanuelle Martini, Bernard S. Lopez, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Laboratoire de Développement des Gonades, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de Radiobiologie Cellulaire et Moléculaire (IRCM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Signalisation, noyaux et innovations en cancérologie (UMR8126), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Radiothérapie Moléculaire et Innovation Thérapeutique (RaMo-IT), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Stabilité Génétique et Oncogenèse (UMR 8200), Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Leibniz Association, Radiothérapie moléculaire (UMR 1030), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Memorial Sloan Kettering Cancer Center (MSKCC), Stabilité génétique, cellules souches et radiations (SGCSR (U_1274 / UMR_E_008)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université Paris Cité (UPCité), Intégrité du génome et cancers (IGC), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut Gustave Roussy (IGR), and Memorial Sloane Kettering Cancer Center [New York]
Subjects: Genetics Homologous recombination, tumorigenesis, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, mouse model, [SDV]Life Sciences [q-bio], aging, RAD51, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biological Sciences
Abstract: Genetic instability is a hallmark of both cancer and aging. Homologous recombination (HR) is a prominent DNA repair pathway maintaining genomic integrity. Mutations in many HR genes lead to cancer predisposition. Paradoxically, the consequences of mutations in the pivotal HR player, RAD51, on cancer development remain puzzling. Moreover, in contrast with other HR genes, RAD51 mouse models are not available to experimentally address the role of RAD51 on aging and carcinogenesis, in vivo. Here, we engineered a mouse model with an inducible dominant negative form of RAD51 (SMRad51) that suppresses RAD51-mediated HR without stimulating alternative non-conservative repair pathways. We found that, in vivo expression of SMRad51 did not trigger tumorigenesis, but instead induced premature aging. We propose that these in vivo phenotypes result from the exhaustion of proliferating progenitors submitted to chronic endogenous replication stress resulting from RAD51-mediated HR suppression. Our data underline the importance of the RAD51 activity for progenitors homeostasis, preventing aging, and more generally for the balance between cancer and aging.
Published: 2022

10. KTE-X19 for relapsed or refractory adult B-cell acute lymphoblastic leukaemia: phase 2 results of the single-arm, open-label, multicentre ZUMA-3 study

Author: Deepa Jeyakumar, Ryan D. Cassaday, Roch Houot, Chaoling Feng, Dimitrios Tzachanis, Maria R. Baer, John M. Rossi, Patrick J. Stiff, Marion Subklewe, Max S. Topp, Behzad Kharabi Masouleh, Bijal D. Shah, Remus Vezan, Martha Arellano, Olalekan O. Oluwole, Aaron C Logan, William G. Wierda, Kristen M. O'Dwyer, Tong Shen, Monique C. Minnema, Jinghui Dong, Daniel J. DeAngelo, Nicolas Boissel, Mehrdad Abedi, Francesca Milletti, Gary J. Schiller, Thibaut Leguay, Armin Ghobadi, Michael R. Bishop, Yi Lin, Jae H. Park, H. Lee Moffitt Cancer Center and Research Institute, Washington University in Saint Louis (WUSTL), Vanderbilt University [Nashville], Helen Diller Family Comprehensive Cancer Center [San Francisco], Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of Washington [Seattle], CHU Bordeaux [Bordeaux], The University of Chicago Medicine [Chicago], University Hospital of Würzburg, University of California [San Diego] (UC San Diego), University of California, Mayo Clinic [Rochester], University of Rochester [USA], Emory University [Atlanta, GA], University of Maryland [Baltimore], David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California-University of California, State University of New York at New Paltz (SUNY New Paltz), State University of New York (SUNY), Memorial Sloan Kettering Cancer Center (MSKCC), Ludwig-Maximilians-Universität München (LMU), California State University [Sacramento], University Medical Center [Utrecht], The University of Texas M.D. Anderson Cancer Center [Houston], Dana-Farber Cancer Institute [Boston], Loyola University [Chicago], University of California [Irvine] (UCI), Kite (Gilead), Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], University of California (UC), University of California (UC)-University of California (UC), University of California [Irvine] (UC Irvine), and Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: Adult, Male, medicine.medical_specialty, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Population, 030204 cardiovascular system & hematology, Immunotherapy, Adoptive, 03 medical and health sciences, 0302 clinical medicine, Refractory, Recurrence, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Internal medicine, medicine, Clinical endpoint, Humans, 030212 general & internal medicine, education, Survival analysis, Aged, Chemotherapy, education.field_of_study, Receptors, Chimeric Antigen, business.industry, General Medicine, Leukapheresis, Middle Aged, Survival Analysis, Minimal residual disease, 3. Good health, Clinical trial, Treatment Outcome, Female, business
Abstract: International audience; BACKGROUND: Despite treatment with novel therapies and allogeneic stem-cell transplant (allo-SCT) consolidation, outcomes in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia remain poor, underlining the need for more effective therapies. METHODS: We report the pivotal phase 2 results of ZUMA-3, an international, multicentre, single-arm, open-label study evaluating the efficacy and safety of the autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy KTE-X19 in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia. Patients were enrolled at 25 sites in the USA, Canada, and Europe. Eligible patients were aged 18 years or older, with Eastern Cooperative Oncology Group performance status of 0-1, and morphological disease in the bone marrow (>5% blasts). After leukapheresis and conditioning chemotherapy, patients received a single KTE-X19 infusion (1 × 10(6) CAR T cells per kg bodyweight). The primary endpoint was the rate of overall complete remission or complete remission with incomplete haematological recovery by central assessment. Duration of remission and relapse-free survival, overall survival, minimal residual disease (MRD) negativity rate, and allo-SCT rate were assessed as secondary endpoints. Efficacy and safety analyses were done in the treated population (all patients who received a dose of KTE-X19). This study is registered with ClinicalTrials.gov, NCT02614066. FINDINGS: Between Oct 1, 2018, and Oct 9, 2019, 71 patients were enrolled and underwent leukapheresis. KTE-X19 was successfully manufactured for 65 (92%) patients and administered to 55 (77%). The median age of treated patients was 40 years (IQR 28-52). At the median follow-up of 16·4 months (13·8-19·6), 39 patients (71%; 95% CI 57-82, p
Published: 2021
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11. Systematically higher Ki67 scores on core biopsy samples compared to corresponding resection specimen in breast cancer: a multi-operator and multi-institutional study

Author: Balazs Acs, Samuel C.Y. Leung, Kelley M. Kidwell, Indu Arun, Renaldas Augulis, Sunil S. Badve, Yalai Bai, Anita L. Bane, John M.S. Bartlett, Jane Bayani, Gilbert Bigras, Annika Blank, Henk Buikema, Martin C. Chang, Robin L. Dietz, Andrew Dodson, Susan Fineberg, Cornelia M. Focke, Dongxia Gao, Allen M. Gown, Carolina Gutierrez, Johan Hartman, Zuzana Kos, Anne-Vibeke Lænkholm, Arvydas Laurinavicius, Richard M. Levenson, Rustin Mahboubi-Ardakani, Mauro G. Mastropasqua, Sharon Nofech-Mozes, C. Kent Osborne, Frédérique M. Penault-Llorca, Tammy Piper, Mary Anne Quintayo, Tilman T. Rau, Stefan Reinhard, Stephanie Robertson, Roberto Salgado, Tomoharu Sugie, Bert van der Vegt, Giuseppe Viale, Lila A. Zabaglo, Daniel F. Hayes, Mitch Dowsett, Torsten O. Nielsen, David L. Rimm, Lisa M. McShane, Torsten Nielsen, Samuel Leung, Signe Borgquist, Angela Chan, Carsten Denkert, Anna Ehinger, Matthew Ellis, Margaret Flowers, Chad Galderisi, Abhi Gholap, Douglas J. Hartman, Judith C. Hugh, Anagha Jadhav, Elizabeth N. Kornaga, Hans Kreipe, Richard Levenson, Mauro Mastropasqua, Takuya Moriya, Hongchao Pan, Liron Pantanowitz, Ernesta Paola Neri, Mei-Yin Polley, Jason Ruan, Takashi Sakatani, Lois Shepherd, Ian Smith, Joseph Sparano, Melanie Spears, Malini Srinivasan, Jane Starczynski, Austin Todd, Shakeel Virk, Yihong Wang, Hua Yang, Zhiwei Zhang, Inti Zlobec, Rigshospitalet [Copenhagen], Copenhagen University Hospital, CHUV, Lausanne (Departement d'Oncologie), St Jude Children's Research Hospital, Laboratorio de Dianas Terapeuticas, Centro Integral Oncologico Clara Campal, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, University of Washington [Seattle], Universitätsklinikum Tübingen - University Hospital of Tübingen, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Institut Gustave Roussy (IGR), Direction de la recherche clinique [Gustave Roussy], Memorial Sloan Kettering Cancer Center (MSKCC), Weill Medical College of Cornell University [New York], Sylvester Comprehensive Cancer Center [Miami, FL, USA] (S3C), and Damage and Repair in Cancer Development and Cancer Treatment (DARE)
Subjects: [SDV]Life Sciences [q-bio], Biopsy, Image Processing, DIGITAL-IMAGE-ANALYSIS, MULTICENTER, Medical and Health Sciences, MESH: Biopsy, Computer-Assisted, REPRODUCIBILITY, NEEDLE BIOPSIES, Receptors, Image Processing, Computer-Assisted, Pathology, MESH: Protein Kinase Inhibitors, 610 Medicine & health, Cancer, Tumor, PROLIFERATION, MESH: Receptor, trkA, KI-67 LABELING INDEX, MESH: Image Processing, Computer-Assisted, Immunohistochemistry, INTERNATIONAL KI67, Receptors, Estrogen, TRK fusion, RELIABILITY, MESH: Receptors, Estrogen, Female, MESH: Biomarkers, Tumor, NTRK gene fusions, MESH: Ki-67 Antigen, International Ki67 in Breast Cancer Working Group of the Breast International Group and North American Breast Cancer Group, [SDV.CAN]Life Sciences [q-bio]/Cancer, Breast Neoplasms, Settore MED/08 - Anatomia Patologica, Non-interventional study, Pathology and Forensic Medicine, Clinical Research, Biomarkers, Tumor, Humans, Ki-67 Antigen, Breast Cancer, BIOMARKER ASSESSMENT, Larotrectinib, MESH: Humans, MESH: Immunohistochemistry, Estrogen, MESH: Pyrimidines, 570 Life sciences, biology, MESH: Female, MESH: Pyrazoles, MESH: Breast Neoplasms, Biomarkers
Abstract: International audience; Abstract Ki67 has potential clinical importance in breast cancer but has yet to see broad acceptance due to inter-laboratory variability. Here we tested an open source and calibrated automated digital image analysis (DIA) platform to: (i) investigate the comparability of Ki67 measurement across corresponding core biopsy and resection specimen cases, and (ii) assess section to section differences in Ki67 scoring. Two sets of 60 previously stained slides containing 30 core-cut biopsy and 30 corresponding resection specimens from 30 estrogen receptor-positive breast cancer patients were sent to 17 participating labs for automated assessment of average Ki67 expression. The blocks were centrally cut and immunohistochemically (IHC) stained for Ki67 (MIB-1 antibody). The QuPath platform was used to evaluate tumoral Ki67 expression. Calibration of the DIA method was performed as in published studies. A guideline for building an automated Ki67 scoring algorithm was sent to participating labs. Very high correlation and no systematic error ( p = 0.08) was found between consecutive Ki67 IHC sections. Ki67 scores were higher for core biopsy slides compared to paired whole sections from resections ( p ≤ 0.001; median difference: 5.31%). The systematic discrepancy between core biopsy and corresponding whole sections was likely due to pre-analytical factors (tissue handling, fixation). Therefore, Ki67 IHC should be tested on core biopsy samples to best reflect the biological status of the tumor.; v2.5, 25 March 2021.
Published: 2022
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12. Y RNAs are conserved endogenous RIG-I ligands across RNA virus infection and are targeted by HIV-1

Author: Nicolas Vabret, Valérie Najburg, Alexander Solovyov, Ramya Gopal, Christopher McClain, Petr Šulc, Sreekumar Balan, Yannis Rahou, Guillaume Beauclair, Maxime Chazal, Hugo Varet, Rachel Legendre, Odile Sismeiro, Raul Y. Sanchez David, Lise Chauveau, Nolwenn Jouvenet, Martin Markowitz, Sylvie van der Werf, Olivier Schwartz, Frédéric Tangy, Nina Bhardwaj, Benjamin D. Greenbaum, Anastassia V. Komarova, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Génomique virale et vaccination, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Memorial Sloan Kettering Cancer Center (MSKCC), Arizona State University [Tempe] (ASU), Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Transcriptome et Epigénome (PF2), Institut Pasteur [Paris] (IP), Biomics (plateforme technologique), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Virus et Immunité - Virus and immunity (CNRS-UMR3569), Rockefeller University [New York], Parker Institute for Cancer Immunotherapy [San Francisco, CA] (PICI), Weill Cornell Medicine [Cornell University], Cornell University [New York], This work was supported by Agence Nationale de Recherches sur le SIDA et les hépatites virales 2012-1 and 2012-2 HIV signature on RIG-I-like receptors to AVK and FT, Agence Nationale pour la Recherche ANR-16-CE15-0025-01 ViroStorm to NJ and GB, Fondation pour la Recherche Medicale FDT20140931129 to RYSD, National Institutes of Health R01CA201189 and R01CA180913 to NB, R01AI081848 to NV, NB, and BDG, U01CA228963 to NV, NB, AS and BDG, R01CA240924 and P30CA008748 to AS and BDG. BDG was supported by a Stand Up To Cancer—National Science Foundation—Lustgarten Foundation Convergence Dream Team Grant sponsored by Stand Up to Cancer, the Lustgarten Foundation, the V Foundation, and the National Science Foundation (NSF 1545935).BDG BDG is The Pershing Square Sohn Prize-Mark Foundation Fellow supported by funding from The Mark Foundation for Cancer Research., and ANR-16-CE15-0025,Viro-Storm,Mécanismes de production incontrôlée de cytokines au cours de l'infection virale(2016)
Subjects: Biological sciences, Multidisciplinary, [SDV]Life Sciences [q-bio], Immunology, Transcriptomics
Abstract: International audience; Pattern recognition receptors (PRRs) protect against microbial invasion by detecting specific molecular patterns found in pathogens and initiating an immune response. Although microbial-derived PRR ligands have been extensively characterized, the contribution and relevance of endogenous ligands to PRR activation remains overlooked. Here, we characterize the landscape of endogenous ligands that engage RIG-I-like receptors (RLRs) upon infection by different RNA viruses. In each infection, several RNAs transcribed by RNA polymerase III (Pol3) specifically engaged RLRs, particularly the family of Y RNAs. Sensing of Y RNAs was dependent on their mimicking of viral secondary structure and their 5′-triphosphate extremity. Further, we found that HIV-1 triggered a VPR-dependent downregulation of RNA triphosphatase DUSP11 in vitro and in vivo, inducing a transcriptome-wide change of cellular RNA 5′-triphosphorylation that licenses Y RNA immunogenicity. Overall, our work uncovers the contribution of endogenous RNAs to antiviral immunity and demonstrates the importance of this pathway in HIV-1 infection.
Published: 2022
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13. Translating Molecules into Imaging—The Development of New PET Tracers for Patients with Melanoma

Author: Laetitia Vercellino, Dorine de Jong, Laurent Dercle, Benoit Hosten, Brian Braumuller, Jeeban Paul Das, Aileen Deng, Antoine Moya-Plana, Camry A’Keen, Randy Yeh, Pascal Merlet, Barouyr Baroudjian, Mary M. Salvatore, Kathleen M. Capaccione, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Marqueurs cardiovasculaires en situation de stress (MASCOT (UMR_S_942 / U942)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Université Paris Cité (UPCité), Memorial Sloan Kettering Cancer Center (MSKCC), Columbia University Medical Center (CUMC), Columbia University [New York], Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Novant Health Cancer Institute - Elizabeth [Charlotte, NC, USA] (NHCIE), Département de cancérologie cervico-faciale [Gustave Roussy] (CCF), Institut Gustave Roussy (IGR), Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse (U981), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Memorial Sloane Kettering Cancer Center [New York], and leboeuf, Christophe
Subjects: [SDV.CAN] Life Sciences [q-bio]/Cancer, Clinical Biochemistry, PET imaging, melanoma, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.DERM] Life Sciences [q-bio]/Human health and pathology/Dermatology, molecular targeting, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology
Abstract: International audience; Melanoma is a deadly disease that often exhibits relentless progression and can have both early and late metastases. Recent advances in immunotherapy and targeted therapy have dramatically increased patient survival for patients with melanoma. Similar advances in molecular targeted PET imaging can identify molecular pathways that promote disease progression and therefore offer physiological information. Thus, they can be used to assess prognosis, tumor heterogeneity, and identify instances of treatment failure. Numerous agents tested preclinically and clinically demonstrate promising results with high tumor-to-background ratios in both primary and metastatic melanoma tumors. Here, we detail the development and testing of multiple molecular targeted PET-imaging agents, including agents for general oncological imaging and those specifically for PET imaging of melanoma. Of the numerous radiopharmaceuticals evaluated for this purpose, several have made it to clinical trials and showed promising results. Ultimately, these agents may become the standard of care for melanoma imaging if they are able to demonstrate micrometastatic disease and thus provide more accurate information for staging. Furthermore, these agents provide a more accurate way to monitor response to therapy. Patients will be able to receive treatment based on tumor uptake characteristics and may be able to be treated earlier for lesions that with traditional imaging would be subclinical, overall leading to improved outcomes for patients.
Published: 2022
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14. How to Register a Live onto a Liver ? Partial Matching in the Space of Varifolds

Author: Pierre-Louis Antonsanti, Thomas Benseghir, Vincent Jugnon, Mario Ghosn, Perrine Chassat, Joan Glaunès, Irène Kaltenmark, Mathématiques Appliquées Paris 5 (MAP5 - UMR 8145), Institut National des Sciences Mathématiques et de leurs Interactions (INSMI)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), General Electric Medical Systems [Buc] (GE Healthcare), General Electric Medical Systems, Memorial Sloan Kettering Cancer Center (MSKCC), Laboratoire de Mathématiques et Modélisation d'Evry (LaMME), and Université d'Évry-Val-d'Essonne (UEVE)-ENSIIE-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)
Subjects: FOS: Computer and information sciences, Varifolds, I.5.4, Computer Vision and Pattern Recognition (cs.CV), Partial Matching Varifolds Large Deformation Diffeomorphic Metric Mapping Multi-Modality Image Registration Computed Tomography Cone Beam Computed Tomography, Image and Video Processing (eess.IV), Computer Science - Computer Vision and Pattern Recognition, FOS: Physical sciences, Partial Matching, Electrical Engineering and Systems Science - Image and Video Processing, 65D19 (Primary) 68U10, 68U07 (Secondary), Physics - Medical Physics, Multi-Modality Image Registration, Computed Tomography, Cone Beam Computed Tomography, FOS: Electrical engineering, electronic engineering, information engineering, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, Large Deformation Diffeomorphic Metric Mapping, I.4.9, [INFO]Computer Science [cs], Medical Physics (physics.med-ph), [MATH]Mathematics [math]
Abstract: Partial shapes correspondences is a problem that often occurs in computer vision (occlusion, evolution in time...). In medical imaging, data may come from different modalities and be acquired under different conditions which leads to variations in shapes and topologies. In this paper we use an asymmetric data dissimilarity term applicable to various geometric shapes like sets of curves or surfaces, assessing the embedding of a shape into another one without relying on correspondences. It is designed as a data attachment for the Large Deformation Diffeomorphic Metric Mapping (LDDMM) framework, allowing to compute a meaningful deformation of one shape onto a subset of the other. We refine it in order to control the resulting non-rigid deformations and provide consistent deformations of the shapes along with their ambient space. We show that partial matching can be used for robust multi-modal liver registration between a Computed Tomography (CT) volume and a Cone Beam Computed Tomography (CBCT) volume. The 3D imaging of the patient CBCT at point of care that we call live is truncated while the CT pre-intervention provides a full visualization of the liver. The proposed method allows the truncated surfaces from CBCT to be aligned non-rigidly, yet realistically, with surfaces from CT with an average distance of 2.6mm(+/- 2.2). The generated deformations extend consistently to the liver volume, and are evaluated on points of interest for the physicians, with an average distance of 5.8mm (+/- 2.7) for vessels bifurcations and 5.13mm (+/- 2.5) for tumors landmarks. Such multi-modality volumes registrations would help the physicians in the perspective of navigating their tools in the patient's anatomy to locate structures that are hardly visible in the CBCT used during their procedures. Our code is available at https://github.com/plantonsanti/PartialMatchingVarifolds., Comment: 30 pages, 11 figures, Special Issue: Information Processing in Medical Imaging (IPMI) 2021, Accepted for publication at the Journal of Machine Learning for Biomedical Imaging (MELBA) https://www.melba-journal.org
Published: 2022

15. Rationale and design of ON-TRK:a novel prospective non-interventional study in patients with TRK fusion cancer treated with larotrectinib

Author: James C. H. Yang, Marcia S. Brose, Gilberto Castro, Edward S. Kim, Ulrik N. Lassen, Serge Leyvraz, Alberto Pappo, Fernando López-Ríos, John A. Reeves, Marc Fellous, Frédérique Penault-Llorca, Erin R. Rudzinski, Ghazaleh Tabatabai, Gilles Vassal, Alexander Drilon, Jonathan Trent, National Taiwan University Cancer Center [Taipei], Abramson Cancer Center [philadelphia], University of Pennsylvania-Perelman School of Medicine, University of Pennsylvania, Instituto do Câncer do Estado = Cancer Institute of the State of São Paulo (ICESP), Levine Cancer Institute, Atrium Health [Charlotte, NC, USA] (LCIAH), Rigshospitalet [Copenhagen], Copenhagen University Hospital, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], St Jude Children's Research Hospital, Hospital Universitario HM Sanchinarro [Madrid, Spain], Bayer HealthCare Pharmaceuticals Inc [Whippany], Bayer HealthCare Pharmaceuticals, Inc. [Basel, Switzerland] (BHCP), Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, University of Washington [Seattle], Universitätsklinikum Tübingen - University Hospital of Tübingen, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Institut Gustave Roussy (IGR), Direction de la recherche [Gustave Roussy], Memorial Sloane Kettering Cancer Center [New York], Weill Medical College of Cornell University [New York], Sylvester Comprehensive Cancer Center [Miami, FL, USA] (S3C), Malbec, Odile, The Levine Cancer Institute, Direction de la recherche clinique [Gustave Roussy], and Memorial Sloan Kettering Cancer Center (MSKCC)
Subjects: Adult, Cancer Research, Oncogene Proteins, Fusion, [SDV]Life Sciences [q-bio], Fibrosarcoma, Neoplasms, Second Primary, Non-interventional study, [SDV] Life Sciences [q-bio], Pyrimidines, Oncology, TRK fusion, Neoplasms, Genetics, Humans, Pyrazoles, Prospective Studies, Gene Fusion, Receptor, trkA, Child, Protein Kinase Inhibitors, NTRK gene fusions, Larotrectinib
Abstract: Background Tropomyosin receptor kinase (TRK) fusion proteins resulting from neurotrophic tyrosine receptor kinase (NTRK) gene fusions are rare primary oncogenic drivers in a wide array of tumors. Larotrectinib is a first-in-class, highly selective, central nervous system-active TRK inhibitor approved by the US Food and Drug Administration (FDA), European Medicines Agency (EMA), and over 40 countries for the treatment of TRK fusion solid tumors in adult and pediatric patients. Due to the rarity of TRK fusion cancer, larotrectinib was granted accelerated approval based on a relatively small number of patients enrolled in three early phase trials. ON-TRK aims to evaluate the safety profile of larotrectinib in a broader population and over extended time periods. Methods ON-TRK is a prospective, non-interventional, open-label, multicenter, multi-cohort, post-approval study in adult and pediatric patients with locally advanced or metastatic TRK fusion cancer treated with larotrectinib that will describe the safety and effectiveness of larotrectinib in real-world practice conditions. Adult patients will be grouped by tumor type and followed for at least 2 years. Patients Discussion The FDA Accelerated Approval Program allows for earlier approval of and patient access to drugs that treat serious conditions and fill an unmet medical need. This study is designed to fulfill post-approval requirements set by the FDA as well as post-marketing requirements set forth by local regulatory bodies and is part of the risk management plan for the EMA. Study registration This study is registered at ClinicalTrials.gov (NCT04142437). Protocol version v2.5, 25 March 2021.
Published: 2022
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16. Candida albicans Isolates 529L and CHN1 Exhibit Stable Colonization of the Murine Gastrointestinal Tract

Author: Pallavi Kakade, Animesh Mishra, Swathi Penumutchu, Iuliana V. Ene, Shen-Huan Liang, Richard J. Bennett, Nicholas L. Tosini, Corrine Maufrais, Tobias M. Hohl, Peter Belenky, Ying Taur, Andrew Y. Koh, Liam D McDonough, Bing Zhai, Brown University, Yale University School of Medicine, University of Texas Southwestern Medical Center [Dallas], Memorial Sloan Kettering Cancer Center (MSKCC), Département de Mycologie - Department of Mycology, Institut Pasteur [Paris], Weill Medical College of Cornell University [New York], This work was supported by National Institutes of Health (NIH) grants R01 AI093808 (TMH), R01 AI139632 (TMH), R21 AI105617 (TMH), R21 AI156157 (TMH), Burroughs Wellcome Fund Investigator in the Pathogenesis of Infectious Diseases Award (TMH), Ludwig Center for Cancer Immunotherapy (TMH), NIH P30 CA008748 (to MSKCC), NIH R01 AI123163 (AYK), K24 AI150992 (AYK), Roberta I. and Normal L. Pollock Fund (AYK), NIH R01 AI41893 (RJB), NIH R01 AI081704 (RJB), NIH R21 AI144651 (RJB), NIH R21 AI139592 (IVE), NIH NIGMS IDeA award P20GM109035 (IVE), Institut Pasteur G5 (IVE), CIFAR Azrieli Global Scholar Award (IVE), NIH NCCIH R21AT010366 (PB), NIDDK R01 DK125382 (PB) and NSF Graduate Research Fellowship award 1644760 (SP)., Yale School of Medicine [New Haven, Connecticut] (YSM), and Institut Pasteur [Paris] (IP)
Subjects: Genotype, medicine.drug_class, [SDV]Life Sciences [q-bio], Antibiotics, microbiome, Cell morphology, Microbiology, 03 medical and health sciences, Mice, Virology, Candida albicans, medicine, Animals, Colonization, Microbiome, Symbiosis, 030304 developmental biology, 0303 health sciences, Gastrointestinal tract, Mice, Inbred BALB C, Mice, Inbred C3H, biology, 030306 microbiology, biology.organism_classification, Commensalism, Corpus albicans, QR1-502, Gastrointestinal Microbiome, Gastrointestinal Tract, Mice, Inbred C57BL, gastrointestinal colonization, Female, strain diversity, fungal biology, Research Article
Abstract: Candida albicans is a pathobiont that colonizes multiple niches in the body including the gastrointestinal (GI) tract, but is also responsible for both mucosal and systemic infections. Despite its prevalence as a human commensal, the murine GI tract is generally refractory to colonization with the C. albicans reference isolate SC5314. Here, we identify two C. albicans isolates, 529L and CHN1, that stably colonize the murine GI tract in three different animal facilities under conditions where SC5314 is lost from this niche. Analysis of the bacterial microbiota did not show notable differences between mice colonized with the three C. albicans strains. We compared the genotypes and phenotypes of these three strains and identified thousands of SNPs and multiple phenotypic differences, including their ability to grow and filament in response to nutritional cues. Despite striking filamentation differences under laboratory conditions, however, analysis of cell morphology in the GI tract revealed that the three isolates exhibited similar filamentation properties in this in vivo niche. Notably, we found that SC5314 is more sensitive to the antimicrobial peptide CRAMP, and the use of CRAMP-deficient mice increased the ability of SC5314 to colonize the GI tract relative to CHN1 and 529L. These studies provide new insights into how strain-specific differences impact C. albicans traits in the host and advance CHN1 and 529L as relevant strains to study C. albicans pathobiology in its natural host niche.IMPORTANCEUnderstanding how fungi colonize the GI tract is increasingly recognized as highly relevant to human health. The animal models used to study Candida albicans commensalism commonly rely on altering the host microbiome (via antibiotic treatment or defined diets) to establish successful GI colonization by the C. albicans reference isolate SC5314. Here, we characterize two C. albicans isolates that can colonize the murine GI tract without antibiotic treatment and can therefore be used as tools for studying fungal commensalism. Importantly, experiments were replicated in three different animal facilities and utilized three different mouse strains. Differential colonization between fungal isolates was not associated with alterations in the bacterial microbiome but rather with distinct responses to CRAMP, a host antimicrobial peptide. This work emphasizes the importance of C. albicans intra-species variation as well as host anti-microbial defense mechanisms in defining commensal interactions.
Published: 2021
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17. The EHA Research Roadmap: Immune-based Therapies for Hematological Malignancies

Author: Irene García Cadenas, Fred Falkenburg, Kate Morgan, Hermann Einsele, Fabio Ciceri, Marcel R.M. van den Brink, Emma C. Morris, Jordi Sierra, Franco Locatelli, Natacha Bolaños, H M Mirjam Heemskerk, Arjan A. van de Loosdrecht, Javier Briones, Michael Hudecek, Roch Houot, Michael O'Dwyer, University Hospital of Würzburg, Hospital de la Santa Creu i Sant Pau, IRCCS San Raffaele Scientific Institute [Milan, Italie], Leiden University Medical Center (LUMC), Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Myeloma Patients Europe, University College of London [London] (UCL), National University of Ireland Maynooth (Maynooth University), Memorial Sloan Kettering Cancer Center (MSKCC), Amsterdam UMC, Einsele, H., Briones, J., Ciceri, F., Cadenas, I. G., Falkenburg, F., Bolanos, N., Heemskerk, H. M. M., Houot, R., Hudecek, M., Locatelli, F., Morgan, K., Morris, E. C., O'Dwyer, M., Sierra, J. G., van den Brink, M., van de Loosdrecht, A. A., Universiteit Leiden, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), IRCCS Ospedale Pediatrico Bambino Gesù [Roma], Weill Medical College of Cornell University [New York], and Amsterdam UMC - Amsterdam University Medical Center
Subjects: medicine.medical_specialty, Platelet disorder, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Clinical science, Hematopoietic stem cell transplantation, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Diseases of the blood and blood-forming organs, Intensive care medicine, IMMUNE THERAPY, 030304 developmental biology, 0303 health sciences, Hematology, business.industry, Normal hematopoiesis, Transfusion medicine, 3. Good health, Blood Disorder, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, European policy, 030220 oncology & carcinogenesis, Perspective, RC633-647.5, business
Abstract: International audience; In 2016, the European Hematology Association (EHA) published the EHA Roadmap for European Hematology Research(1) aiming to highlight achievements in the diagnostics and treatment of blood disorders, and to better inform European policy makers and other stakeholders about the urgent clinical and scientific needs and priorities in the field of hematology. Each section was coordinated by 1-2 section editors who were leading international experts in the field. In the 5 years that have followed, advances in the field of hematology have been plentiful. As such, EHA is pleased to present an updated Research Roadmap, now including 11 sections, each of which will be published separately. The updated EHA Research Roadmap identifies the most urgent priorities in hematology research and clinical science, therefore supporting a more informed, focused, and ideally a more funded future for European Hematology Research. the 11 EHA Research Roadmap sections include normal hematopoiesis; malignant lymphoid diseases; malignant myeloid diseases; anemias and related diseases; platelet disorders; blood coagulation and hemostatic disorders; transfusion medicine; infections in hematology; hematopoietic stem cell transplantation; CAR-T and Other cell-based immune therapies; and gene therapy.
Published: 2021
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18. Transcriptional Regulation of the Glutamate/GABA/Glutamine Cycle in Adult Glia Controls Motor Activity and Seizures in Drosophila

Author: Angela Giangrande, Heinz Jungbluth, Catarina Gonçalves-Pimentel, Celine Diebold, David Mazaud, Frank Hirth, Sandra Proelss, Manolis Fanto, Benjamin Kottler, Nadine Tüchler, Eric C. Lai, Yoshihiro Yuasa, Celine Deneubourg, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Cattenoz, Pierre, King‘s College London, and Memorial Sloan Kettering Cancer Center (MSKCC)
Subjects: Male, 0301 basic medicine, Nervous system, glia, [SDV]Life Sciences [q-bio], Glutamine, Glutamic Acid, Motor Activity, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Seizures, microRNA, Genetic model, Transcriptional regulation, medicine, Animals, Drosophila Proteins, Neurotransmitter, ComputingMilieux_MISCELLANEOUS, gamma-Aminobutyric Acid, Research Articles, glutamate/GABA/glutamine, Homeodomain Proteins, biology, General Neuroscience, Glutamate receptor, biology.organism_classification, [SDV] Life Sciences [q-bio], MicroRNAs, Drosophila melanogaster, 030104 developmental biology, medicine.anatomical_structure, Gene Expression Regulation, nervous system, chemistry, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, Drosophila, repo, Neuroglia, Neuroscience, 030217 neurology & neurosurgery, Cellular/Molecular
Abstract: International audience; The fruitfly Drosophila melanogaster has been extensively used as a genetic model for the maintenance of nervous system's functions. Glial cells are of utmost importance in regulating the neuronal functions in the adult organism and in the progression of neurological pathologies. Through a microRNA-based screen in adult Drosophila glia, we uncovered the essential role of a major glia developmental determinant, repo, in the adult fly. Here, we report that Repo expression is continuously required in adult glia to transcriptionally regulate the highly conserved function of neurotransmitter recycling in both males and females. Transient loss of Repo dramatically shortens fly lifespan, triggers motor deficits, and increases the sensibility to seizures, partly due to the impairment of the glutamate/GABA/glutamine cycle. Our findings highlight the pivotal role of transcriptional regulation of genes involved in the glutamate/GABA/glutamine cycle in glia to control neurotransmitter levels in neurons and their behavioral output. The mechanism identified here in Drosophila exemplifies how adult functions can be modulated at the transcriptional level and suggest an active synchronized regulation of genes involved in the same pathway. The process of neurotransmitter recycling is of essential importance in human epileptic and psychiatric disorders and our findings may thus have important consequences for the understanding of the role that transcriptional regulation of neurotransmitter recycling in astrocytes has in human disease.SIGNIFICANCE STATEMENT Glial cells are an essential support to neurons in adult life and have been involved in a number of neurological disorders. What controls the maintenance and modulation of glial functions in adult life is not fully characterized. Through a miR overexpression screen in adult glia in Drosophila, we identify an essential role in adult glia of repo, which directs glial differentiation during embryonic development. Repo levels modulate, via transcriptional regulation, the ability of glial cells to support neurons in the glutamate/GABA/glutamine cycle. This leads to significant abnormalities in motor behavior as assessed through a novel automated paradigm. Our work points to the importance of transcriptional regulation in adult glia for neurotransmitter recycling, a key process in several human neurological disorders.
Published: 2019
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19. The OpenGATE ecosystem for Monte Carlo simulation in medical physics

Author: David Sarrut, Nicolas Arbor, Thomas Baudier, Damian Borys, Ane Etxebeste, Hermann Fuchs, Jan Gajewski, Loïc Grevillot, Sébastien Jan, George C Kagadis, Han Gyu Kang, Assen Kirov, Olga Kochebina, Wojciech Krzemien, Antony Lomax, Panagiotis Papadimitroulas, Christian Pommranz, Emilie Roncali, Antoni Rucinski, Carla Winterhalter, Lydia Maigne, Imagerie Tomographique et Radiothérapie, Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Silesian University of Technology, EBG MedAustron GmbH, Medizinische Universität Wien = Medical University of Vienna, Polish Academy of Sciences (PAN), Université Paris-Saclay, LaBoratoire d'Imagerie biOmédicale MultimodAle Paris-Saclay (BIOMAPS), Service Hospitalier Frédéric Joliot (SHFJ), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Patras, National Institutes for Quantum and Radiological Science and Technology (QST), Memorial Sloan Kettering Cancer Center (MSKCC), High Energy Physics Division, National Centre for Nuclear Research, Uniwersytet Jagielloński w Krakowie = Jagiellonian University (UJ), Center for Proton Therapy, Paul Scherrer Institut, Departement Physik [ETH Zürich] (D-PHYS), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), BIOEMTECH, Werner Siemens Imaging Center, University of California [Davis] (UC Davis), University of California (UC), Laboratoire de Physique de Clermont (LPC), and Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne (UCA)
Subjects: [PHYS]Physics [physics], Radiological and Ultrasound Technology, Physics, Computer Simulation, Radiology, Nuclear Medicine and imaging, Monte Carlo, Gate, Geant4, simulation, Monte Carlo Method, [PHYS.PHYS.PHYS-DATA-AN]Physics [physics]/Physics [physics]/Data Analysis, Statistics and Probability [physics.data-an], Ecosystem, Software
Abstract: This paper reviews the ecosystem of GATE, an open-source Monte Carlo toolkit for medical physics. Based on the shoulders of Geant4, the principal modules (geometry, physics, scorers) are described with brief descriptions of some key concepts (Volume, Actors, Digitizer). The main source code repositories are detailed together with the automated compilation and tests processes (Continuous Integration). We then described how the OpenGATE collaboration managed the collaborative development of about one hundred developers during almost 20 years. The impact of GATE on medical physics and cancer research is then summarized, and examples of a few key applications are given. Finally, future development perspectives are indicated.
Published: 2022
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20. Concerted cutting by Spo11 illuminates meiotic DNA break mechanics

Author: Tim J. Cooper, Scott Keeney, Margaret R. Crawford, Bertrand Llorente, Valerie Garcia, Corentin Claeys Bouuaert, Matthew J. Neale, Dominic Johnson, Genome Damage and Stability Centre, University of Sussex, LIBST - Louvain Institute of Biomolecular Science and Technology, Memorial Sloan Kettering Cancer Center (MSKCC), Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Garcia, Valerie, University of Sussex, Louvain Institute of Biomolecular Science and Technology (LIBST), and Université Catholique de Louvain = Catholic University of Louvain (UCL)
Subjects: Spo11, Saccharomyces cerevisiae Proteins, DNA Repair, [SDV]Life Sciences [q-bio], Saccharomyces cerevisiae, Genetic recombination, Deep sequencing, Article, law.invention, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Meiosis, law, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, DNA Breaks, Double-Stranded, 030304 developmental biology, Mice, Knockout, 0303 health sciences, Multidisciplinary, Endodeoxyribonucleases, biology, fungi, Mechanics, biology.organism_classification, [SDV] Life Sciences [q-bio], chemistry, biology.protein, Recombinant DNA, 030217 neurology & neurosurgery, DNA, Recombination
Abstract: Genetic recombination arises during meiosis through the repair of DNA double-strand breaks (DSBs) that are created by Spo11, a topoisomerase-like protein1,2. Spo11 DSBs form preferentially in nucleosome-depleted regions termed hotspots3,4, yet how Spo11 engages with its DNA substrate to catalyse DNA cleavage is poorly understood. Although most recombination events are initiated by a single Spo11 cut, here we show in Saccharomyces cerevisiae that hyperlocalized, concerted Spo11 DSBs separated by 33 to more than 100 base pairs also form, which we term ‘double cuts’. Notably, the lengths of double cuts vary with a periodicity of 10.5 base pairs, which is conserved in yeast and mice. This finding suggests a model in which the orientation of adjacent Spo11 molecules is fixed relative to the DNA helix—a proposal supported by the in vitro DNA-binding properties of the Spo11 core complex. Deep sequencing of meiotic progeny identifies recombination scars that are consistent with repair initiated from gaps generated by adjacent Spo11 DSBs. Collectively, these results revise our present understanding of the mechanics of Spo11-DSB formation and expand on the original concepts of gap repair during meiosis to include DNA gaps that are generated by Spo11 itself. A small proportion of Spo11-dependent DNA double-strand breaks are ‘double cuts’—adjacent breaks that occur in concert—revealing that gap repair during meiosis includes that of DNA gaps generated by Spo11 itself.
Published: 2021
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21. Current and Future Role of Medical Imaging in Guiding the Management of Patients With Relapsed and Refractory Non-Hodgkin Lymphoma Treated With CAR T-Cell Therapy

Author: Dorine de Jong, Laetitia Vercellino, Salim Kanoun, Lawrence H. Schwartz, Roberta Di Blasi, Laurent Dercle, Ran Reshef, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Cité (UPCité), Memorial Sloan Kettering Cancer Center (MSKCC), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Columbia University Irving Medical Center (CUIMC), New York Presbyterian Hospital, and leboeuf, Christophe
Subjects: Oncology, CT scan, medicine.medical_specialty, Cancer Research, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Mini Review, medicine.medical_treatment, lymphoma, [SDV.CAN]Life Sciences [q-bio]/Cancer, CAR T-cell, Refractory, Refractory Non-Hodgkin Lymphoma, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, medicine, Medical imaging, prognostic biomarker, RC254-282, business.industry, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Immunotherapy, medicine.disease, Chimeric antigen receptor, FDG PET/CT, Lymphoma, Clinical trial, [SDV.IB.IMA] Life Sciences [q-bio]/Bioengineering/Imaging, CAR T-cell therapy, immunotherapy, business
Abstract: International audience; Chimeric antigen receptor (CAR) T-cells are a novel immunotherapy available for patients with refractory/relapsed non-Hodgkin lymphoma. In this indication, clinical trials have demonstrated that CAR T-cells achieve high rates of response, complete response, and long-term response (up to 80%, 60%, and 40%, respectively). Nonetheless, the majority of patients ultimately relapsed. This review provides an overview about the current and future role of medical imaging in guiding the management of non-Hodgkin lymphoma patients treated with CAR T-cells. It discusses the value of predictive and prognostic biomarkers to better stratify the risk of relapse, and provide a patient-tailored therapeutic strategy. At baseline, high tumor volume (assessed on CT-scan or on [18F]-FDG PET/CT) is a prognostic factor associated with treatment failure. Response assessment has not been studied extensively yet. Available data suggests that current response assessment developed on CT-scan or on [18F]-FDG PET/CT for cytotoxic systemic therapies remains relevant to estimate lymphoma response to CAR T-cell therapy. Nonetheless, atypical patterns of response and progression have been observed and should be further analyzed. The potential advantages as well as limitations of artificial intelligence and radiomics as tools providing high throughput quantitative imaging features is described.
Published: 2021
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22. Global guideline for the diagnosis and management of the endemic mycoses: an initiative of the European Confederation of Medical Mycology in cooperation with the International Society for Human and Animal Mycology

Author: Peter-Michael Rath, Methee Chayakulkeeree, Alessandro C. Pasqualotto, Christopher C. Kibbler, María José Buitrago, Thuy Le, Neil M Ampel, Flavio Queiroz-Telles, Ferry Hagen, Oliver A. Cornely, Paul E. Verweij, Ana Alastruey-Izquierdo, Ariya Chindamporn, Nelesh P. Govender, Carol A. Kauffman, Graeme Meintjes, Darius Armstrong-James, Chris Kenyon, Grégory Jouvion, Ilan S. Schwartz, Olusola Ayanlowo, Jean-Pierre Gangneux, John W Baddley, George Richard Thompson, Jasper Fuk-Woo Chan, David R. Andes, Tobias M. Hohl, Low Lee Lee, Andrej Spec, Cao Cun-wei, Robert Krause, Ebrahim Variava, Marisa H. Miceli, David C M Kong, Leili Chamani-Tabriz, Mohammad Taghi Hedayati, Bridget M. Barker, Nikolai Klimko, Leila Maria Lopes Bezerra, University of California [Davis] (UC Davis), University of California, Duke University [Durham], Chulalongkorn University [Bangkok], University of Michigan Medical School [Ann Arbor], University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Instituto de Salud Carlos III [Madrid] (ISC), University of Arizona, University of Wisconsin-Madison, Imperial College London, University of Lagos, University of Maryland School of Medicine, University of Maryland System, The Pathogen and Microbiome Institute, Northern Arizona University [Flagstaff], State University of Rio de Janeiro, The University of Hong Kong (HKU), Mahidol University [Bangkok], University Hospital of Cologne [Cologne], Guangxi University [Nanning], Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), National Institute for Communicable Diseases [Johannesburg] (NICD), University of the Witwatersrand [Johannesburg] (WITS), University Medical Center [Utrecht], Mazandaran University of Medical Sciences, Memorial Sloan Kettering Cancer Center (MSKCC), Neuropathologie expérimentale / Experimental neuropathology, Institut Pasteur [Paris]-Université de Paris (UP), Maladies génétiques d'expression pédiatrique [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institute of Tropical Medicine [Antwerp] (ITM), University College of London [London] (UCL), University of Ballarat [Australie] (FedUni), Institute of Biophysics [Graz], Medical University Graz, University of Cape Town, Ruhrlandklinik University Hospital, Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Federal University of Technology - Paraná (UTFPR), Radboud University Medical Center [Nijmegen], University of Alberta, Federal University of Health Sciences of Porto Alegre = Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), University of California (UC), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Maladies génétiques d'expression pédiatrique (U933), and Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP]
Subjects: medicine.medical_specialty, Consensus, Endemic Diseases, [SDV]Life Sciences [q-bio], International Cooperation, Clinical Sciences, Clinical Decision-Making, Medizin, MEDLINE, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Guidelines as Topic, Global Health, Microbiology, Article, Histoplasmosis, Vaccine Related, 03 medical and health sciences, 0302 clinical medicine, All institutes and research themes of the Radboud University Medical Center, Risk Factors, Biodefense, Mycology, Epidemiology, medicine, Animals, Humans, 030212 general & internal medicine, Intensive care medicine, 0303 health sciences, Sporotrichosis, 030306 microbiology, Paracoccidioidomycosis, business.industry, Prevention, Guideline, medicine.disease, 3. Good health, Europe, Emerging Infectious Diseases, Good Health and Well Being, Infectious Diseases, Mycoses, Medical Microbiology, Public Health and Health Services, Infection, business, Blastomycosis
Abstract: International audience; The global burden of the endemic mycoses (blastomycosis, coccidioidomycosis, emergomycosis, histoplasmosis, paracoccidioidomycosis, sporotrichosis, and talaromycosis) continues to rise yearly and these infectious diseases remain a leading cause of patient morbidity and mortality worldwide. Management of the associated pathogens requires a thorough understanding of the epidemiology, risk factors, diagnostic methods and performance characteristics in different patient populations, and treatment options unique to each infection. Guidance on the management of these infections has the potential to improve prognosis. The recommendations outlined in this Review are part of the "One World, One Guideline" initiative of the European Confederation of Medical Mycology. Experts from 23 countries contributed to the development of these guidelines. The aim of this Review is to provide an up-to-date consensus and practical guidance in clinical decision making, by engaging physicians and scientists involved in various aspects of clinical management.
Published: 2021
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23. Apport des nouveaux tests moléculaires dans le diagnostic d’un mélanome sur nævus congénital chez un nourrisson

Author: Frédéric Lauwers, Klaus J. Busam, Emilie Tournier, Nicolas Meyer, R. Lazova, Sylvie Fraitag, M. Masson Regnault, A. de Berail, Aude Maza, A. de la Fouchardière, Laurence Lamant, L. Carfagna, Juliette Mazereeuw-Hautier, Hôpital Larrey [Toulouse], CHU Toulouse [Toulouse], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Service d'anatomopathologie, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse], Service de Chirurgie maxillo-faciale et stomatologie, Centre hospitalier universitaire de Nantes (CHU Nantes), Institut Technique du Porc [Toulouse] (ITP [Toulouse]), Institut Technique du Porc (ITP), Memorial Sloan Kettering Cancer Center (MSKCC), and Centre hospitalier universitaire de Poitiers (CHU Poitiers)
Subjects: Gynecology, 030207 dermatology & venereal diseases, 03 medical and health sciences, medicine.medical_specialty, 0302 clinical medicine, business.industry, [SDV]Life Sciences [q-bio], medicine, Dermatology, business, 3. Good health
Abstract: Resume Introduction Les cas de melanomes se developpant chez le nourrisson sont rares et de diagnostic difficile. Nous rapportons le cas d’une enfant presentant un naevus congenital geant du cuir chevelu complique d’un melanome d’apparition precoce explore par les nouveaux outils diagnostiques disponibles. Observation Notre patiente presentait a la naissance une tumeur congenitale cervico-mandibulaire de 15 cm de grand axe avec extension para-pharyngee et osteolyse sous-jacente. L’histologie a 7 mois de vie, couplee a de l’immunohistochimie (IHC), concluait a un melanome developpe sur un naevus congenital, en raison de la presence de nombreuses atypies cytonucleaires, de mitoses, de foyers de necrose et d’une forte expression de P53 ainsi que d’un index de proliferation (Ki67) eleve. Le bilan d’extension etait negatif. Des chirurgies iteratives et une surveillance etaient realisees jusqu’a l’âge de 7 ans. A cette echeance, l’absence de metastases conduisait a realiser de nouvelles analyses sur les prelevements initiaux pour authentifier le diagnostic. L’etude de l’expression de certains facteurs de transcription par IHC recemment decrite, l’hybridation genomique comparative et la spectrometrie de masse guidee par l’histologie, bien que suspects, ne permettaient pas, a eux seuls, de conclure formellement a une lesion maligne. A 7 ans et demi, l’enfant developpait des metastases hepatiques et pulmonaires traitees par l’association ipilimumab + nivolumab. L’enfant decedait 5 mois plus tard. Conclusion Ce cas illustre la complexite du diagnostic de melanome chez le nourrisson et la possibilite d’une evolution metastatique tardive. Il rappelle la necessite d’un avis d’expert et parfois de combiner plusieurs outils pour affirmer le diagnostic et adapter la prise en charge.
Published: 2020
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24. Risk factors and a prognostic score for survival after autologous stem-cell transplantation for relapsed or refractory Hodgkin lymphoma

Author: M. Jürgens, Martin Hutchings, B. von Tresckow, Michael Fuchs, Peter Borchmann, Paul J Bröckelmann, S.J. McCall, Horst Müller, Craig H. Moskowitz, Andreas Engert, Franck Morschhauser, Olivier Casasnovas, University Hospital of Cologne [Cologne], Service d'Hématologie Clinique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Rigshospitalet [Copenhagen], Memorial Sloan Kettering Cancer Center ( MSKCC ), Service d'hématologie, Hôpital Claude Huriez-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Copenhagen University Hospital, Memorial Sloane Kettering Cancer Center [New York], Hôpital Claude Huriez [Lille], and CHU Lille-CHU Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)
Subjects: Adult, Male, Oncology, medicine.medical_specialty, medicine.medical_treatment, Salvage therapy, [SDV.CAN]Life Sciences [q-bio]/Cancer, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 03 medical and health sciences, 0302 clinical medicine, Autologous stem-cell transplantation, Recurrence, Internal medicine, Refractory Hodgkin Lymphoma, Humans, risk factors, score, Medicine, ASCT, Aged, Proportional Hazards Models, relapse, Chemotherapy, Framingham Risk Score, business.industry, Hazard ratio, Hematopoietic Stem Cell Transplantation, Hematology, Middle Aged, Hodgkin Disease, Survival Analysis, Chemotherapy regimen, 3. Good health, Surgery, Transplantation, 030220 oncology & carcinogenesis, Female, prognosis, business, Hodgkin lymphoma, 030215 immunology
Abstract: IF 11.855; International audience; Background:Novel agents are changing the treatment of relapsed or refractory Hodgkin lymphoma (HL). Nevertheless, high-dose chemotherapy and autologous stem-cell transplantation (ASCT) are considered standard of care in eligible patients. To identify patients who could benefit most from novel therapeutic approaches, we investigated a comprehensive set of risk factors (RFs) for survival after ASCT.Methods:In this multinational prognostic multivariable modeling study, 23 potential RFs were retrospectively evaluated in HL patients from nine prospective trials with multivariable Cox proportional hazards regression analyses (part I). The resulting prognostic score was then validated in an independent clinical sample (part II).Results:In part I, we identified 656 patients treated for relapsed/refractory HL between 1993 and 2013 with a median follow-up of 60 months after ASCT. The majority of potential RFs had significant impact on progression-free survival (PFS) with hazard ratios (HR) ranging from 1.39 to 2.22. The multivariable analysis identified stage IV disease, time to relapse ≤3 months, ECOG performance status ≥1, bulk ≥5 cm and inadequate response to salvage chemotherapy [
Published: 2017
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25. Molecular characterization of sarcomatoid clear cell renal cell carcinoma unveils new candidate oncogenic drivers

Author: Nizar M. Tannir, Yiyu Dong, Ronan Flippot, Xiaoping Su, Morgan Rouprêt, Jose A. Karam, Paul Russo, Eva Compérat, Gabriel G. Malouf, James J. Hsieh, Satish K. Tickoo, Ying-Bei Chen, Renzo G. DiNatale, Hui Yao, A. Ari Hakimi, Roger Mouawad, Jean Philippe Spano, Roy Mano, Kyle A. Blum, David Khayat, Thai H. Ho, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Strasbourg, Institut de Cancérologie de Strasbourg Europe (ICANS), Memorial Sloan Kettering Cancer Center (MSKCC), The University of Texas M.D. Anderson Cancer Center [Houston], CHU Tenon [AP-HP], Sorbonne Université (SU), Epidémiologie, Systèmes d'Information, Modélisation, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), MD Anderson Cancer Center [Houston], The University of Texas Health Science Center at Houston (UTHealth), Mayo Clinic [Scottsdale], Mayo Clinic, Mayo Clinic [Rochester], Washington University in Saint Louis (WUSTL), and univOAK, Archive ouverte
Subjects: Male, Cell, Gene regulatory network, lcsh:Medicine, Mice, 0302 clinical medicine, Gene Regulatory Networks, lcsh:Science, Cancer genetics, Cancer, Laser capture microdissection, YAP1, Neurofibromin 2, 0303 health sciences, Multidisciplinary, Kidney Neoplasms, Up-Regulation, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Signal Transduction, animal structures, [SDV.CAN]Life Sciences [q-bio]/Cancer, Laser Capture Microdissection, Protein Serine-Threonine Kinases, Biology, Article, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Carcinoma, Animals, Humans, Genetic Predisposition to Disease, Hippo Signaling Pathway, Carcinoma, Renal Cell, Adaptor Proteins, Signal Transducing, Cell Proliferation, 030304 developmental biology, Cell Nucleus, Hippo signaling pathway, Cell growth, lcsh:R, YAP-Signaling Proteins, Sequence Analysis, DNA, medicine.disease, Clear cell renal cell carcinoma, Transcriptional Coactivator with PDZ-Binding Motif Proteins, Mutation, Trans-Activators, Cancer research, lcsh:Q, Neoplasm Transplantation, Transcription Factors
Abstract: Sarcomatoid clear-cell renal cell carcinomas (sRCC) are associated with dismal prognosis. Genomic alterations associated with sarcomatoid dedifferentiation are poorly characterized. We sought to define the genomic landscape of sRCC and uncover potentially actionable therapeutic targets. We assessed the genomic landscape of sRCC using targeted panel sequencing including patients with microdissected sarcomatoid and epithelial components. Along with common genomic alterations associated with clear-cell histology, we found that Hippo was one of the most frequently altered pathways in these tumours. Hippo alterations were differentially enriched in sRCC compared to non-sRCC. Functional analysis showed that Hippo members mutations were associated with higher nuclear accumulation of YAP/TAZ, core effectors of the Hippo pathway. In a NF2-mutant sRCC model, YAP1 knockdown and NF2 reconstitution suppressed cell proliferation, tumour growth and invasion, both in vitro and in vivo. Overall, we show that Hippo pathway alterations are a feature of sRCC, and enable the exploration of the Hippo pathway as a novel potential therapeutic target.
Published: 2020
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26. Baseline cardiovascular risk assessment in cancer patients scheduled to receive cardiotoxic cancer therapies: a position statement and new risk assessment tools from the Cardio-Oncology Study Group of the Heart Failure Association of the European Society of Cardiology in collaboration with the International Cardio-Oncology Society

Author: Lyon, Alexander R., Dent, Susan, Stanway, Susanna, Earl, Helena, Brezden‐Masley, Christine, Cohen‐Solal, Alain, Tocchetti, Carlo G., Moslehi, Javid, Groarke, John D., Bergler‐Klein, Jutta, Khoo, Vincent, Tan, Li Ling, Anker, Markus S., Haehling, Stephan, Maack, Christoph, Pudil, Radek, Barac, Ana, Thavendirnathan, Paaladinesh, Ky, Bonnie, Neilan, Tomas G., Belenkov, Yury, Rosen, Stuart D., Iakobishvili, Zaza, Sverdlov, Aaron L., Hajjar, Ludhmila A., Macedo, Ariane V. S., Manisty, Charlotte, Ciardiello, Fortunato, Farmakis, Dimitrios, De Boer, Rudolf A., Skouri, Hadi, Suter, Thomas M., Cardinale, Daniela, Witteles, Ronald M., Fradley, Michael G., Herrmann, Joerg, Cornell, Robert F., Wechelaker, Ashutosh, Mauro, Michael J., Milojkovic, Dragana, Lavallade, Hugues, Ruschitzka, Frank, Coats, Andrew J. S., Seferovic, Petar M., Chioncel, Ovidiu, Thum, Thomas, Bauersachs, Johann, Andres, M. Sol, Wright, David J., López‐Fernández, Teresa, Plummer, Chris, Lenihan, Daniel, Imperial College London, Duke University [Durham], The Royal Marsden, University of Cambridge [UK] (CAM), Mount Sinai Hospital [Toronto, Canada] (MSH), Marqueurs cardiovasculaires en situation de stress (MASCOT (UMR_S_942 / U942)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of Naples Federico II = Università degli studi di Napoli Federico II, Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), Medizinische Universität Wien = Medical University of Vienna, Monash University [Melbourne], Shanghai Center for Plant Stress Biology [CAS] (PSC), Chinese Academy of Sciences [Beijing] (CAS), German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Georg-August-University = Georg-August-Universität Göttingen, Hannover Medical School [Hannover] (MHH), Charles University [Prague] (CU), Georgetown University [Washington] (GU), University Health Network, University of Toronto, University of Pennsylvania, Massachusetts General Hospital [Boston], Sechenov First Moscow State Medical University, University College of London [London] (UCL), Tel Aviv University (TAU), University of Newcastle [Australia] (UoN), Universidade de São Paulo = University of São Paulo (USP), Università degli studi della Campania 'Luigi Vanvitelli' = University of the Study of Campania Luigi Vanvitelli, University of Cyprus [Nicosia] (UCY), University Medical Center Groningen [Groningen] (UMCG), American University of Beirut Faculty of Medicine and Medical Center (AUB), University of Bern, IRCCS Ospedale San Raffaele [Milan, Italy], Stanford University, Mayo Clinic [Rochester], Memorial Sloan Kettering Cancer Center (MSKCC), Hammersmith Hospital NHS Imperial College Healthcare, King's College Hospital (KCH), University hospital of Zurich [Zurich], University of Warwick [Coventry], Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS San Raffaele Pisana), University of Belgrade [Belgrade], Emergency Institute for Cardiovascular Diseases 'Prof. Dr. C.C. Iliescu' [Bucharest, Romania], University of Medicine and Pharmacy 'Carol Davila' Bucharest (UMPCD), Royal Brompton Hospital, Liverpool Heart and Chest Hospital NHS Trust [UK] (LH&CH), La Paz University Hospital, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), leboeuf, Christophe, Lyon, Alexander R, Dent, Susan, Stanway, Susanna, Earl, Helena, Brezden-Masley, Christine, Cohen-Solal, Alain, Tocchetti, Carlo G, Moslehi, Javid, Groarke, John D, Bergler-Klein, Jutta, Khoo, Vincent, Tan, Li Ling, Anker, Markus S, von Haehling, Stephan, Maack, Christoph, Pudil, Radek, Barac, Ana, Thavendirnathan, Paaladinesh, Ky, Bonnie, Neilan, Tomas G, Belenkov, Yury, Rosen, Stuart D, Iakobishvili, Zaza, Sverdlov, Aaron L, Hajjar, Ludhmila A, Macedo, Ariane V S, Manisty, Charlotte, Ciardiello, Fortunato, Farmakis, Dimitrio, De Boer, Rudolf A, Skouri, Hadi, Suter, Thomas M, Cardinale, Daniela, Witteles, Ronald M, Fradley, Michael G, Herrmann, Joerg, Cornell, Robert F, Wechelaker, Ashutosh, Mauro, Michael J, Milojkovic, Dragana, de Lavallade, Hugue, Ruschitzka, Frank, Coats, Andrew J S, Seferovic, Petar M, Chioncel, Ovidiu, Thum, Thoma, Bauersachs, Johann, Andres, M Sol, Wright, David J, López-Fernández, Teresa, Plummer, Chri, Lenihan, Daniel, Lyon, Alexander R., Brezden‐masley, Christine, Cohen‐solal, Alain, Tocchetti, Carlo G., Groarke, John D., Bergler‐klein, Jutta, Anker, Markus S., Haehling, Stephan, Neilan, Tomas G., Rosen, Stuart D., Sverdlov, Aaron L., Hajjar, Ludhmila A., Macedo, Ariane V. S., De Boer, Rudolf A., Suter, Thomas M., Witteles, Ronald M., Fradley, Michael G., Cornell, Robert F., Mauro, Michael J., Lavallade, Hugue, Coats, Andrew J. S., Seferovic, Petar M., Andres, M. Sol, Wright, David J., and López‐fernández, Teresa
Subjects: Male, Heart failure, Androgen Antagonists, Antineoplastic Agents, Middle Aged, Risk Assessment, Cardiotoxicity, Risk prediction, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Cardio-oncology, risk factor, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Cardiovascular Diseases, Heart Disease Risk Factors, Risk Factors, Neoplasms, Humans, Female, Aged
Abstract: This position statement from the Heart Failure Association of the European Society of Cardiology Cardio-Oncology Study Group in collaboration with the International Cardio-Oncology Society presents practical, easy-to-use and evidence-based risk stratification tools for oncologists, haemato-oncologists and cardiologists to use in their clinical practice to risk stratify oncology patients prior to receiving cancer therapies known to cause heart failure or other serious cardiovascular toxicities. Baseline risk stratification proformas are presented for oncology patients prior to receiving the following cancer therapies: anthracycline chemotherapy, HER2-targeted therapies such as trastuzumab, vascular endothelial growth factor inhibitors, second and third generation multi-targeted kinase inhibitors for CML targeting BCR-ABL, multiple myeloma therapies (proteasome inhibitors and immunomodulatory drugs), RAF and MEK inhibitors or androgen deprivation therapies. Applying these risk stratification proformas will allow clinicians to stratify cancer patients into low, medium, high and very high risk of cardiovascular complications prior to starting treatment, with the aim of improving personalised approaches to minimise the risk of cardiovascular toxicity from cancer therapies. This article is protected by copyright. All rights reserved.
Published: 2020
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27. Prediction of Breast Cancer Treatment-Induced Fatigue by Machine Learning Using Genome-Wide Association Data

Author: Paul Cottu, Anne-Laure Martin, Anne Boland, Cécile Charles, Jung Hun Oh, Marina Rousseau, Ines Vaz-Luis, Gwenn Menvielle, Joseph O. Deasy, Stefan Michiels, Céline Besse, Emilie Thomas, Jean-François Deleuze, Olivier Tredan, Patricia A. Ganz, Sandrine Boyault, Sibille Everhard, Fabrice Andre, Antonio Di Meglio, Ann H. Partridge, Agnès Dumas, Christelle Levy, Sangkyu Lee, Memorial Sloan Kettering Cancer Center (MSKCC), Institut Gustave Roussy (IGR), Prédicteurs moléculaires et nouvelles cibles en oncologie (PMNCO), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre Léon Bérard [Lyon], Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Fondation Synergie Lyon Cancer [Lyon], Institut Curie [Paris], Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), UNICANCER, University of California [Los Angeles] (UCLA), University of California (UC), Dana-Farber Cancer Institute [Boston], Centre d'Etude du Polymorphisme Humain (CEPH), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset-Université Paris Cité (UPCité), Synergie Lyon Cancer [Lyon], and Gestionnaire, Hal Sorbonne Université
Subjects: Cancer Research, [SDV]Life Sciences [q-bio], Single-nucleotide polymorphism, Genome-wide association study, Machine learning, computer.software_genre, Article, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, medicine, Clinical endpoint, 030304 developmental biology, 0303 health sciences, Surrogate endpoint, business.industry, Cancer, medicine.disease, [SDV] Life Sciences [q-bio], Oncology, Quartile, 030220 oncology & carcinogenesis, Anxiety, Artificial intelligence, medicine.symptom, business, computer
Abstract: Background We aimed at predicting fatigue after breast cancer treatment using machine learning on clinical covariates and germline genome-wide data. Methods We accessed germline genome-wide data of 2799 early-stage breast cancer patients from the Cancer Toxicity study (NCT01993498). The primary endpoint was defined as scoring zero at diagnosis and higher than quartile 3 at 1 year after primary treatment completion on European Organization for Research and Treatment of Cancer quality-of-life questionnaires for Overall Fatigue and on the multidimensional questionnaire for Physical, Emotional, and Cognitive fatigue. First, we tested univariate associations of each endpoint with clinical variables and genome-wide variants. Then, using preselected clinical (false discovery rate < 0.05) and genomic (P Results Statistically significant clinical associations were found only with Emotional and Cognitive Fatigue, including receipt of chemotherapy, anxiety, and pain. Some single nucleotide polymorphisms had some degree of association (P Conclusions Genomic analyses in this large cohort of breast cancer survivors suggest a possible genetic role for severe Cognitive Fatigue that warrants further exploration.
Published: 2019
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28. The C-terminal Domain of piggyBac Transposase Is Not Required for DNA Transposition

Author: Yan Jaszczyszyn, Yves Bigot, Peter Arensburger, Linda Beauclair, Nicolas Buisine, Thierry Lecomte, Florian Guillou, Laura Helou, Hugues Dardente, Alex Kentsis, Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), California State Polytechnic University [Pomona] (CAL POLY POMONA), Physiologie moléculaire et adaptation (PhyMA), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Groupe innovation et ciblage cellulaire (GICC), EA 7501 [2018-...] (GICC EA 7501), Université de Tours (UT), Memorial Sloan Kettering Cancer Center (MSKCC), Cornell University [New York], Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)
Subjects: Gene isoform, Transposable element, transposon, Transposases, Nerve Tissue Proteins, Biology, Article, Chromosomes, Insert (molecular biology), Transposition (music), Mice, 03 medical and health sciences, 0302 clinical medicine, Protein Domains, Structural Biology, vertebrate, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology, Peptide sequence, Gene, ComputingMilieux_MISCELLANEOUS, Transposase, 030304 developmental biology, Recombination, Genetic, Genetics, DNA cleavage, 0303 health sciences, insertion preference, neuron, Transposase activity, DNA Transposable Elements, 030217 neurology & neurosurgery, HeLa Cells
Abstract: International audience; PiggyBac(PB)-like elements (pble) are members of a eukaryotic DNA transposon family. This family is of interest to evolutionary genomics because pble transposases have been domesticated at least 9 times in vertebrates. The amino acid sequence of pble transposases can be split into three regions: an acidic N-terminal domain (similar to 100 aa), a central domain (similar to 400 aa) containing a DD[D/E] catalytic triad, and a cysteine-rich domain (CRD; similar to 90 aa). Two recent reports suggested that a functional CRD is required for pble transposase activity. Here we found that two CRD-deficient pble transposases, a PB variant and an isoform encoded by the domesticated PB-derived vertebrate transposase gene 5 (pgbd5) trigger transposition of the Ifp2 pble. When overexpressed in HeLa cells, these CRD-deficient transposases can insert Ifp2 elements with proper and improper transposon ends, associated with deleterious effects on cells. Finally, we found that mouse CRD-deficient transposase Pgbd5, as well as PB, do not insert pbles at random into chromosomes. Transposition events occurred more often in genic regions, in the neighbourhood of the transcription start sites and were often found in genes predominantly expressed in the human central nervous system.
Published: 2021
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29. Loss of Small-RNA-Directed DNA Methylation in the Plant Cell Cycle Promotes Germline Reprogramming and Somaclonal Variation

Author: Mark T.A. Donoghue, Linda Hanley-Bowdoin, Ashley M. Brooks, Chantal LeBlanc, Milos Tanurdžić, Emily E. Wear, Filipe Borges, William F. Thompson, Benjamin Berube, Robert A. Martienssen, Cold Spring Harbor Laboratory (CSHL), Institut Jean-Pierre Bourgin (IJPB), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Memorial Sloan Kettering Cancer Center (MSKCC), North Carolina State University [Raleigh] (NC State), University of North Carolina System (UNC), Yale University [New Haven], University of Queensland [Brisbane], National Institute of Environmental Health Sciences [Durham] (NIEHS-NIH), National Institutes of Health [Bethesda] (NIH), Plant Genome Research Program of the National Science Foundation grant IOS-1025830, and Cold Spring Harbor Laboratory Cancer Center (support grant 5PP30CA045508)
Subjects: 0301 basic medicine, DNA, Plant, Arabidopsis, General Biochemistry, Genetics and Molecular Biology, Histones, Cytosine, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Gene Expression Regulation, Plant, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Epigenetics, RNA, Small Interfering, biology, Cell Cycle, DNA replication, Methylation, DNA Methylation, Plants, Cell cycle, Cell biology, Germ Cells, 030104 developmental biology, Histone, chemistry, DNA methylation, biology.protein, General Agricultural and Biological Sciences, Reprogramming, 030217 neurology & neurosurgery, DNA
Abstract: International audience; 5-methyl cytosine is widespread in plant genomes in both CG and non-CG contexts. During replication, hemi-methylation on parental DNA strands guides symmetric CG methylation on nascent strands, but non-CG methylation requires modified histones and small RNA guides. Here, we used immortalized Arabidopsis cell suspensions to sort replicating nuclei and determine genome-wide cytosine methylation dynamics during the plant cell cycle. We find that symmetric mCG and mCHG are selectively retained in actively dividing cells in culture, whereas mCHH is depleted. mCG becomes transiently asymmetric during S phase but is rapidly restored in G2, whereas mCHG remains asymmetric throughout the cell cycle. Hundreds of loci gain ectopic CHG methylation, as well as 24-nt small interfering RNAs (siRNAs) and histone H3 lysine dimethylation (H3K9me2), without gaining CHH methylation. This suggests that spontaneous epialleles that arise in plant cell cultures are stably maintained by siRNA and H3K9me2 independent of the canonical RNA-directed DNA methylation (RdDM) pathway. In contrast, loci that fail to produce siRNA may be targeted for demethylation when the cell cycle arrests. Comparative analysis with methylomes of various tissues and cell types suggests that loss of small-RNA-directed non-CG methylation during DNA replication promotes germline reprogramming and epigenetic variation in plants propagated as clones.
Published: 2021
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30. Reproducible Summary Tables with the gtsummary Package

Author: Michael Curry, Daniel D. Sjoberg, Karissa Whiting, Jessica A. Lavery, Joseph Larmarange, Larmarange, Joseph, Memorial Sloan Kettering Cancer Center (MSKCC), Centre population et développement (CEPED - UMR_D 196), and Institut de Recherche pour le Développement (IRD)-Université Paris Cité (UPCité)
Subjects: [STAT]Statistics [stat], Statistics and Probability, Numerical Analysis, business.industry, Medicine, [INFO]Computer Science [cs], [INFO] Computer Science [cs], Statistics, Probability and Uncertainty, business, [STAT] Statistics [stat]
Abstract: International audience; The gtsummary package provides an elegant and flexible way to create publication-ready summary tables in R. A critical part of the work of statisticians, data scientists, and analysts is summarizing data sets and regression models in R and publishing or sharing polished summary tables. The gtsummary package was created to streamline these everyday analysis tasks by allowing users to easily create reproducible summaries of data sets, regression models, survey data, and survival data with a simple interface and very little code. The package follows a tidy framework, making it easy to integrate with standard data workflows, and offers many table customization features through function arguments, helper functions, and custom themes.
Published: 2021
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31. Minimum Information about a Biosynthetic Gene cluster

Author: Patrick Caffrey, Renzo Kottmann, Eriko Takano, Sean Doyle, Axel A. Brakhage, Matthew Cummings, Juan Pablo Gomez-Escribano, Yvonne Mast, Ryan F. Seipke, Rob Lavigne, Markus Nett, Hans-Wilhelm Nützmann, Jan Claesen, David H. Sherman, Daniel Petras, Pablo Cruz-Morales, Carl J. Balibar, Anne Osbourn, Oscar P. Kuipers, Leonilde M. Moreira, Xinyu Liu, Marcia S. Osburne, Bohdan Ostash, David P. Fewer, Changsheng Zhang, Pelin Yilmaz, Mohamed S. Donia, Anja Greule, Hyun Uk Kim, Nicholas J. Tobias, Frank Oliver Glöckner, Christoph Geiger, Chia Y. Lee, William H. Gerwick, Philipp Wiemann, Bertolt Gust, Susan E. Jensen, Wilfred A. van der Donk, Jan Kormanec, Ben Shen, Christopher M. Thomas, Jason Micklefield, Srikanth Duddela, R. Cameron Coates, René De Mot, Anthony S. Haines, Neha Garg, Guohui Pan, Roderich D. Süssmuth, Hyung Jin Kwon, Jonathan D. Walton, Lena Gerwick, Jörn Piel, Monika Ehling-Schulz, Zhenhua Tian, Jonathan L. Klassen, Xiaohui Yan, Emily A. Monroe, Yunchang Xie, Russell J. Cox, Keishi Ishida, Grace Yim, Stefano Donadio, Nadine Ziemert, Yuta Tsunematsu, Matthew L. Hillwig, Miroslav Petricek, Sylvie Lautru, Tilmann Weber, Andrew W. Truman, Rainer Breitling, Peter Kötter, Nikos C. Kyrpides, Stephanie Düsterhus, Christian Hertweck, Hideaki Oikawa, Sean F. Brady, Christopher T. Walsh, Adam C. Jones, Marcus A. Moore, Bradley S. Moore, Barrie Wilkinson, Simone M. Mantovani, Nathan A. Moss, Elizabeth E. Wyckoff, Emily P. Balskus, Kapil Tahlan, Fengan Yu, Monica Höfte, Jos M. Raaijmakers, Taifo Mahmud, Yit-Heng Chooi, Yi Tang, Andreas Bechthold, Douglas A. Mitchell, Joanne M. Willey, Helge B. Bode, John B. Biggins, Margherita Sosio, Yi-Qiang Cheng, Carmen Méndez, Leonard Kaysser, Joleen Masschelein, Daniel Krug, Federico Rosconi, Marnix H. Medema, Kaarina Sivonen, Tomohisa Kuzuyama, Mikko Metsä-Ketelä, Esther K. Schmitt, Carsten Kegler, Andriy Luzhetskyy, Gilles P. van Wezel, Bai Linquan, Kai Blin, Jens Nielsen, Bertrand Aigle, Amrita Pati, Harald Gross, Muriel Viaud, Pieter C. Dorrestein, Carla S. Jones, Michael A. Fischbach, Shelley M. Payne, Zhe Rui, Gerard D. Wright, Wen Liu, Alexey V. Melnik, Barry Scott, Brett A. Neilan, Nancy P. Keller, Rainer Borriss, Katrin Jungmann, Michalis Hadjithomas, Evi Stegmann, Daniel J. Edwards, F. Jerry Reen, Alexander Kristian Apel, Wolfgang Wohlleben, Michael J. Smanski, Leonard Katz, Fergal O'Gara, Eric J. N. Helfrich, Sergey B. Zotchev, Olivier Ploux, Arnold J. M. Driessen, Rolf Müller, Jean-Luc Pernodet, K. D. Entian, José A. Salas, Irene de Bruijn, Francisco Barona-Gómez, Jianhua Ju, Jon Clardy, Molecular Microbiology, Molecular Genetics, Jacobs University [Bremen], Microbial genomics and bioinformatics research group, Max Planck Institute for Marine Microbiology, Max-Planck-Gesellschaft-Max-Planck-Gesellschaft, Max-Planck-Gesellschaft, Atmospheric Chemistry Observations and Modeling Laboratory (ACOML), National Center for Atmospheric Research [Boulder] (NCAR), Department of Food and Environmental Sciences, Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Collaborative Mass Spectrometry Innovation Center, University of California [San Diego] (UC San Diego), University of California (UC)-University of California (UC), Heilongjiang Institute of Science and Technology, Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Merck Stiftungsprofessur fûr Molekulare Biotechnologie Fachbereich Biowissenscharten, Goethe-University Frankfurt am Main, Department of Opto-Mechatronics Engineering and Cogno-Mechatronics Engineering, Pusan National University, University of Liverpool, College of Computer Science and Technology [Zhejiang] (Zhejiang University), University of Florida [Gainesville] (UF), School of Management, University of Science and Technology of China [Hefei] (USTC), State Key Laboratory of Nuclear Physics and Technology (SKL-NPT), Peking University [Beijing], Massachusetts Institute of Technology (MIT), Memorial Sloane Kettering Cancer Center [New York], South China Sea Institute of Oceanology, Chinese Academy of Sciences [Beijing] (CAS), Dynamique des Génomes et Adaptation Microbienne (DynAMic), Institut National de la Recherche Agronomique (INRA)-Université de Lorraine (UL), Institut für Biologie [Berlin] (IFB), Humboldt University Of Berlin, School of Biomolecular and Biomedical Science and Centre for Synthesis and Chemical Biology, University College Dublin [Dublin] (UCD), Parallélisme, Réseaux, Systèmes, Modélisation (PRISM), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Centre National de la Recherche Scientifique (CNRS), Skaggs School of Pharmacy and Pharmaceutical Sciences [San Diego], Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pixyl Medical [Grenoble], Integrated Optical MicroSystems (IOMS), University of Twente-MESA+ Institute for Nanotechnology, 7Lehrstuhl für Mikrobielle Ökologie, Department für Grundlagen der Biowissenschaften, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Service Néphrologie Pédiatrique, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Advanced Resources and Risk Technology, Laboratory of Phytopathology (K.C., H.S., B.A., M.H.), Universiteit Gent = Ghent University (UGENT), Trifork Aarhus C, Aalborg University [Denmark] (AAU), Centers for Disease Control and Prevention [Atlanta] (CDC), Centers for Disease Control and Prevention, Groupe d'Etude de la Matière Condensée (GEMAC), Groningen Biomolecular Sciences and Biotechnology Institute (GBB), University of Groningen [Groningen], DOE Joint Genome Institute [Walnut Creek], Microbiologie Moléculaire des Actinomycètes (ACTINO), Département Microbiologie (Dpt Microbio), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut de génétique et microbiologie [Orsay] (IGM), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Laboratory of Gene Technology, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Joint Center for Structural Genomics (JCSG), Stanford University, Centre européen de recherche et d'enseignement des géosciences de l'environnement (CEREGE), Institut de Recherche pour le Développement (IRD)-Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherches et d'Applications Pédagogiques en Langues (CRAPEL), Université Nancy 2, Space Sciences Laboratory [Berkeley] (SSL), University of California [Berkeley] (UC Berkeley), Polytechnic Institute of Leiria, NMR Laboratory, Université de Mons, Université de Mons (UMons), School of Biomedical Science, Curtin University [Perth], Planning and Transport Research Centre (PATREC)-Planning and Transport Research Centre (PATREC), BIOMERIT Research Centre, School of Microbiology, University College Cork (UCC), Department of Engineering Science, University of Oxford, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Laboratoire Charles Friedel, Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Laboratory of Phytopathology, Wageningen University and Research [Wageningen] (WUR), Department of Microbial Ecology, Netherlands Institute of Ecology, Department of Animal Production, Universidad de Córdoba = University of Córdoba [Córdoba], IMV Technologies, Gulliver (UMR 7083), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Institut für Chemie, Technical University of Berlin / Technische Universität Berlin (TU), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Centre de Recherche Paul Pascal (CRPP), Université de Bordeaux (UB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), DEPARTMENT OF CHEMISTRY, Durham University, Molekulare Ökologie, Joint Attosecond Science Laboratory, University of Ottawa and National Research Council, Department of Mechanical and Aerospace Engineering [Univ California Davis] (MAE - UC Davis), University of California [Davis] (UC Davis), University of Helsinki, University of California-University of California, Université de Lorraine (UL)-Institut National de la Recherche Agronomique (INRA), Humboldt-Universität zu Berlin, University of Twente [Netherlands]-MESA+ Institute for Nanotechnology, Technische Universität München [München] (TUM), Universiteit Gent = Ghent University [Belgium] (UGENT), Department of Biosystems, KU Leuven, Aix Marseille Université (AMU)-Institut national des sciences de l'Univers (INSU - CNRS)-Collège de France (CdF (institution))-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), University of California [Berkeley], NMR and Molecular Imaging Laboratory [Mons], University of Mons [Belgium] (UMONS), University of Oxford [Oxford], Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC), Universidad de Córdoba [Cordoba], Technische Universität Berlin (TU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Department of Mechanical and Aerospace Engineering [Davis], Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology in Zürich [Zürich] (ETH Zürich), University of Florida [Gainesville], Institut für Biologie, Humboldt Universität zu Berlin, Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Ghent University [Belgium] (UGENT), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Institut de Biologie Intégrative de la Cellule (I2BC), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay, Stanford University [Stanford], Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Collège de France (CdF)-Institut national des sciences de l'Univers (INSU - CNRS)-Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA), NMR and Molecular Imaging Laboratory, Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay, Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS), Wageningen University and Research Centre [Wageningen] (WUR), Gulliver, ESPCI ParisTech-Centre National de la Recherche Scientifique (CNRS), Technische Universität Berlin (TUB), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Max Planck Society (GERMANY), Max Planck Society (GERMANY)-Max Planck Society (GERMANY), Laboratoire Leprince-Ringuet ( LLR ), Institut National de Physique Nucléaire et de Physique des Particules du CNRS ( IN2P3 ) -École polytechnique ( X ) -Centre National de la Recherche Scientifique ( CNRS ), Atmospheric Chemistry Observations and Modeling Laboratory ( ACOML ), National Center for Atmospheric Research [Boulder] ( NCAR ), University of California [San Diego] ( UC San Diego ), Eidgenössische Technische Hochschule [Zürich] ( ETH Zürich ), University of Science and Technology of China [Hefei] ( USTC ), State Key Laboratory of Nuclear Physics and Technology ( SKL-NPT ), Massachusetts Institute of Technology ( MIT ), Memorial Sloan Kettering Cancer Center ( MSKCC ), Shanghai Ocean University, Dynamique des Génomes et Adaptation Microbienne ( DynAMic ), Institut National de la Recherche Agronomique ( INRA ) -Université de Lorraine ( UL ), University College Dublin [Dublin] ( UCD ), Parallélisme, Réseaux, Systèmes, Modélisation ( PRISM ), Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Centre National de la Recherche Scientifique ( CNRS ), Grenoble Institut des Neurosciences ( GIN ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Grenoble-Université Joseph Fourier - Grenoble 1 ( UJF ), Integrated Optical MicroSystems ( IOMS ), Technische Universität München [München] ( TUM ), Ghent University [Belgium] ( UGENT ), Aalborg University [Denmark] ( AAU ), Centers for Disease Control and Prevention [Atlanta] ( CDC ), Groupe d'Etude de la Matière Condensée ( GEMAC ), Groningen Biomolecular Sciences and Biotechnology Institute ( GBB ), Microbiologie Moléculaire des Actinomycètes ( ACTINO ), Département Microbiologie ( Dpt Microbio ), Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ), Institut de génétique et microbiologie [Orsay] ( IGM ), Université Paris-Sud - Paris 11 ( UP11 ) -Centre National de la Recherche Scientifique ( CNRS ), Joint Center for Structural Genomics ( JCSG ), Centre européen de recherche et d'enseignement de géosciences de l'environnement ( CEREGE ), Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Aix Marseille Université ( AMU ) -Collège de France ( CdF ) -Institut National de la Recherche Agronomique ( INRA ) -Institut national des sciences de l'Univers ( INSU - CNRS ), Centre de Recherches et d'Applications Pédagogiques en Langues ( CRAPEL ), Space Sciences Laboratory [Berkeley] ( SSL ), Université de Mons ( UMons ), Planning and Transport Research Centre ( PATREC ) -Planning and Transport Research Centre ( PATREC ), University College Cork ( UCC ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ), Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ), Wageningen University and Research Centre [Wageningen] ( WUR ), ESPCI ParisTech, Technische Universität Berlin ( TUB ), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Centre de recherche Paul Pascal, CNRS, Université de Bordeaux ( UPR8641 ), Centre de Recherche Paul Pascal, CNRS, Université de Bordeaux, University Durham, University of California [Davis] ( UC Davis ), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), [GIN] Grenoble Institut des Neurosciences (GIN), Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), and Saarland University, Building A4.1, 66123 Saarbruecken, Germany.
Subjects: MESH : Protein Biosynthesis, protein synthesis, Operon, MESH : Polysaccharides, International Cooperation, MESH: Plants, plant, Review, MESH: Terpenes, gene cluster, polyketide, data base, genetic database, Gene cluster, acyltransferase, Databases, Genetic, MESH : Metagenome, MESH : Genetic Markers, genetics, terpene, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), ComputingMilieux_MISCELLANEOUS, MESH : Peptides, MESH: Peptides, biology, fungus, nonribosomal peptide synthesis, Plants, bacterium, peptide, priority journal, MESH: Protein Biosynthesis, Multigene Family, MESH : Terpenes, MESH: Computational Biology, Genetic Markers, MESH: Terminology as Topic, Bioinformatics, MESH : Multigene Family, biological activity, Article, metagenome, Alkaloids, Manchester Institute of Biotechnology, Terminology as Topic, Bioinformatica, MESH : Bacteria, Peptide Biosynthesis, MESH : Databases, Genetic, Molecular Biology, MESH : Fungi, MESH: Polyketides, standardization, secondary metabolism, [ SDV ] Life Sciences [q-bio], Bacteria, ta1182, Computational Biology, MESH : Terminology as Topic, operon, Laboratorium voor Phytopathologie, MESH: International Cooperation, gene function, Metagenomics, polysaccharide, Laboratory of Phytopathology, chemical structure, Metagenome, MESH: Multigene Family, EPS, biosynthesis, Peptides, MESH : Computational Biology, MESH : International Cooperation, [SDV]Life Sciences [q-bio], MESH: Genetic Markers, information, MESH : Alkaloids, Synthetic biology, MESH: Peptide Biosynthesis, Nucleic Acid-Independent, database, MESH: Databases, Genetic, Genetics, MESH : Polyketides, MESH : Peptide Biosynthesis, Nucleic Acid-Independent, ddc:540, standards, Peptide Biosynthesis, Nucleic Acid-Independent, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, nomenclature, genetic marker, alkaloid derivative, MESH: Fungi, Biology, MESH : Plants, peptide derivative, Polyketide, MESH: Alkaloids, Polysaccharides, ddc:570, Life Science, 14. Life underwater, Secondary metabolism, enzyme specificity, Gene, nonhuman, Terpenes, Fungi, nucleotide sequence, Cell Biology, MESH: Metagenome, ResearchInstitutes_Networks_Beacons/manchester_institute_of_biotechnology, alkaloid, MESH: Bacteria, MESH: Polysaccharides, 13. Climate action, Polyketides, Protein Biosynthesis, synthetic biology, metabolism
Abstract: M.H.M. was supported by a Rubicon fellowship of the Netherlands Organization for Scientific Research (NWO;Rubicon 825.13.001). The work of R.K. was supported by the European Union’s Seventh Framework Programme(Joint Call OCEAN.2011–2: Marine microbial diversity—new insights into marine ecosystems functioning and its biotechnological potential) under the grant agreement no.287589 (Micro B3). M.C. was supported by a Biotechnology and Biological Sciences Research Council (BBSRC)studentship (BB/J014478/1). The GSC is supported by funding from the Natural Environment Research Council(UK), the National Institute for Energy Ethics and Society(NIEeS; UK), the Gordon and Betty Moore Foundation,the National Science Foundation (NSF; US) and the US Department of Energy. The Manchester Synthetic Biology Research Centre, SYNBIOCHEM, is supported by BBSRC/Engineering and Physical Sciences Research Council(EPSRC) grant BB/M017702/1, Medema, M.H., Kottmann, R., Yilmaz, P., Cummings, M., Biggins, J.B., Blin, K., De Bruijn, I., Chooi, Y.H., Claesen, J., Coates, R.C., Cruz-Morales, P., Duddela, S., Düsterhus, S., Edwards, D.J., Fewer, D.P., Garg, N., Geiger, C., Gomez-Escribano, J.P., Greule, A., Hadjithomas, M., Haines, A.S., Helfrich, E.J.N., Hillwig, M.L., Ishida, K., Jones, A.C., Jones, C.S., Jungmann, K., Kegler, C., Kim, H.U., Kötter, P., Krug, D., Masschelein, J., Melnik, A.V., Mantovani, S.M., Monroe, E.A., Moore, M., Moss, N., Nützmann, H.-W., Pan, G., Pati, A., Petras, D., Reen, F.J., Rosconi, F., Rui, Z., Tian, Z., Tobias, N.J., Tsunematsu, Y., Wiemann, P., Wyckoff, E., Yan, X., Yim, G., Yu, F., Xie, Y., Aigle, B., Apel, A.K., Balibar, C.J., Balskus, E.P., Barona-Gómez, F., Bechthold, A., Bode, H.B., Borriss, R., Brady, S.F., Brakhage, A.A., Caffrey, P., Cheng, Y.Q., Clardy, J., Cox, R.J., De Mot, R., Donadio, S., Donia, M.S., Van Der Donk, W.A., Dorrestein, P.C., Doyle, S., Driessen, A.J.M., Ehling-Schulz, M., Entian, K.-D., Fischbach, M.A., Gerwick, L., Gerwick, W.H., Gross, H., Gust, B., Hertweck, C., Höfte, M., Jensen, S.E., Ju, J., Katz, L., Kaysser, L., Klassen, J.L., Keller, N.P., Kormanec, J., Kuipers, O.P., Kuzuyama, T., Kyrpides, N.C., Kwon, H.-J., Lautru, S., Lavigne, R., Lee, C.Y., Linquan, B., Liu, X., Liu, W., Luzhetskyy, A., Mahmud, T., Mast, Y., Méndez, C., Metsä-Ketelä, M., Micklefield, J., Mitchell, D.A., Moore, B.S., Moreira, L.M., Müller, R., Neilan, B.A., Nett, M., Nielsen, J., O'Gara, F., Oikawa, H., Osbourn, A., Osburne, M.S., Ostash, B., Payne, S.M., Pernodet, J.-L., Petricek, M., Piel, J., Ploux, O., Raaijmakers, J.M., Salas, J.A., Schmitt, E.K., Scott, B., Seipke, R.F., Shen, B., Sherman, D.H., Sivonen, K., Smanski, M.J., Sosio, M., Stegmann, E., Süssmuth, R.D., Tahlan, K., Thomas, C.M., Tang, Y., Truman, A.W., Viaud, M., Walton, J.D., Walsh, C.T., Weber, T., Van Wezel, G.P., Wilkinson, B., Willey, J.M., Wohlleben, W., Wright, G.D., Ziemert, N., Zhang, C., Zotchev, S.B., Breitling, R., Takano, E., Glöckner, F.O.
Published: 2015
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32. TIRR regulates 53BP1 by masking its histone methyl-lysine binding function

Author: William T. Yewdell, Khyati Meghani, Pascal Drané, Yizhou He, Shweta Chaubey, Alexandre Detappe, Evi Soutoglou, Nishita Parnandi, Xiaofeng Zheng, Marie Eve Brault, Maria Victoria Botuyan, Christian Münch, Jayanta Chaudhuri, Alkmini Kalousi, Gaofeng Cui, Georges Mer, J. Wade Harper, Dipanjan Chowdhury, Dana-Farber Cancer Institute [Boston], Mayo Clinic [Rochester], Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Memorial Sloan Kettering Cancer Center (MSKCC), Harvard Medical School [Boston] (HMS), Weill Cornell Medicine [New York], Broad Institute of MIT and Harvard (BROAD INSTITUTE), and Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]
Subjects: 0301 basic medicine, Multidisciplinary, Tudor domain, biology, DNA repair, Chemistry, Protein domain, Plasma protein binding, Bioinformatics, Cell biology, Histone H4, 03 medical and health sciences, 030104 developmental biology, Histone, biology.protein, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Binding site, Protein kinase A
Abstract: P53-binding protein 1 (53BP1) is a multi-functional double-strand break repair protein that is essential for class switch recombination in B lymphocytes and for sensitizing BRCA1-deficient tumours to poly-ADP-ribose polymerase-1 (PARP) inhibitors. Central to all 53BP1 activities is its recruitment to double-strand breaks via the interaction of the tandem Tudor domain with dimethylated lysine 20 of histone H4 (H4K20me2). Here we identify an uncharacterized protein, Tudor interacting repair regulator (TIRR), that directly binds the tandem Tudor domain and masks its H4K20me2 binding motif. Upon DNA damage, the protein kinase ataxia-telangiectasia mutated (ATM) phosphorylates 53BP1 and recruits RAP1-interacting factor 1 (RIF1) to dissociate the 53BP1-TIRR complex. However, overexpression of TIRR impedes 53BP1 function by blocking its localization to double-strand breaks. Depletion of TIRR destabilizes 53BP1 in the nuclear-soluble fraction and alters the double-strand break-induced protein complex centring 53BP1. These findings identify TIRR as a new factor that influences double-strand break repair using a unique mechanism of masking the histone methyl-lysine binding function of 53BP1.
Published: 2017
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33. The multidisciplinary management of gastro-oesophageal junction tumours: European Society of Digestive Oncology (ESDO): Expert discussion and report from the 16th ESMO World Congress on Gastrointestinal Cancer, Barcelona

Author: Van Laethem, J.-L., Carneiro, F., Ducreux, M., Messman, H., Lordick, F., Ilson, D.H., Allum, W., Haustermans, K, Lepage, C., Matysiak-Budnik, T., Cats, A, Schmiegel, W, Cervantes, A, Van Cutsem, E, Rougier, Ph, Seufferlein, Th, Service de Gastro-Entérologie, d'Hépato-Pancréatologie et d'Oncologie Digestive - Endoscopie Digestive (hôpital Erasme), Université Libre de Bruxelles [Bruxelles] (ULB)-Hôpital Erasme (Bruxelles), Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) and Medical Fa, Oncologie digestive, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Institut Gustave Roussy (IGR), Department of Internal Medicine (Klinikum Augsburg), Klinikum Augsburg, Universität Leipzig [Leipzig], Memorial Sloane Kettering Cancer Center [New York], Royal Marsden Hospital NHS Foundation Trust, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), University Hospitals Leuven [Leuven], Service d'hépato-gastroentérologie et cancérologie digestive (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Service d'hépato-gastro-entérologie, cancérologie digestive et assistance nutritionnelle [CHU de Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Netherlands Cancer Institute (NKI), Antoni van Leeuwenhoek Hospital, Medizinische Universitätsklinik, Ruhr-Universität Bochum [Bochum], Abtlg. Gastroenterologie und Hepatologie, INCLIVA, Universitat de València (UV), Université Paris Descartes - Paris 5 (UPD5), Universität Ulm - Ulm University [Ulm, Allemagne], Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Université Libre de Bruxelles [Bruxelles] ( ULB ) -Hôpital Erasme (Bruxelles), Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Institut Gustave Roussy ( IGR ), Memorial Sloan Kettering Cancer Center ( MSKCC ), Katholieke Universiteit Leuven ( KU Leuven ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Centre hospitalier universitaire de Nantes ( CHU Nantes ), Netherlands Cancer Institute ( NKI ), Universitat de València ( UV ), Université Paris Descartes - Paris 5 ( UPD5 ), Ulm University, Université libre de Bruxelles (ULB)-Hôpital Erasme [Bruxelles] (ULB), and Université libre de Bruxelles (ULB)
Subjects: Esophageal Neoplasms, Esophageal Cancer, Adenocarcinoma, Clinical-Trial, Phase-Iii Trial, Medical Oncology, World Health Organization, Endoscopy, Gastrointestinal, Drug Therapy, Gastrectomy, Stomach Neoplasms, Perioperative Chemotherapy, Humans, Societies, Medical, Neoplasm Staging, Randomized Controlled Trials as Topic, Radiofrequency Ablation, Evidence-Based Medicine, Nutritional Support, Palliative Care, Endoscopic treatment, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Congresses as Topic, Term Survival Differences, Advanced Gastric-Cancer, Spain, Advanced Esophagogastric Cancer, Practice Guidelines as Topic, Gastro-oesophageal junction cancer, [ SDV.MHEP.HEG ] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Endoscopic Submucosal Dissection, Esophagogastric Junction, Resectable Esophageal, Esophagostomy, Multimodal therapy
Abstract: IF 2.719; International audience; The management of GOJ cancers remains controversial and may vary between countries. Evidence-based attitudes and guidelines are not easy to elaborate since most of the trials and studies reported mixed cases of oesophageal (both adenocarcinoma and squamous cell tumours), GOJ and gastric cancers. The aim of this expert discussion and position paper is to elaborate practical recommendations that integrate evidence-reported literature and experience-based attitude covering all clinical aspects of GOJ cancer across different specialities and countries in Europe.Opinion leaders, selected on scientific merit were asked to answer to a prepared set of questions covering the approach of GOJ tumours from definition to therapeutic strategies. All answers were then discussed during a plenary session and reported here in providing a well-balanced reflection of both clinical expertise and updated evidence-based medicine.Definition, classification, diagnosis and staging of GOJ tumours were updated and debated. Therapeutic aspects including endoscopic therapy, surgical management, both multimodal curative and palliative management were also reviewed for proposing practical and consensual positions and recommendations whenever possible.GOJ tumours deserve specific attention,not only for uniformising clinical management across countries but also for performing specific clinical and translational research,mainly in the curative perioperative setting.
Published: 2016
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34. Proportions of blood-borne Vd1þ and Vd2þ T-cells are associated with overall survival of melanoma patients treated with ipilimumab

Author: Kilian Wistuba-Hamprecht, Marnix H Geukes Foppen, Bastian Schilling, Karin Haehnel, Jedd D. Wolchok, Emanuela Romano, Elisabeth Steinhagen-Thiessen, Alexander Martens, Mariaelena Capone, Phillip Wong, Dirk Schadendorf, Jianda Yuan, Amir Khammari, Ilja Demuth, Brigitte Dréno, Claus Garbe, Graham Pawelec, Christian U. Blank, Michael A. Postow, Benjamin Weide, Paolo A. Ascierto, Anis Larbi, Department of Internal Medicine II, Eberhard Karls Universität Tübingen-Center for Medical Research, University of Tübingen, The Netherlands Cancer Institute, Memorial Sloan Kettering Cancer Center ( MSKCC ), Weill Medical College of Cornell University [New York], Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Recherche en Cancérologie / Nantes - Angers ( CRCNA ), CHU Angers-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Laennec-Centre National de la Recherche Scientifique ( CNRS ) -Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes ( CHU Nantes ), Service de dermatologie [Nantes], Université de Nantes ( UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Istituto Nazionale Tumori IRCCS, Charité University Medical Center, Institute of Human Genetics, Singapore Immunology Network ( SIgN ), Agency for Science Technology and Research, German Cancer Consortium, Department of Dermatology, University Hospital Essen, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen-Center for Medical Research, Memorial Sloane Kettering Cancer Center [New York], Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Singapore Immunology Network (SIgN), Biomedical Sciences Institute (BMSI), and Bernardo, Elizabeth
Subjects: Oncology, Male, Cancer Research, Cellular differentiation, medicine.medical_treatment, Medizin, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 0302 clinical medicine, T-Lymphocyte Subsets, Medicine, Cytotoxic T cell, Melanoma, Aged, 80 and over, medicine.diagnostic_test, Antibodies, Monoclonal, Cell Differentiation, Receptors, Antigen, T-Cell, gamma-delta, Middle Aged, Flow Cytometry, Prognosis, 3. Good health, 030220 oncology & carcinogenesis, Biomarker (medicine), Female, Immunotherapy, medicine.drug, Adult, medicine.medical_specialty, Ipilimumab, [SDV.CAN]Life Sciences [q-bio]/Cancer, Antineoplastic Agents, Article, Flow cytometry, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Biomarkers, Tumor, Humans, Aged, business.industry, Case-control study, medicine.disease, Case-Control Studies, Immunology, business, 030215 immunology
Abstract: International audience; Human γδ T-cells possess regulatory and cytotoxic capabilities, and could potentially influence the efficacy of immunotherapies. We analysed the frequencies of peripheral γδ T-cells, including their most prominent subsets (Vδ1+ and Vδ2+ cells) and differentiation states in 109 melanoma patients and 109 healthy controls. We additionally analysed the impact of γδ T-cells on overall survival (OS) calculated from the first dose of ipilimumab in melanoma patients. Higher median frequencies of Vδ1+ cells and lower median frequencies of Vδ2+ cells were identified in patients compared to healthy subjects (Vδ1+: 30% versus 15%, Vδ2+: 39% versus 64%, both p < 0.001). Patients with higher frequencies of Vδ1+ cells (≥30%) had poorer OS (p = 0.043) and a Vδ1+ differentiation signature dominated by late-differentiated phenotypes. In contrast, higher frequencies of Vδ2+ cells (≥39%) were associated with longer survival (p = 0.031) independent of the M category or lactate dehydrogenase level. Patients with decreasing frequencies of Vδ2+ cells under ipilimumab treatment had worse OS and a lower rate of clinical benefit than patients without such decreases. Therefore, we suggest frequencies of both Vδ1+ and Vδ2+ cells as candidate biomarkers for outcome in melanoma patients following ipilimumab. Further studies are needed to validate these results and to clarify whether they represent prognostic associations or whether γδ T-cells are specifically and/or functionally linked to the mode of action of ipilimumab.
Published: 2016
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35. Obesity As a Risk Factor for Anthracyclines and Trastuzumab Cardiotoxicity in Breast Cancer: A Systematic Review and Meta-Analysis

Author: Charles Guenancia, Marianne Zeller, Sylvain Ladoire, Yves Cottin, Catherine Vergely, Daniela Cardinale, Luc Rochette, Annick Lefebvre, François Ghiringhelli, Anthony F. Yu, Physiopathologie et épidémiologie cérébro-cardiovasculaire [Dijon] (PEC2), Université de Bourgogne (UB)-Université Bourgogne Franche-Comté [COMUE] (UBFC), European Institute of Oncology [Milan] (ESMO), Memorial Sloane Kettering Cancer Center [New York], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bourgogne (UB), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Centre Hospitalier Universitaire de Reims ( CHU Reims ), European Institute of Oncology, European Institute of Oncology [Milan] ( ESMO ), Memorial Sloan Kettering Cancer Center ( MSKCC ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Vergely, Catherine, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), and Centre Hospitalier Universitaire de Reims (CHU Reims)
Subjects: Oncology, Cancer Research, medicine.medical_specialty, Cardiac Dysfunction, Population, Clinical-Trials, [SDV.CAN]Life Sciences [q-bio]/Cancer, 030204 cardiovascular system & hematology, Overweight, Cardiovascular-Disease, Adjuvant Study-Group, Heart-Failure, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Trastuzumab, Internal medicine, medicine, Chemotherapy, Body-Mass Index, Risk factor, 2. Zero hunger, Cardiotoxicity, business.industry, Publication bias, Odds ratio, ORIGINAL REPORTS, medicine.disease, Doxorubicin-Induced Cardiotoxicity, 3. Good health, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, 030220 oncology & carcinogenesis, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Therapy, Metabolic syndrome, medicine.symptom, business, medicine.drug
Abstract: PurposePatients with metabolic syndrome have a greater risk of cardiovascular disease, although their susceptibility to chemotherapy-induced cardiac disease is not well documented. The aim of this meta-analysis was to assess associations between obesity or being overweight and cardiotoxicity from anthracyclines and sequential anthracyclines and trastuzumab in patients with breast cancer.MethodsWe performed a random-effects analysis and a network meta-analysis and assessed publication bias. We included 15 studies and 8,745 patients with breast cancers who were treated with anthracyclines and sequential anthracyclines and trastuzumab.ResultsCombination of obesity and being overweight was significantly associated with a greater risk of developing cardiotoxicity after anthracyclines and a sequential anthracyclines and trastuzumab regimen in patients with breast cancer. Pooled odds ratio for cardiotoxicity was 1.38 (95% CI, 1.06 to 1.80; I2= 43%; N = 8,745) for overweight or obesity (body mass index > 25 kg/m2), 1.47 (95% CI, 0.95 to 2.28; I2= 47%; n = 2,615) for obesity, and 1.15 (95% CI, 0.83 to 1.58; I2= 27%; n = 2,708) for overweight. Associations were independent of study design, year of publication, drug regimen (anthracyclines alone v sequential anthracyclines and trastuzumab), or definitions of cardiotoxicity and of overweight or obesity. There was no evidence of publication bias; however, we could not separate the contributions of obesity-related cardiovascular risk factors, such as diabetes and hypertension, from that of obesity itself in this largely unadjusted analysis.ConclusionOur findings in a largely unadjusted analysis suggest that overweight and obesity are risk factors for cardiotoxicity from anthracyclines and sequential anthracyclines and trastuzumab.
Published: 2016
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36. Immunodynamics: a cancer immunotherapy trials network review of immune monitoring in immuno-oncology clinical trials

Author: Joshua Brody, Thomas O. Kleen, Martin A. Cheever, Silvia C. Formenti, Guido Kroemer, Aurélien Marabelle, Antoni Ribas, Bernard A. Fox, Mary L. Disis, George E. Peoples, Tito Serafini, Don M. Benson, Holbrook E Kohrt, Laurence Zitvogel, H. Kim Lyerly, Jeffrey S. Weber, Paul M. Sondel, Ilan R. Kirsch, Jedd D. Wolchok, Ignacio Melero, Jérôme Galon, Karolina Palucka, Holden T. Maecker, Michael Kalos, Harlan Robins, Carl H. June, Ronald Levy, Lewis L. Lanier, Eric Vivier, William H. Robinson, Kunle Odunsi, Paul C. Tumeh, Nina Bhardwaj, Jos Melenhorst, Jeffrey S. Miller, Cancer Institute, New York University Langone Medical Center (NYU Langone Medical Center), NYU System (NYU)-NYU System (NYU), Department of Computer Science, Dartmouth College [Hanover], Department Radiation Oncology (Weill Cornell Medicine), Weill Medical College of Cornell University [New York], Integrative cancer immunology laboratory Paris FR, Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cellular Technology Ltd, Shaker Heights, Plateforme de métabolomique, Direction de la recherche [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Service de biologie [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université Paris Descartes - Paris 5 (UPD5), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Distributed Programming Laboratory (LPD), Ecole Polytechnique Fédérale de Lausanne (EPFL), Laboratoire d'Informatique de Grenoble (LIG ), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Département d’Innovation Thérapeutique et essais précoces [Gustave Roussy] (DITEP), Institut Gustave Roussy (IGR), Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Dept. of Immunology, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Dept. of Oncology, Clínica Universidad de Navarra [Pamplona], Department of Gynecologic Oncology, Roswell Park Cancer Institute [Buffalo], Développement de nouveaux vaccins pour le traitement de maladies virales chroniques, Institut National de la Santé et de la Recherche Médicale (INSERM), Comprehensive Cancer Center, Nuon Therpeutics Inc., Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Memorial Sloane Kettering Cancer Center [New York], New York University Langone Medical Center, Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Apoptose, cancer et immunité ( U848 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Distributed Programming Laboratory ( LPD ), Ecole Polytechnique Fédérale de Lausanne ( EPFL ), Laboratoire d'Informatique de Grenoble ( LIG ), Université Pierre Mendès France - Grenoble 2 ( UPMF ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut National Polytechnique de Grenoble ( INPG ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ), Département d’Innovation Thérapeutique et essais précoces [Gustave Roussy] ( DITEP ), Institut Gustave Roussy ( IGR ), Immunologie des tumeurs et immunothérapie ( UMR 1015 ), Centre d'Investigation Clinique en Biotherapie des cancers ( CIC 1428 , CBT 507 ), Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre d'Immunologie de Marseille - Luminy ( CIML ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Memorial Sloan Kettering Cancer Center ( MSKCC ), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Laboratoire d'Informatique de Grenoble (LIG), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), École Pratique des Hautes Études (EPHE), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Roswell Park Cancer Institute [Buffalo] (RPCI), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ), and Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS )
Subjects: 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, medicine.medical_treatment, Immunology, Review, 03 medical and health sciences, 0302 clinical medicine, Immune system, Cancer immunotherapy, Internal medicine, medicine, Immunology and Allergy, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Pharmacology, business.industry, Clinical study design, Cancer, Immunotherapy, Biomarker, medicine.disease, 3. Good health, Clinical trial, 030104 developmental biology, Drug development, 13. Climate action, 030220 oncology & carcinogenesis, Pharmacodynamics, Molecular Medicine, [SDV.IMM]Life Sciences [q-bio]/Immunology, business
Abstract: International audience; The efficacy of PD-1/PD-L1 targeted therapies in addition to anti-CTLA-4 solidifies immunotherapy as a modality to add to the anticancer arsenal. Despite raising the bar of clinical efficacy, immunologically targeted agents raise new challenges to conventional drug development paradigms by highlighting the limited relevance of assessing standard pharmacokinetics (PK) and pharmacodynamics (PD). Specifically, systemic and intratumoral immune effects have not consistently correlated with standard relationships between systemic dose, toxicity, and efficacy for cytotoxic therapies. Hence, PK and PD paradigms remain inadequate to guide the selection of doses and schedules, both starting and recommended Phase 2 for immunotherapies. The promise of harnessing the immune response against cancer must also be considered in light of unique and potentially serious toxicities. Refining immune endpoints to better inform clinical trial design represents a high priority challenge. The Cancer Immunotherapy Trials Network investigators review the immunodynamic effects of specific classes of immunotherapeutic agents to focus immune assessment modalities and sites, both systemic and importantly intratumoral, which are critical to the success of the rapidly growing field of immuno-oncology.
Published: 2016
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37. Specification of tissue-resident macrophages during organogenesis

Author: Christian E. Jacome-Galarza, Florian Halbritter, Matthias Farlik, Iván Ballesteros, Patrick Günther, Johanna Klughammer, Marc Beyer, Christoph Bock, Elisa Gomez-Perdiguero, Frederic Geissmann, Yasuhiro Kobayashi, Elvira Mass, Lucile Crozet, Kristian Händler, Joachim L. Schultze, Memorial Sloan Kettering Cancer Center (MSKCC), CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria, Life and Medical Sciences Institute for Genomics and Immunoregulation, University of Bonn, Weill Cornell Graduate School of Medical Sciences, Weill Medical College of Cornell University [New York], Institute for Oral Science, Matsumoto Dental University, Centre for Cellular and Molecular Biology of Inflammation [London, UK] (CMCBI), King‘s College London, German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Medizinische Universität Wien = Medical University of Vienna, and Max Planck Institute for Informatics [Saarbrücken]
Subjects: 0301 basic medicine, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Organogenesis, physiology [Hematopoiesis], Gene Expression, cytology [Kupffer Cells], metabolism [Kupffer Cells], Mice, Idb3 protein, mouse, Macrophage, Tissue homeostasis, ComputingMilieux_MISCELLANEOUS, Embryonic Induction, Erythroid Precursor Cells, Multidisciplinary, Microglia, genetics [Cell Differentiation], metabolism [Myeloid Progenitor Cells], Kupffer cell, Gene Expression Regulation, Developmental, genetics [Receptors, Chemokine], Cell Differentiation, Cell biology, genetics [Hematopoiesis], Cytokine, medicine.anatomical_structure, Organ Specificity, Female, Receptors, Chemokine, Stem cell, metabolism [Inhibitor of Differentiation Proteins], Macrophage colony-stimulating factor, cytology [Erythroid Precursor Cells], Kupffer Cells, CX3C Chemokine Receptor 1, cytology [Embryo, Mammalian], Embryonic Development, cytology [Macrophages], Biology, Article, 03 medical and health sciences, medicine, Animals, Myeloid Progenitor Cells, Macrophages, metabolism [Erythroid Precursor Cells], Embryo, Mammalian, Mice, Mutant Strains, Hematopoiesis, 030104 developmental biology, Immunology, ddc:320, metabolism [Macrophages], Inhibitor of Differentiation Proteins, Cx3cr1 protein, mouse, cytology [Myeloid Progenitor Cells], Transcriptome
Abstract: INTRODUCTION Embryonic development and tissue homeostasis depend on cooperation between specialized cell types. Resident macrophages are professional phagocytes that survey their surroundings; eliminate unfit cells, microorganisms, and metabolic waste; and produce a large range of bioactive molecules and growth factors. Resident macrophages also serve tissue-specific purposes: For example, microglia in the central nervous system support neuronal circuit development, Kupffer cells scavenge blood particles and dying red blood cells in the liver, and alveolar macrophages uptake surfactant and remove airborne pollutants and microbes from the airways. Resident macrophage diversity in adult mice is reflected in tissue-specific gene expression profiles, which may be due to responses to specific cues from their microenvironment, different developmental processes, and the contribution of distinct progenitors cell types. Altogether, the mechanisms responsible for the generation of tissue-resident macrophage diversity remain unclear. RATIONALE Tissue-resident macrophages originate, at least in part, from mesodermal erythro-myeloid progenitors (EMPs) from the yolk sac, which invade the embryo proper at the onset of organogenesis. These tissue-resident macrophages are also self-maintained in postnatal tissues, independently of definitive hematopoietic stem cells (HSCs) in a steady state. We therefore hypothesized that resident macrophages represent a founding cell type within most organ anlagen. In this model, the generation of macrophage diversity, as observed in the tissues of postnatal mice, may be integral to organogenesis. RESULTS To test this hypothesis and explore the molecular basis of macrophage diversity in mammals, we performed a spatiotemporal analysis of macrophage development in mice, from embryonic day 9 (E9) to 3 weeks after birth. Unbiased single-cell RNA sequencing (RNA-seq) analysis of CD45 + cells, combined with RNA-seq analyses of sorted cell populations, genetic fate mapping, and in situ analyses, revealed that EMPs give rise to a population of premacrophages (pMacs) that colonize the whole embryo from E9.5, as they acquire a core macrophage differentiation program that includes pattern recognition, scavengers, and cytokine receptors. The chemokine receptor Cx3cr1 is up-regulated in pMacs and is important for embryo colonization, which is delayed in Cx3cr1 -deficient embryos. Fate mapping of pMacs using a Tnfrsf11a –Cre reporter labels homogeneously fetal and adult tissue-resident macrophages but not HSCs and their progeny. Transcriptional regulators that identify postnatal tissue-resident macrophages in the brain, liver, kidney, skin, and lung were specifically up-regulated immediately after colonization. These dynamic changes mark the onset of diversification into adult macrophages. We identified Id3 as a Kupffer cell–specific transcriptional regulator. Deletion of Id3 in pMacs resulted in Kupffer cell deficiency but did not affect development of microglia and kidney macrophages. CONCLUSION Our study shows that EMP-derived precursors colonize embryonic tissues and simultaneously acquire a full core macrophage program. This is followed by their diversification into tissue-specific macrophages during organogenesis, likely via the expression of distinct sets of transcriptional regulators. These results indicate that differentiation of tissue-resident macrophages is an integral part of organogenesis and identify a spatiotemporal molecular road map for the generation of macrophage diversity in vivo. Our findings provide a conceptual framework to analyze and understand the consequence(s) of genetic variation for macrophage contribution to development, homeostasis, and disease pathogenesis in different tissues and will support efforts to differentiate specialized macrophages in vitro.
Published: 2016
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38. MAP and kinesin-dependent nuclear positioning is required for skeletal muscle function

Author: Eric S. Folker, Thomas Metzger, Edgar R. Gomes, Bruno Cadot, M u Xu, Mary K. Baylies, Vincent Gache, Brian E. Richardson, Cornell University [New York], Groupe Myologie, Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Memorial Sloan Kettering Cancer Center (MSKCC), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and CADOT, Bruno
Subjects: Microtubule-associated protein, nuclear positioning, [SDV]Life Sciences [q-bio], Muscle Fibers, Skeletal, Kinesins, Biology, Microtubules, primary myotubes, Article, Cell Line, Mice, Multinucleate, Microtubule, mental disorders, Cell polarity, medicine, Animals, nuclear movement, Muscle, Skeletal, Cells, Cultured, Cell Nucleus, Multidisciplinary, Myogenesis, Cell Polarity, Skeletal muscle, Kinesin, Cell Compartmentation, Protein Structure, Tertiary, Cell biology, [SDV] Life Sciences [q-bio], Cell nucleus, Drosophila melanogaster, Phenotype, medicine.anatomical_structure, Organ Specificity, Larva, MAP, Muscle, Drosophila, C2C12, Microtubule-Associated Proteins, Locomotion, psychological phenomena and processes, Protein Binding
Abstract: International audience; The basic unit of skeletal muscle in all metazoans is the multinucleate myofibre, within which individual nuclei are regularly positioned. The molecular machinery responsible for myonuclear positioning is not known. Improperly positioned nuclei are a hallmark of numerous diseases of muscle, including centronuclear myopathies, but it is unclear whether correct nuclear positioning is necessary for muscle function. Here we identify the microtubule-associated protein ensconsin (Ens)/microtubule-associated protein 7 (MAP7) and kinesin heavy chain (Khc)/Kif5b as essential, evolutionarily conserved regulators of myonuclear positioning in Drosophila and cultured mammalian myotubes. We find that these proteins interact physically and that expression of the Kif5b motor domain fused to the MAP7 microtubule-binding domain rescues nuclear positioning defects in MAP7-depleted cells. This suggests that MAP7 links Kif5b to the microtubule cytoskeleton to promote nuclear positioning. Finally, we show that myonuclear positioning is physiologically important. Drosophila ens mutant larvae have decreased locomotion and incorrect myonuclear positioning, and these phenotypes are rescued by muscle-specific expression of Ens. We conclude that improper nuclear positioning contributes to muscle dysfunction in a cell-autonomous fashion.
Published: 2012
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39. Baseline Peripheral Blood Biomarkers Associated with Clinical Outcome of Advanced Melanoma Patients Treated with Ipilimumab

Author: Phillip Wong, Dirk Schadendorf, Christian U. Blank, Antje Sucker, Bastian Schilling, Thomas Eigentler, Jianda Yuan, Emanuela Romano, Alexander Martens, Marnix H Geukes Foppen, Kilian Wistuba-Hamprecht, Mariaelena Capone, Jedd D. Wolchok, Graham Pawelec, Brigitte Dréno, Claus Garbe, Amir Khammari, Peter Martus, Anna Maria Di Giacomo, Jessica C. Hassel, Michael A. Postow, Paolo A. Ascierto, Benjamin Weide, Michele Maio, Department of Internal Medicine II, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen-Center for Medical Research, University of Tübingen, Department of Dermatology [Tubingen, Germany], Tübingen University Hospital [Germany], The Netherlands Cancer Institute, Memorial Sloane Kettering Cancer Center [New York], Weill Medical College of Cornell University [New York], Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de dermatologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Dermatology, University Hospital Essen, Fondazione IRCCS Istituto Nazionale dei Tumori, Division of Medical Oncology and Immunotherapy, University Hospital of Siena, German Cancer Consortium, Heidelberg University Hospital [Heidelberg], Department of Immunology [Tübingen, Germany], Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Bernardo, Elizabeth, University of Tübingen [Germany], Eberhard Karls Universität Tübingen-Center for Medical Research, Memorial Sloan Kettering Cancer Center ( MSKCC ), Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Nantes ( UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Centre de Recherche en Cancérologie / Nantes - Angers ( CRCNA ), and CHU Angers-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Laennec-Centre National de la Recherche Scientifique ( CNRS ) -Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes ( CHU Nantes )
Subjects: Male, Oncology, Cancer Research, medicine.medical_specialty, Skin Neoplasms, Lymphocyte, Medizin, Ipilimumab, [SDV.CAN]Life Sciences [q-bio]/Cancer, T-Lymphocytes, Regulatory, Article, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 03 medical and health sciences, Antineoplastic Agents, Immunological, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Biomarkers, Tumor, medicine, Humans, Lymphocyte Count, IL-2 receptor, Adverse effect, Melanoma, Aged, L-Lactate Dehydrogenase, Proportional hazards model, business.industry, Myeloid-Derived Suppressor Cells, FOXP3, Cancer, medicine.disease, 3. Good health, Treatment Outcome, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Immunology, Erythrocyte Count, Biomarker (medicine), Female, business, 030215 immunology, medicine.drug
Abstract: Purpose: To identify baseline peripheral blood biomarkers associated with clinical outcome following ipilimumab treatment in advanced melanoma patients. Experimental Design: Frequencies of myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg), serum lactate dehydrogenase (LDH), routine blood counts, and clinical characteristics were assessed in 209 patients. Endpoints were overall survival (OS) and best overall response. Statistical calculations were done by Kaplan–Meier and Cox regression analysis, including calibration and discrimination by C-statistics. Results: Low baseline LDH, absolute monocyte counts (AMC), Lin−CD14+HLA-DR−/low-MDSC frequencies, and high absolute eosinophil counts (AEC), relative lymphocyte counts (RLC), and CD4+CD25+FoxP3+-Treg frequencies were significantly associated with better survival, and were considered in a combination model. Patients (43.5%) presenting with the best biomarker signature had a 30% response rate and median survival of 16 months. In contrast, patients with the worst biomarkers (27.5%) had only a 3% response rate and median survival of 4 months. The occurrence of adverse events correlated with neither baseline biomarker signatures nor the clinical benefit of ipilimumab. In another model, limited to the routine parameters LDH, AMC, AEC, and RLC, the number of favorable factors (4 vs. 3 vs. 2–0) was also associated with OS (P < 0.001 for all pairwise comparisons) in the main study and additionally in an independent validation cohort. Conclusions: A baseline signature of low LDH, AMC, and MDSCs as well as high AEC, Tregs, and RLC is associated with favorable outcome following ipilimumab. Prospective investigation of the predictive impact of these markers following ipilimumab and other treatments, e.g., PD-1 antibodies, is warranted. Clin Cancer Res; 22(12); 2908–18. ©2016 AACR.
Published: 2016
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40. Development and function of tissue resident macrophages in mice

Author: Katrin Kierdorf, Elisa Gomez Perdiguero, Marco Prinz, Frederic Geissmann, Centre for Cellular and Molecular Biology of Inflammation [London, UK] (CMCBI), King‘s College London, institute of neuropathology, University of Freiburg [Freiburg], Memorial Sloan Kettering Cancer Center (MSKCC), Macrophages et Cellules endothéliales / Macrophages and Endothelial Cells, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0303 health sciences, business.industry, Macrophages, Stem Cells, Immunology, Models, Biological, Article, 03 medical and health sciences, Mice, 0302 clinical medicine, Immune system, Immunology and Allergy, Macrophage, Medicine, [SDV.IMM]Life Sciences [q-bio]/Immunology, Animals, business, [SDV.BDD]Life Sciences [q-bio]/Development Biology, 030217 neurology & neurosurgery, Function (biology), Homeostasis, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract: Macrophages are important for tissue development, homeostasis as well as immune response upon injury or infection. For a long time they were only seen as one uniform group of phagocytes with a common origin and similar functions. However, this view has been challenged in the last decade and revealed a complex diversity of tissue resident macrophages. Here, we want to present the current view on macrophage development and tissue specification and we will discuss differences as well as common patterns between heterogeneous macrophage subpopulations.
Published: 2015
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41. Classification of current anticancer immunotherapies

Author: Chiara Castelli, Axel Hoos, Anna Karolina Palucka, Aitziber Buqué, Kenneth J. Pienta, Aled Clayton, Daniel E. Speiser, Jean-Pierre Mach, Klas Kärre, Richard G. Vile, Maha Ayyoub, Norma Bloy, Theresa L. Whiteside, Eli Gilboa, Naiyer A. Rizvi, Cornelis J. M. Melief, Alexander Knuth, Bruno Silva-Santos, Lisa M. Coussens, James E. Talmadge, Jean-Yves Blay, Rolf Kiessling, Lorenzo Moretta, Alexander M.M. Eggermont, Estaban Celis, Anne Caignard, Mario P. Colombo, Abhishek D. Garg, José Manuel Bravo-San Pedro, Pramod K. Srivastava, Dmitry I. Gabrilovich, Wolf H. Fridman, Catherine Sautès-Fridman, Eric Tartour, Fabrizio Mattei, Patrizia Agostinis, Philipp Beckhove, Laura Bracci, Vincenzo Cerundolo, Giuseppe Giaccone, Fernando Aranda, Angel Porgador, Elisa E. Baracco, Radek Spisek, Jean Pierre Abastado, Michael T. Lotze, Ron N. Apte, Federica Cavallo, Benoît Van den Eynde, Weiping Zou, François Ghiringhelli, Hans Schreiber, Jitka Fucikova, Lorenzo Galluzzi, Adekunke Odunsi, Erika Vacchelli, Roland S. Liblau, Hideho Okada, Hiroshi Shiku, Laurence Zitvogel, Pawel Kalinski, Guido Kroemer, Oliver Kepp, George C. Prendergast, Eva Klein, Francesca Castoldi, Enrico Lugli, Jedd D. Wolchok, Anne Hosmalin, Sjoerd H. van der Burg, Hermann Wagner, Mark J. Smyth, Nicholas P. Restifo, Dirk Jäger, John M. Kirkwood, Gabriel A. Rabinovich, Sacha Gnjatic, Madhav V. Dhodapkar, E. A. Mittendorf, Douglas T. Fearon, Ignacio Melero, Marcus E. Peter, Jérôme Galon, Domenico Mavilio, Laura Senovilla, Claire E. Lewis, Barbara Seliger, Jeffrey S. Weber, UCL - SSS/DDUV - Institut de Duve, Apoptose, cancer et immunité (Equipe labellisée Ligue contre le cancer - CRC - Inserm U1138), Institut Gustave Roussy (IGR)-Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Université Paris-Sud - Paris 11 (UP11), Sotio a.c., Pole d’innovation thérapeutique en oncologie, Institut de Recherches Internationales Servier, Cell Death Research and Therapy (CDRT) Laboratory, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Group of Immune receptors of the Innate and Adaptive System, Institut d’Investigacions Biomédiques August Pi i Sunyer (IDIBAPS), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Cancer Vaccines and Immune Regulation, Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Translational Immunology Division, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Dept. of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità (ISS), Alloimmunité-Autoimmunité-Transplantation (A2T), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unit of Immunotherapy of Human Tumors, Dept. of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori - National Cancer Institute [Milan], Molecular Biotechnology Center, Dept. of Molecular Biotechnology and Health Sciences, Università degli studi di Torino = University of Turin (UNITO), Cancer Immunology, Inflammation and Tolerance Program, Augusta University, University System of Georgia (USG)-University System of Georgia (USG), MRC Human Immunology Unit, The Weatherall Institute of Molecular Medicine, University of Oxford-University of Oxford, Department of Oncology - Pathology, Cancer Center Karolinska [Karolinska Institutet] (CCK), Karolinska Institutet [Stockholm]-Karolinska Institutet [Stockholm], Institute of Cancer & Genetics, Cardiff University, Velindre Cancer Centre, Knight Cancer Institute, Oregon Health and Science University [Portland] (OHSU), Sect. of Hematology and Immunobiology,Yale Cancer Center, Yale University [New Haven], Institut Gustave Roussy (IGR), Cold Spring Harbor Laboratory, NY, Cold Spring Harbor, Centre de Recherche des Cordeliers (CRC), Dept. of Immunology, 2nd Faculty of Medicine and University Hospital Motol, Charles University [Prague] (CU), Dept. of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Lombardi Comprehensive Cancer Center, Georgetown University [Washington] (GU), Dept. of Microbiology and Immunology, Sylvester Comprehensive Cancer Center, University of Miami [Coral Gables], Glaxo Smith Kline, Cancer Immunotherapy Consortium, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), National Center for Tumor Diseases, University Medical Center Heidelberg, Hillman Cancer Center, University of Pittsburg, Department of Surgery, Cancer Institute-University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Dept. of Immunology and Infectious Diseases and Microbiology, University of Pittsburgh (PITT), Dept. of Microbiology, Tumor and Cell Biology, Karolinska Institutet [Stockholm], Plateforme de métabolomique, Direction de la recherche [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Dept. of Oncology, Karolinska Institute Hospital, Cancer Institute Laboratory, Academic Unit of Inflammation and Tumour Targeting, Dept. of Oncology, University of Sheffield Medical School, Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Institute, Institut de Biochimie, Université de Lausanne = University of Lausanne (UNIL), Dept. of Medical Biotechnologies and Translational Medicine, Università degli Studi di Milano = University of Milan (UNIMI), Dept. of Immunology, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Clínica Universidad de Navarra [Pamplona], ISA Therapeutics, Dept. of Immunohematology and Blood Transfusion, Leiden University Medical Center (LUMC), Universiteit Leiden-Universiteit Leiden, Research Dept. of Surgical Oncology, The University of Texas, Istituto Giannina Gaslini, Center for Immunotherapy [Buffalo], Roswell Park Cancer Institute [Buffalo] (RPCI), Dept. of Neurological Surgery, University of California [San Francisco] (UC San Francisco), University of California (UC)-University of California (UC), The Jackson Laboratory [Bar Harbor] (JAX), Div. of Hematology/Oncology, Northwestern University, The James Buchanan Brady Urological Institute, The Johns Hopkins Medical Institutions, Shraga Segal Department of Microbiology and Immunology, Ben-Gurion University of the Negev (BGU)-Faculty of Health Sciences and Cancer Research Center, Cell Biology and Signaling Program, Thomas Jefferson University-Sidney Kimmel Cancer Center, Jefferson (Philadelphia University + Thomas Jefferson University)-Jefferson (Philadelphia University + Thomas Jefferson University), Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental [Buenos Aires] (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas [Buenos Aires] (CONICET)-Consejo Nacional de Investigaciones Científicas y Técnicas [Buenos Aires] (CONICET), Memorial Sloane Kettering Cancer Center [New York], Dept. of Pathology, The Cancer Research Center, University of Chicago, Institute of Medical Immunology, Martin-Luther-Universität Halle Wittenberg (MLU), Department of Immuno-gene Therapy, Mie University, Instituto de Medicina Molecular, Universidade de Lisboa = University of Lisbon (ULISBOA), Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, School of Medicine, University of Queensland [Brisbane], Ludwig Cancer Research Center, Dept. of Immunology, University of Connecticut (UCONN), Carole and Ray Neag Comprehensive Cancer Center, Laboratory of Transplantation Immunology, Dept. of Pathology and Microbiology, University of Nebraska Medical Center, University of Nebraska System-University of Nebraska System, Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'immunologie biologique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Dept. of Clinical Oncology, Université Catholique de Louvain = Catholic University of Louvain (UCL), Ludwig Institute for Cancer Research, de Duve Institute, Dept. of Molecular Medicine and Immunology, Mayo Clinic College of Medicine, Institute of Medical Microbiology, Immunology and Hygiene, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Donald A. Adam Comprehensive Melanoma Research Center, H. Lee Moffitt Cancer Center & Research Institute, University of Pittsburgh School of Medicine, Dept. of Medicine and Ludwig Center, Weill Medical College of Cornell University [New York], Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Medical School, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Pôle de biologie, GK is supported by the Ligue contre le Cancer(équipe labelisée), Agence Nationale de la Recherche(ANR), Association pour la recherche sur le cancer (ARC), Cancéropôle Ile-de-France, Institut National du Cancer(INCa), Fondation Bettencourt-Schueller, Fondation deFrance, Fondation pour la Recherche Médicale (FRM), theEuropean Commission (ArtForce), the European ResearchCouncil (ERC), the LabEx Immuno-Oncology, the SIRICStratified Oncology Cell DNA Repair and Tumor ImmuneElimination (SOCRATE), the SIRIC Cancer Researchand Personalized Medicine (CARPEM), and the ParisAlliance of Cancer Research Institutes (PACRI). MPC issupported by Association for Cancer Research (AIRC). SGis supported by Cancer Vaccine Collaborative and CancerResearch Institute. MJS is supported by the NationalHealth and Medical Research Council of Australia, the QIMR Berghofer Medical Research Institute, andthe Susan G Komen Breast Cancer Foundation. FM issupported by a grant from the Italian Ministry of Health., Repositório da Universidade de Lisboa, Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Istituto Superiore di Sanità, Università degli studi di Torino (UNITO), University of Oxford [Oxford]-University of Oxford [Oxford], University of Pennsylvania [Philadelphia], Georgetown University, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lausanne (UNIL), University of Milan, Roswell Park Cancer Institute [Buffalo], University of California [San Francisco] (UCSF), University of California-University of California, Universidade de Lisboa (ULISBOA), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Bos, Mireille, Apoptose, cancer et immunité ( Equipe labellisée Ligue contre le cancer - CRC - Inserm U1138 ), Institut Gustave Roussy ( IGR ) -Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Descartes - Paris 5 ( UPD5 ), Université Paris-Sud - Paris 11 ( UP11 ), Catholic University of Leuven ( KU Leuven ), Institut de cancérologie de l'Ouest - Nantes ( ICO Nantes ), CRLCC Paul Papin-CRLCC René Gauducheau, Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), German Cancer Research Center, Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Alloimmunité-Autoimmunité-Transplantation ( A2T ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Università degli studi di Torino ( UNITO ), Georgia Regents University Cancer Center, Cancer Center Karolinska [Karolinska Institutet] ( CCK ), Oregon Health & Science University [Portland] ( OHSU ), Institut Gustave Roussy ( IGR ), Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Charles University, Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), University of Miami, Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Cancer Institute-University of Pittsburgh, University of Pittsburgh, Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Centre de Physiopathologie de Toulouse Purpan ( CPTP ), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Lausanne ( UNIL ), Center for Immunotherapy, University of California [San Francisco] ( UCSF ), The Jackson Laboratory for Genomics Medicine, Ben-Gurion University of the Negev ( BGU ) -Faculty of Health Sciences and Cancer Research Center, Instituto de Biología y Medicina Experimental (IBYME), National Cancer Institute (NCI), Memorial Sloan Kettering Cancer Center ( MSKCC ), Martin Luther University Halle-Wittenberg, Mie University Graduate School of Medicine, Universidade de Lisboa ( ULISBOA ), University of Lausanne, University of Connecticut School of Medicine, Paris-Centre de Recherche Cardiovasculaire ( PARCC - U970 ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Université Catholique de Louvain ( UCL ), Technical University of Munich ( TUM ), Centre d'Investigation Clinique en Biotherapie des cancers ( CIC 1428 , CBT 507 ), Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Immunologie des tumeurs et immunothérapie ( UMR 1015 ), and Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM )
Subjects: immunostimulatory cytokines, medicine.medical_treatment, Review, Bioinformatics, DNA-based vaccines, Efficacy, 0302 clinical medicine, Cancer immunotherapy, Neoplasms, peptide-based vaccines, 0303 health sciences, Patología, purl.org/becyt/ford/3.1 [https], CANCER, 3. Good health, Medicina Básica, Oncology, checkpoint blockers, 030220 oncology & carcinogenesis, QR180, purl.org/becyt/ford/3 [https], Immunotherapy, CIENCIAS MÉDICAS Y DE LA SALUD, medicine.drug_class, Inmunología, adoptive cell transfer, dendritic cell-based interventions, oncolytic viruses, Toll-like receptor agonists, Monoclonal antibody, RC0254, 03 medical and health sciences, Immune system, Antigen, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, IMMUNOTHERAPIES, business.industry, Cancer, medicine.disease, R1, Oncolytic virus, Immunology, business
Abstract: © 2014. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited., During the past decades, anticancer immunotherapy has evolved from a promising therapeutic option to a robust clinical reality. Many immunotherapeutic regimens are now approved by the US Food and Drug Administration and the European Medicines Agency for use in cancer patients, and many others are being investigated as standalone therapeutic interventions or combined with conventional treatments in clinical studies. Immunotherapies may be subdivided into "passive" and "active" based on their ability to engage the host immune system against cancer. Since the anticancer activity of most passive immunotherapeutics (including tumor-targeting monoclonal antibodies) also relies on the host immune system, this classification does not properly reflect the complexity of the drug-host-tumor interaction. Alternatively, anticancer immunotherapeutics can be classified according to their antigen specificity. While some immunotherapies specifically target one (or a few) defined tumor-associated antigen(s), others operate in a relatively non-specific manner and boost natural or therapy-elicited anticancer immune responses of unknown and often broad specificity. Here, we propose a critical, integrated classification of anticancer immunotherapies and discuss the clinical relevance of these approaches.
Published: 2014

42. Structure, recognition and adaptive binding in RNA aptamer complexes

Author: Licong Jiang, Asif K Suri, Sylvie Nonin, Dinshaw J. Patel, Feng Jiang, R. Ajay Kumar, Pei Fan, Cibles Thérapeutiques et conception de médicaments (CiTCoM - UMR 8038), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Memorial Sloan Kettering Cancer Center (MSKCC), and Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)
Subjects: Riboswitch, Models, Molecular, Magnetic Resonance Spectroscopy, Stereochemistry, Flavin Mononucleotide, Aptamer, Oligonucleotides, Flavin mononucleotide, 010402 general chemistry, Arginine, 01 natural sciences, Cofactor, 03 medical and health sciences, chemistry.chemical_compound, Molecular recognition, Structural Biology, Nucleic acid structure, amino acid and aminoglycoside antibiotic ligands, Molecular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, biology, sequence speci®c recognition and discrimination, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], RNA aptamer complexes, RNA, Proteins, cofactor, Adenosine Monophosphate, 0104 chemical sciences, Amino acid, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Biochemistry, chemistry, biology.protein, Tobramycin, Citrulline, Nucleic Acid Conformation, NMR based solution structures
Abstract: International audience; Novel features of RNA structure, recognition and discrimination have been recently elucidated through the solution structural characterizion of RNA aptamers that bind cofactors, aminoglycoside antibiotics, amino acids and peptides with high af®nity and speci®city. This review presents the solution structures of RNA aptamer complexes with adenosine monophosphate,¯avin mononucleotide, arginine/citrulline and tobramycin together with an example of hydrogen exchange measurements of the base-pair kinetics for the AMP-RNA aptamer complex. A comparative analysis of the structures of these RNA aptamer complexes yields the principles, patterns and diversity associated with RNA architecture, molecular recognition and adaptive binding associated with complex formation.
Published: 1997
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43. Additional Hydrogen Bonds and Base-Pair Kinetics in the Symmetrical AMP-DNA Aptamer Complex

Author: Sylvie Nonin-Lecomte, Chin H. Lin, Dinshaw J. Patel, Cibles Thérapeutiques et conception de médicaments (CiTCoM - UMR 8038), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Memorial Sloan Kettering Cancer Center (MSKCC), Laboratoire de cristallographie et RMN biologiques (LCRB - UMR 8015), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)
Subjects: Magnetic Resonance Spectroscopy, Time Factors, Base pair, Aptamer, Molecular Sequence Data, Biophysics, 010402 general chemistry, Ligands, 01 natural sciences, Phosphates, 03 medical and health sciences, Nuclear magnetic resonance, Binding site, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Binding Sites, Base Sequence, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Chemistry, Ligand, Hydrogen bond, Hydrogen Bonding, Nuclear magnetic resonance spectroscopy, DNA, Acceptor, Adenosine Monophosphate, 3. Good health, 0104 chemical sciences, Dissociation constant, Crystallography, Kinetics, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Models, Chemical, RNA, Protons, Research Article
Abstract: International audience; The solution structure of an adenosine monophosphate (AMP)-DNA aptamer complex has been determined previously [Lin, C. H., and Patel, D.J. (1997) Chem. Biol. 4:817-832]. On a symmetrical aptamer complex containing the same binding loop, but with better resolved spectra, we have identified two additional hydrogen bond-mediated associations in the binding loop. One of these involves a rapidly exchanging G imino proton. The phosphate group of the AMP ligand was identified as the acceptor by comparison with other aptamer complexes. Imino proton exchange measurements also yielded the dissociation constants of the stem and binding loop base pairs. This study shows that nuclear magnetic resonance-based imino proton exchange is a good probe for detection of weak hydrogen-bond associations.
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44. Role of SUMO-1-modified PML in nuclear body formation

Author: Stefan Müller, Simona Ronchetti, Paul S. Freemont, Pier Paolo Pandolfi, Anne Dejean, Sue Zhong, Biologie moléculaire des infections virales et cancérologie [Paris], Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Memorial Sloan Kettering Cancer Center (MSKCC), Cornell University [New York], Supported by the National Cancer Institute (CA-08748, CA-71692, and CA74031 awarded to P.P.P.). S.M. was supported by a fellowship from the Association for International Cancer Research. S.R. was partially supported by Centro Nazionale per la Ricerca. P.P.P. is a Scholar of the Leukemia Society of America., and Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: MESH: Neoplasm Proteins, Exonucleases, Keratinocytes, viruses, [SDV]Life Sciences [q-bio], Apoptosis, Promyelocytic Leukemia Protein, Biochemistry, Autoantigens, MESH: Recombinant Proteins, Mice, 0302 clinical medicine, MESH: Promyelocytic Leukemia Protein, MESH: Animals, Lymphocytes, Nuclear protein, Cells, Cultured, Protein PML, Genetics, 0303 health sciences, MESH: Exonucleases, Intracellular Signaling Peptides and Proteins, virus diseases, Nuclear Proteins, Antigens, Nuclear, Hematology, Transfection, MESH: Transcription Factors, MESH: Keratinocytes, Recombinant Proteins, Cell biology, Neoplasm Proteins, MESH: Mutagenesis, Site-Directed, medicine.anatomical_structure, MESH: Autoantigens, 030220 oncology & carcinogenesis, embryonic structures, MESH: Exoribonucleases, MESH: Molecular Chaperones, Co-Repressor Proteins, MESH: Cells, Cultured, Acute promyelocytic leukemia, MESH: Cell Nucleus, Immunology, SUMO-1 Protein, MESH: Co-Repressor Proteins, MESH: Carrier Proteins, Biology, 03 medical and health sciences, Promyelocytic leukemia protein, Death-associated protein 6, MESH: Intracellular Signaling Peptides and Proteins, medicine, MESH: Ubiquitins, Animals, MESH: Tumor Suppressor Proteins, MESH: Antigens, Nuclear, MESH: Mice, Ubiquitins, 030304 developmental biology, Cell Nucleus, MESH: Apoptosis, MESH: SUMO-1 Protein, Tumor Suppressor Proteins, Cell Biology, Fibroblasts, medicine.disease, Cell nucleus, MESH: Fibroblasts, Exoribonucleases, biology.protein, Mutagenesis, Site-Directed, MESH: Lymphocytes, Carrier Proteins, MESH: Nuclear Proteins, Nuclear localization sequence, Molecular Chaperones, Transcription Factors
Abstract: The tumor-suppressive promyelocytic leukemia (PML) protein of acute promyelocytic leukemia (APL) has served as one of the defining components of a class of distinctive nuclear bodies (NBs). PML is delocalized from NBs in APL cells and is degraded in cells infected by several viruses. In these cells, NBs are disrupted, leading to the aberrant localization of NB proteins. These results have suggested a critical role for the NB in immune response and tumor suppression and raised the question of whether PML is crucial for the formation or stability of NB. In addition, PML is, among other proteins, covalently modified by SUMO-1. However, the functional relevance of this modification is unclear. Here, we show in primary PML(-/-) cells of various histologic origins, that in the absence of PML, several NB proteins such as Sp100, CBP, ISG20, Daxx, and SUMO-1 fail to accumulate in the NB and acquire aberrant localization patterns. Transfection of PML in PML(-/-) cells causes the relocalization of NB proteins. By contrast, a PML mutant that can no longer be modified by SUMO-1 fails to do so and displays an aberrant nuclear localization pattern. Therefore, PML is required for the proper formation of the NB. Conjugation to SUMO-1 is a prerequisite for PML to exert this function. These data shed new light on both the mechanisms underlying the formation of the NBs and the pathogenesis of APL. (Blood. 2000;95:2748-2752)
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45. Editorial Expression of Concern: Identification of DNA hypermethylation of SOX9 in association with bladder cancer progression using CpG microarrays.

Author: Aleman A, Adrien L, Lopez-Serra L, Cordon-Cardo C, Esteller M, Belbin TJ, and Sanchez-Carbayo M
Published: 2024
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46. Real-world treatment patterns and outcomes in patients with HR+/HER2- metastatic breast cancer treated with chemotherapy in the United States.

Author: Tolaney SM, Punie K, Carey LA, Kurian AW, Ntalla I, Sjekloca N, Shah A, Rehnquist MK, Stokes M, Fraeman K, Verret W, and Jhaveri K
Subjects: Humans, Female, Middle Aged, Retrospective Studies, Aged, United States, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Treatment Outcome, Receptors, Estrogen metabolism, Receptors, Progesterone metabolism, Neoplasm Metastasis, Progression-Free Survival, Capecitabine therapeutic use, Capecitabine pharmacology, Polyether Polyketides, Furans, Ketones, Breast Neoplasms drug therapy, Breast Neoplasms pathology, Breast Neoplasms mortality, Receptor, ErbB-2 metabolism
Abstract: Background: Until recently, treatment options for patients with hormone receptor-positive/human epidermal growth factor 2-negative (HR+/HER2-) metastatic breast cancer (mBC) and resistance to endocrine therapy were limited to chemotherapy. This real-world study describes treatment patterns and outcomes in patients treated with chemotherapy in the United States before approval of antibody-drug conjugates., Patients and Methods: This retrospective, observational study included adults with HR+/HER2- mBC from the ConcertAI Patient360™ Breast Cancer dataset who initiated their first chemotherapy in the metastatic setting between January 2011 and June 2021. Treatment patterns were described; real-world overall survival, time to next treatment or death, and real-world progression-free survival were evaluated for all eligible patients and patients treated with subsequent chemotherapy. Index dates were the start date of each chemotherapy treatment., Results: Among 1545 eligible patients, 76% were white, 12% had Eastern Cooperative Oncology Group performance status ≥2, 38% had de novo mBC, and median age was 61 years (range, 52-69 years). Within the index period, capecitabine was used the most as the first chemotherapy agent and decreased in later treatments, while the use of eribulin increased between first and fourth chemotherapies. Median (95% confidence interval) real-world overall survival was 23.3 months (21.3-25.4 months) from start of first chemotherapy, time to next treatment or death was 6.5 months (5.9-7.1 months), and real-world progression-free survival was 6.9 months (6.4-7.6 months); median times from second, third, and fourth chemotherapies decreased with each additional chemotherapy treatment., Conclusions: This real-world study demonstrates that for patients with HR+/HER2- mBC, chemotherapy provides relatively limited survival benefit which decreases with each additional chemotherapy line, and highlights the need for improved treatment options., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Published: 2024
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47. Broad-spectrum antibiotics disrupt homeostatic efferocytosis.

Author: Saavedra PHV, Trzeciak AJ, Lipshutz A, Daman AW, O'Neal AJ, Liu ZL, Wang Z, Romero-Pichardo JE, Rojas WS, Zago G, van den Brink MRM, Josefowicz SZ, Lucas CD, Anderson CJ, Rudensky AY, and Perry JSA
Subjects: Animals, Mice, Humans, Butyrates pharmacology, Macrophages, Peritoneal metabolism, Macrophages, Peritoneal drug effects, Apoptosis drug effects, Macrophages metabolism, Macrophages drug effects, Gastrointestinal Microbiome drug effects, Mice, Inbred C57BL, Membrane Proteins metabolism, Membrane Proteins genetics, Efferocytosis, Homeostasis, Phagocytosis drug effects, Anti-Bacterial Agents pharmacology
Abstract: The clearance of apoptotic cells, termed efferocytosis, is essential for tissue homeostasis and prevention of autoimmunity 1 . Although past studies have elucidated local molecular signals that regulate homeostatic efferocytosis in a tissue 2,3 , whether signals arising distally also regulate homeostatic efferocytosis remains elusive. Here, we show that large peritoneal macrophage (LPM) display impairs efferocytosis in broad-spectrum antibiotics (ABX)-treated, vancomycin-treated and germ-free mice in vivo, all of which have a depleted gut microbiota. Mechanistically, the microbiota-derived short-chain fatty acid butyrate directly boosts efferocytosis efficiency and capacity in mouse and human macrophages, and rescues ABX-induced LPM efferocytosis defects in vivo. Bulk messenger RNA sequencing of butyrate-treated macrophages in vitro and single-cell messenger RNA sequencing of LPMs isolated from ABX-treated and butyrate-rescued mice reveals regulation of efferocytosis-supportive transcriptional programmes. Specifically, we find that the efferocytosis receptor T cell immunoglobulin and mucin domain containing 4 (TIM-4, Timd4) is downregulated in LPMs of ABX-treated mice but rescued by oral butyrate. We show that TIM-4 is required for the butyrate-induced enhancement of LPM efferocytosis capacity and that LPM efferocytosis is impaired beyond withdrawal of ABX. ABX-treated mice exhibit significantly worse disease in a mouse model of lupus. Our results demonstrate that homeostatic efferocytosis relies on distal metabolic signals and suggest that defective homeostatic efferocytosis may explain the link between ABX use and inflammatory disease 4-7 ., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
Published: 2024
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48. Current unmet needs in locally advanced (unresectable) or metastatic dedifferentiated liposarcoma, the relevance of progression-free survival as clinical endpoint, and expectations for future clinical trial design: an international Delphi consensus report.

Author: Schöffski P, Jones RL, Agulnik M, Blay JY, Chalmers A, Italiano A, Pink D, Stacchiotti S, Valverde C, Vincenzi B, Wagner MJ, and Maki R
Subjects: Humans, Clinical Trials as Topic, Europe, Research Design, Liposarcoma therapy, Liposarcoma mortality, Liposarcoma pathology, Delphi Technique, Progression-Free Survival, Consensus
Abstract: Background: Locally advanced (unresectable) or metastatic dedifferentiated liposarcoma (DDLPS) is a common presentation of liposarcoma. Despite established diagnostic and treatment guidelines for DDLPS, critical clinical gaps remain driven by diagnostic challenges, symptom burden and the lack of targeted, safe and effective treatments. The objective of this study was to gather expert opinions from Europe and the United States on the management, unmet needs and expectations for clinical trial design as well as the value of progression-free survival (PFS) in this disease. Other aims included raising awareness and educate key stakeholders across healthcare systems., Materials and Methods: An international panel of 12 sarcoma key opinion leaders (KOLs) was recruited. The study consisted of two rounds of surveys with pre-defined statements. Experts scored each statement on a 9-point Likert scale. Consensus agreement was defined as ≥75% of experts scoring a statement with ≥7. Revised statements were discussed in a consensus meeting., Results: Consensus was reached on 43 of 55 pre-defined statements across disease burden, treatment paradigm, unmet needs, value of PFS and its association with overall survival (OS), and cross-over trial design. Twelve statements were deprioritised or merged with other statements. There were no statements where experts disagreed., Conclusion: This study constitutes the first international Delphi panel on DDLPS. It aimed to explore KOL perception of the disease burden and unmet need in DDLPS, the value of PFS, and its potential translation to OS benefit, as well as the relevance of a cross-over trial design for DDLPS therapies. Results indicate an alignment across Europe and the United States regarding DDLPS management, unmet needs, and expectations for clinical trials. Raising awareness of critical clinical gaps in relation to DDLPS can contribute to improving patient outcomes and supporting the development of innovative treatments., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Published: 2024
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49. Body mass index and adiposity influence responses to immune checkpoint inhibition in endometrial cancer.

Author: Gómez-Banoy N, Ortiz E, Jiang CS, Dagher C, Sevilla C, Girshman J, Pagano A, Plodkowski A, Zammarrelli WA, Mueller JJ, Aghajanian C, Weigelt B, Makker V, Cohen P, and Osorio JC
Abstract: Background: Obesity is the foremost risk factor in the development of endometrial cancer (EC). However, the impact of obesity on the response to immune checkpoint inhibitors (ICI) in EC remains poorly understood. This retrospective study investigates the association between body mass index (BMI), body fat distribution, and clinical and molecular characteristics of EC patients treated with ICI., Methods: We analyzed progression-free survival (PFS) and overall survival (OS) in EC patients treated with ICI, categorized by BMI, fat mass distribution, and molecular subtypes. Incidence of immune-related adverse events (irAE) after ICI was also assessed based on BMI status., Results: 524 EC patients were included in the study. Overweight and obese patients exhibited a significantly prolonged PFS and OS compared to normal BMI patients after treatment with ICI. Multivariable Cox regression analysis confirmed the independent association of overweight and obesity with improved PFS and OS. Elevated visceral adipose tissue (VAT) was identified as a strong independent predictor for improved PFS to ICI. Associations between obesity and OS/PFS were particularly significant in the copy number-high/ TP53 abnormal (CN-H/ TP53 abn) EC molecular subtype. Finally, obese patients demonstrated a higher irAE rate compared to normal BMI individuals., Conclusion: Obesity is associated with improved outcomes to ICI in EC patients and a higher rate of irAEs. This association is more pronounced in the CN-H/ TP53 abn EC molecular subtype., Funding: NIH/NCI Cancer Center Support Grant P30CA008748 (MSK). K08CA266740 and MSK Gerstner Physician Scholars Program (J.C.O). RUCCTS Grant #UL1 TR001866 (N.G-B and C.S.J). Cycle for survival and Breast Cancer Research Foundation grants (B.W).
Published: 2024
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50. Author Correction: T cell-encoded CD80 and 4-1BBL induce auto- and transcostimulation, resulting in potent tumor rejection.

Author: Stephan MT, Ponomarev V, Brentjens RJ, Chang AH, Dobrenkov KV, Heller G, and Sadelain M
Published: 2024
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