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1. Exogenous and Endogenous Risk Factors for Early-onset Colorectal Cancer (DEMETRA)

Author: Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy, Ospedale Civile Guglielmo da Saliceto, Piacenza, Italy, Centro di Riferimento Oncologico di Aviano, Aviano, Italy, Azienda Ospedaliero-Universitaria Consorziale Policlinico di Bari, Bari, Italy, Gastroenterology Unit, University Hospital of Padova, Padova, Italy, Clinical Gastroenterology Unit, Azienda Ospedaliero Universitaria Careggi, Firenze, Italy, IRCCS Arcispedale S. Maria Nuova - Azienda Ospedaliera di Reggio Emilia, Reggio Emilia, Italy, Azienda Ospedaliera San Gerardo di Monza, Monza, Italy, Azienda ULSS5 Polesana, Rovigo, Italy, Istituto Tumori Regina Elena - IRCCS IFO, Roma, Italy, University Hospital of Padova, Padova, Italy, IRCCS De Bellis, Castellana Grotte, Italy, University Hospital HELIOS Klinikum Wuppertal, Center for Hereditary Tumors, University of Witten-Herdecke, Wuppertal, Germany, Hospital of the University of Munich (LMU), Campus Großhadern, Munich, Germany, Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Spain, Helsinki University Hospital, Helsinki, Finland, Oslo University Hospital (OUS), Institute for Cancer Genetics and Informatics Norwegian Radium Hospital, Oslo, Norway, Department of Medicine University of Chicago Medicine, Illinois, USA, University of Colorado Hospital, CO, USA, University of Michigan Ann Arbor, Michigan, USA, Columbia University Irving Medical Center, New York, NY, The James Comprehensive Cancer Center, Columbus, OH, USA, Ohio State University, Cleveland Clinic Main Campus, Cleveland, OH, USA, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia, and Cavestro Giulia Martina MD PhD, Prof Cavestro Giulia Martina
Published: 2023

2. Pembrolizumab Plus Pemetrexed and Platinum in Nonsquamous Non–Small-Cell Lung Cancer: 5-Year Outcomes From the Phase 3 KEYNOTE-189 Study

Author: Marina C. Garassino, Shirish Gadgeel, Giovanna Speranza, Enriqueta Felip, Emilio Esteban, Manuel Dómine, Maximilian J. Hochmair, Steven F. Powell, Helge G. Bischoff, Nir Peled, Francesco Grossi, Ross R. Jennens, Martin Reck, Rina Hui, Edward B. Garon, Takayasu Kurata, Jhanelle E. Gray, Paul Schwarzenberger, Erin Jensen, M. Catherine Pietanza, Delvys Rodríguez-Abreu, Institut Català de la Salut, [Garassino MC] Knapp Center for Biomedical Discovery, University of Chicago Medicine & Biological Sciences, Chicago, IL. Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. [Gadgeel S] Henry Ford Cancer Institute/Henry Ford Health, Detroit, MI. [Speranza G] Centre Integré de Cancérologie de la Montérégie, Hôpital Charles-Le Moyne, Greenfield Park, QC, Canada. [Felip E] Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Esteban E] Department of Medical Oncology, Hospital Universitario Central de Asturias, Oviedo, Spain. [Dómine M] Department of Oncology, Hospital Universitario Fundación Jiménez Díaz, IIS-FJD, Madrid, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Cancer Research, Oncology, Otros calificadores::/uso terapéutico [Otros calificadores], Therapeutics::Therapeutics::Drug Therapy::Antineoplastic Protocols::Therapeutics::Drug Therapy::Antineoplastic Combined Chemotherapy Protocols [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], terapéutica::terapéutica::farmacoterapia::protocolos antineoplásicos::terapéutica::farmacoterapia::protocolos de quimioterapia antineoplásica combinada [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Medicaments antineoplàstics - Ús terapèutic, Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], Other subheadings::/therapeutic use [Other subheadings], Neoplasms::Neoplasms by Site::Thoracic Neoplasms::Respiratory Tract Neoplasms::Lung Neoplasms::Bronchial Neoplasms::Carcinoma, Bronchogenic::Carcinoma, Non-Small-Cell Lung [DISEASES], neoplasias::neoplasias por localización::neoplasias torácicas::neoplasias del tracto respiratorio::neoplasias pulmonares::neoplasias de los bronquios::carcinoma broncogénico::carcinoma de pulmón de células no pequeñas [ENFERMEDADES], Other subheadings::Other subheadings::/drug therapy [Other subheadings], Pulmons - Càncer - Tractament
Abstract: Pembrolizumab; Non-small-cell lung cancer Pembrolizumab; Cáncer de pulmón de células no pequeñas Pembrolizumab; Càncer de pulmó de cèl·lules no petites Clinical trials frequently include multiple end points that mature at different times. The initial report, typically on the based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We present 5-year outcomes from the phase 3 KEYNOTE-189 study (ClinicalTrials.gov identifier: NCT02578680). Eligible patients with previously untreated metastatic nonsquamous non-small-cell lung cancer without EGFR/ALK alterations were randomly assigned 2:1 to pembrolizumab 200 mg or placebo once every 3 weeks for up to 35 cycles with pemetrexed and investigator's choice of carboplatin/cisplatin for four cycles, followed by maintenance pemetrexed until disease progression or unacceptable toxicity. Primary end points were overall survival (OS) and progression-free survival (PFS). Among 616 randomly assigned patients (n = 410, pembrolizumab plus pemetrexed-platinum; n = 206, placebo plus pemetrexed-platinum), median time from random assignment to data cutoff (March 8, 2022) was 64.6 (range, 60.1-72.4) months. Hazard ratio (95% CI) for OS was 0.60 (0.50 to 0.72) and PFS was 0.50 (0.42 to 0.60) for pembrolizumab plus platinum-pemetrexed versus placebo plus platinum-pemetrexed. 5-year OS rates were 19.4% versus 11.3%. Toxicity was manageable. Among 57 patients who completed 35 cycles of pembrolizumab, objective response rate was 86.0% and 3-year OS rate after completing 35 cycles (approximately 5 years after random assignment) was 71.9%. Pembrolizumab plus pemetrexed-platinum maintained OS and PFS benefits versus placebo plus pemetrexed-platinum, regardless of programmed cell death ligand-1 expression. These data continue to support pembrolizumab plus pemetrexed-platinum as a standard of care in previously untreated metastatic non-small-cell lung cancer without EGFR/ALK alterations.
Published: 2023

3. Design Considerations for Clinical Trials of Autonomic Modulation Therapies Targeting Hypertension and Heart Failure

Author: Kenneth M. Stein, Felix Mahfoud, Robert S. Kieval, Gaetano M. De Ferrari, Hermann Haller, Ileana L. Piña, Nadim Yared, Faiez Zannad, Sverre E. Kjeldsen, George L. Bakris, Michel Azizi, Wendy Gattis Stough, Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), College of Pharmacy and Health Sciences [Campbell University], Campbell University College, Universitätsklinikum des Saarlandes, Institute of Medical Engineering and Science [Cambridge] (IMES), Massachusetts Institute of Technology (MIT), ASH Comprehensive Hypertension Center [The University of Chicago Medicine], The University of Chicago Medicine [Chicago], Oslo University Hospital [Oslo], Institute of Clinical Medicine [Oslo], Faculty of Medicine [Oslo], University of Oslo (UiO)-University of Oslo (UiO), CVRx, Inc., Medizinische Hochschule Hannover (MHH), Fondazione IRCCS Policlinico San Matteo [Pavia], Università di Pavia, Montefiore-Einstein Cancer Center, Boston Scientific, 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), CIC AP-HP (hegp Ex-Broussais)/inserm, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Università degli Studi di Pavia = University of Pavia (UNIPV), Centre d'investigation clinique plurithématique Pierre Drouin (CIC-P), Fondazione IRCCS Policlinico San Matteo, and Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)
Subjects: medicine.medical_specialty, Baroreceptor, MESH: Clinical Trials as Topic, Pressoreceptors, Spinal cord stimulation, 030204 cardiovascular system & hematology, Pharmacology, Autonomic Nervous System, MESH: Hypertension, MESH: Autonomic Nervous System, MESH: Pressoreceptors, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal Medicine, medicine, Humans, 030212 general & internal medicine, Intensive care medicine, ComputingMilieux_MISCELLANEOUS, Pharmaceutical industry, Heart Failure, Clinical Trials as Topic, MESH: Humans, business.industry, medicine.disease, 3. Good health, Clinical trial, Autonomic nervous system, Blood pressure, Heart failure, Hypertension, MESH: Heart Failure, Autonomic modulation, business
Abstract: Several device-based approaches to autonomic nervous system modulation are under investigation for the treatment of resistant hypertension and heart failure (Table 1).1 This line of research has evolved from the recognition that these diseases originate or are worsened by excess sympathetic activity and loss of parasympathetic tone.9–13 Drug therapies, including β-blockers, α-blockers, and centrally acting antihypertensive drugs, can modulate these neurohormonal systems, but they are often insufficient to control blood pressure (BP) or are limited by side effects or nonadherence. Technological innovations have produced devices that modulate the autonomic nervous system, including renal denervation, carotid baroreceptor stimulation, vagal nerve stimulation, and spinal cord stimulation. View this table: Table 1. Select Completed and Ongoing Clinical Trials of Autonomic Modulation Therapies in Hypertension and Heart Failure In Europe, several autonomic modulation therapy devices have received the Conformite Europeenne mark.14 US Food and Drug Administration evaluation of these devices is ongoing. The need for adequately powered, randomized, controlled studies with longer follow-up to capture definitive evidence of safety and effectiveness has been noted.14–17 The 9th and 10th Global Cardiovascular Clinical Trialists Forum (Paris, France, December 2012 and December 2013) convened a panel of primary investigators of ongoing trials, along with biostatisticians, National Institutes of Health scientists, European, and United States regulators, and medical device and pharmaceutical industry scientists to discuss the strengths and limitations of current clinical trials, optimal designs for future trials, approvability of new devices, and considerations for integrating these technologies into practice. This article summarizes the key discussion points and identifies knowledge gaps in this field that need to be addressed by additional research. The mechanisms of autonomic modulation are complex, and a comprehensive review of these mechanisms is outside the scope of this article. Briefly, all existing strategies aim to decrease central sympathetic outflow. Renal …
Published: 2014

4. Evaluation of flow of chorioretinal capillaries in healthy black and white subjects using optical coherence tomography angiography

Author: Nathalie Massamba, Lindsay Chun, Bahram Bodaghi, Sarah Hilkert Rodriguez, Seenu M. Hariprasad, Anna Mackin, Dimitra Skondra, Rose C. Dimitroyannis, Institut de la Vision, Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and The University of Chicago Medicine [Chicago]
Subjects: Adult, Male, Fovea Centralis, medicine.medical_specialty, genetic structures, Science, Black People, Article, White People, Perimeter, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Foveal, Ophthalmology, Retinal capillary, medicine, Humans, Prospective Studies, Fluorescein Angiography, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, 030304 developmental biology, 0303 health sciences, Multidisciplinary, Choroid, business.industry, Significant difference, Parafovea, Retinal Vessels, Diagnostic markers, Optical coherence tomography angiography, Blood flow, Foveal avascular zone, Healthy Volunteers, Capillaries, Cross-Sectional Studies, Vision disorders, Regional Blood Flow, 030221 ophthalmology & optometry, Medicine, Female, business, Tomography, Optical Coherence
Abstract: This study compared macular capillary parameters between healthy black and white subjects using optical coherence tomography angiography (OCTA). We measured vessel density (VD) of superficial (SCP), intermediate (ICP), and deep (DCP) capillary plexuses and choriocapillaris blood flow area (BFA) of the fovea, parafovea and total 3 mm-diameter circular area centered on the fovea, as well as the foveal avascular zone (FAZ) parameters, controlling for axial length. Black subjects had lower foveal and parafoveal VD in the SCP (p = 0.043 and p = 0.014) and the ICP (p = 0.014 and p = 0.002). In the DCP, black subjects had a trend toward lower foveal and parafoveal VD. Black subjects had decreased choriocapillaris BFA in the total 3 mm area (p = 0.011) and the parafovea (p = 0.033), larger FAZ area (p = 0.006) and perimeter (p = 0.014), and a higher capillary density in a 300 μm wide region around the FAZ (FD-300) (p = 0.001). There was no significant difference in FAZ acircularity index. To our knowledge, this is the first report analyzing the three distinct retinal capillary plexuses and identifying differing baseline VD, choriocapillaris and FAZ parameters in healthy young black compared to white subjects. Larger studies are needed to validate these findings and better understand racial differences in vulnerability to ocular diseases.
Published: 2021

5. Genetic and physiological insights into the diazotrophic activity of a non‐cyanobacterial marine diazotroph

Author: Aurélie Joublin‐Delavat, Katia Touahri, Pauline Crétin, Amandine Morot, Sophie Rodrigues, Bruno Jesus, Florian Trigodet, François Delavat, Unité en Sciences Biologiques et Biotechnologies de Nantes (US2B), Centre National de la Recherche Scientifique (CNRS)-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), Institut de Chimie de Strasbourg, Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire des Sciences de l'Environnement Marin (LEMAR) (LEMAR), Institut de Recherche pour le Développement (IRD)-Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER)-Université de Brest (UBO)-Institut Universitaire Européen de la Mer (IUEM), Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Brest (UBO)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Brest (UBO)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biotechnologie et Chimie Marines (LBCM), Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Institut Universitaire Européen de la Mer (IUEM), Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Brest (UBO)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut Des Substances et Organismes de la Mer - UR 2160 (ISOMER), Nantes Université - UFR des Sciences Pharmaceutiques et Biologiques (Nantes Univ - UFR Pharmacie), Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes université - UFR des Sciences et des Techniques (Nantes univ - UFR ST), Nantes Université - pôle Sciences et technologie, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Sciences et technologie, Nantes Université (Nantes Univ), and The University of Chicago Medicine [Chicago]
Subjects: [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Nitrogen, Nitrogen Fixation, Oceans and Seas, Humans, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Noncommunicable Diseases, Cyanobacteria, Microbiology, Ecology, Evolution, Behavior and Systematics
Abstract: Nitrogen (N2) fixation, or diazotrophy, supports a large part of primary production in oceans. Culture-independent approaches highlighted the presence in abundance of marine non-cyanobacterial diazotrophs (NCD) but their ecophysiology remains elusive, mostly because of the low number of isolated NCD and because of the lack of available genetic tools for these isolates. Here, a dual genetic and functional approach allowed unveiling the ecophysiology of a marine NCD affiliated to the species Vibrio diazotrophicus. Physiological characterization of the first marine NCD mutant obtained so far was performed using a soft-gellan assay, demonstrating that a ΔnifH mutant in not able to grow in nitrogen-deprived media. Furthermore, we demonstrated that V. diazotrophicus produces a thick biofilm under diazotrophic conditions, suggesting biofilm production as an adaptive response of this NCD to cope with the inhibition of nitrogen-fixation by molecular oxygen. Finally, the genomic signature of V. diazotrophicus is essentially absent from metagenomic data of Tara Ocean expeditions, despite having been isolated from various marine environments. We think that the genetically tractable V. diazotrophicus strain used in this study may serve as an ideal model to study the ecophysiology of these overlooked procaryotic group.
Published: 2022

6. Mineralocorticoid receptor antagonists in diabetic kidney disease — mechanistic and therapeutic effects

Author: George L. Bakris, Jonatan Barrera-Chimal, Ixchel Lima-Posada, Frederic Jaisser, Universidad Nacional Autónoma de México (UNAM), Instituto Nacional de Cardiologia Ignacio Chavez, 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), The University of Chicago Medicine [Chicago], Centre d'investigation clinique [Nancy] (CIC), Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), and ANR-19-CE14-0032,Fly2HumanSPA,Dérégulations induites par le facteur de susceptibilité majeur à la spondyloarthrite HLA-B27 : de la drosophile aux cellules de patients(2019)
Subjects: 0303 health sciences, Finerenone, business.industry, [SDV]Life Sciences [q-bio], Therapeutic effect, Type 2 diabetes, Disease, 030204 cardiovascular system & hematology, Pharmacology, medicine.disease, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Mineralocorticoid receptor, Nephrology, medicine, Albuminuria, medicine.symptom, business, MRAS, 030304 developmental biology, Kidney disease
Abstract: International audience; Chronic kidney disease (CKD) is the leading complication in type 2 diabetes (T2D) and current therapies that limit CKD progression and the development of cardiovascular disease (CVD) include angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers and sodium–glucose co-transporter 2 (SGLT2) inhibitors. Despite the introduction of these therapeutics, an important residual risk of CKD progression and cardiovascular death remains in patients with T2D. Mineralocorticoid receptor antagonists (MRAs) are a promising therapeutic option in diabetic kidney disease (DKD) owing to the reported effects of mineralocorticoid receptor activation in inflammatory cells, podocytes, fibroblasts, mesangial cells and vascular cells. In preclinical studies, MRAs consistently reduce albuminuria, CKD progression, and activation of fibrotic and inflammatory pathways. DKD clinical studies have similarly demonstrated that steroidal MRAs lead to albuminuria reduction compared with placebo, although hyperkalaemia is a major secondary effect. Non-steroidal MRAs carry a lower risk of hyperkalaemia than steroidal MRAs, and the large FIDELIO-DKD clinical trial showed that the non-steroidal MRA finerenone also slowed CKD progression and reduced the risk of adverse cardiovascular outcomes compared with placebo in patients with T2D. Encouragingly, other non-steroidal MRAs have anti-albuminuric properties in DKD. Whether or not combining MRAs with other renoprotective drugs such as SGLT2 inhibitors might provide additive protective effects warrants further investigation.
Published: 2021

7. Body weight changes in patients with type 2 diabetes and a recent acute coronary syndrome: an analysis from the EXAMINE trial

Author: João Pedro Ferreira, Cyrus R. Mehta, Faiez Zannad, Patrick Rossignol, George L. Bakris, William B. White, Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), Faculdade de Medicina da Universidade do Porto (FMUP), Universidade do Porto, The University of Chicago Medicine [Chicago], Cytel Corportation, University of Connecticut (UCONN), The EXAMINE study was funded by Takeda but the present analysis did not receive funding, Universidade do Porto = University of Porto, and BOZEC, Erwan
Subjects: Male, Time Factors, Endocrinology, Diabetes and Metabolism, Weight changes, Type 2 diabetes, Comorbidity, 030204 cardiovascular system & hematology, Weight Gain, Body Mass Index, 0302 clinical medicine, Piperidines, Weight loss, Risk Factors, Medicine, Original Investigation, Randomized Controlled Trials as Topic, Incidence, Middle Aged, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3. Good health, Treatment Outcome, Female, medicine.symptom, Cardiology and Cardiovascular Medicine, Alogliptin, medicine.medical_specialty, Acute coronary syndrome, Cardiovascular outcomes, 030209 endocrinology & metabolism, Risk Assessment, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Diabetes mellitus, Weight Loss, Humans, Diseases of the circulatory (Cardiovascular) system, Acute Coronary Syndrome, Uracil, Aged, Dipeptidyl-Peptidase IV Inhibitors, business.industry, Proportional hazards model, medicine.disease, Diabetes Mellitus, Type 2, Heart failure, RC666-701, business, Weight gain
Abstract: Background Patients with type 2 diabetes (T2D) may experience frequent body weight changes over time. The prognostic impact of these weight changes (gains or losses) requires further study. Aims To study the associations between changes in body weight (intentional or unintentional) with subsequent outcomes. Methods The EXAMINE trial included 5380 patients with T2D and a recent acute coronary syndrome, who were randomized to alogliptin or placebo. Time-updated Cox models and mixed effects models were used to test the associations between changes in body weight and subsequent outcomes over a median follow-up of 1.6 (1.0–2.1) years. Results During the post-randomization follow-up period, 1044 patients (19.4%) experienced a weight loss ≥ 5% of baseline weight, 2677 (49.8%) had a stable weight, and 1659 (30.8%) had a ≥ 5 % weight gain. Patients with weight loss were more frequently women and had more co-morbid conditions. In contrast, patients who gained ≥ 5% weight were more frequently men with less co-morbid conditions. A weight loss ≥ 5% was independently associated with a higher risk of subsequent adverse outcomes, including all-cause mortality: adjusted HR (95% CI) = 1.79 (1.33–2.42), P Conclusions In patients with T2D who had a recent ACS/MI, a ≥ 5% loss of body weight was associated with a higher risk of subsequent cardiovascular events and mortality.
Published: 2021

8. International consensus on the prevention of venous and arterial thrombotic events in patients with inflammatory bowel disease

Author: Tim Raine, Siew C. Ng, Edouard Louis, David T. Rubin, Peter Bossuyt, Fernando Magro, Laurent Peyrin-Biroulet, Subrata Ghosh, Silvio Danese, Paulo Gustavo Kotze, Véronique Regnault, Fábio Vieira Teixeira, Patrick Lacolley, Alfredo Papa, Taku Kobayashi, Stéphane Zuily, Richard B. Gearry, Sameer Al Awadhi, Pablo Olivera, Zuily, Stephane [0000-0002-9326-6881], Kotze, Paulo G [0000-0002-9632-6691], Bossuyt, Peter [0000-0003-4027-7365], Ghosh, Subrata [0000-0002-1713-7797], Kobayashi, Taku [0000-0002-2073-4234], Ng, Siew C [0000-0002-6850-4454], Papa, Alfredo [0000-0002-4186-7298], Raine, Tim [0000-0002-5855-9873], Rubin, David T [0000-0001-5647-1723], Danese, Silvio [0000-0001-7341-1351], Peyrin-Biroulet, Laurent [0000-0003-2536-6618], Apollo - University of Cambridge Repository, Centro de Educación Médica e Investigaciones Clínicas (CEMIC), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Pontifical Catholic University of Paraná (PUCPR), Pontifical Catholic University of Paraná, Rashid Hospital, Imelda General Hospital, University of Otago [Dunedin, Nouvelle-Zélande], University of Birmingham [Birmingham], Kitasato University, NIHR Biomedical Research Centre [London], Guy's and St Thomas' NHS Foundation Trust-King‘s College London, Centre Hospitalier Universitaire de Liège (CHU-Liège), Hospital de São João [Porto], The Chinese University of Hong Kong [Hong Kong], Fondazione 'Policlinico Universitario A. Gemelli' [Rome], Cambridge University Hospitals - NHS (CUH), University of Cambridge [UK] (CAM), The University of Chicago Medicine [Chicago], Istituto Clinico Humanitas [Milan] (IRCCS Milan), Humanitas University [Milan] (Hunimed), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)
Subjects: Evidence-Based Guidelines, medicine.medical_specialty, [SDV]Life Sciences [q-bio], International Cooperation, Settore MED/12 - GASTROENTEROLOGIA, education, Anti-Inflammatory Agents, MEDLINE, 030204 cardiovascular system & hematology, Risk Assessment, Inflammatory bowel disease, 03 medical and health sciences, 0302 clinical medicine, Fibrinolytic Agents, Risk Factors, Epidemiology, Humans, Medicine, In patient, Risk factor, Intensive care medicine, Hepatology, business.industry, Patient Acuity, Gastroenterology, Thrombosis, Guideline, Evidence-based medicine, Inflammatory Bowel Diseases, medicine.disease, digestive system diseases, 3. Good health, Hospitalization, Cardiovascular diseases, 030211 gastroenterology & hepatology, business
Abstract: Patients with inflammatory bowel disease (IBD) are at increased risk of thrombotic events. Therapies for IBD have the potential to modulate this risk. The aims of this Evidence-Based Guideline were to summarize available evidence and to provide practical recommendations regarding epidemiological aspects, prevention and drug-related risks of venous and arterial thrombotic events in patients with IBD. A virtual meeting took place in May 2020 involving 14 international IBD experts and 3 thrombosis experts from 12 countries. Proposed statements were voted upon in an anonymous manner. Agreement was defined as at least 75% of participants voting as ‘fully agree’ or ‘mostly agree’ with each statement. For each statement, the level of evidence was graded according to the Scottish Intercollegiate Guidelines Network (SIGN) grading system. Consensus was reached for 19 statements. Patients with IBD harbour an increased risk of venous and arterial thrombotic events. Thromboprophylaxis is indicated during hospitalization of any cause in patients with IBD. Disease activity is a modifiable risk factor in patients with IBD, and physicians should aim to achieve deep remission to reduce the risk. Exposure to steroids should be limited. Antitumour necrosis factor agents might be associated with a reduced risk of thrombotic events., Patients with inflammatory bowel disease (IBD) are at increased risk of thrombotic events. This Evidence-Based Guideline presents an international consensus on the prevention of venous and arterial thrombotic events in patients with IBD, and includes 19 recommendations for clinical practice.
Published: 2021

9. 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

10. Ustekinumab is more effective than azathioprine to prevent endoscopic postoperative recurrence in Crohn's disease

Author: Buisson, Anthony, Nancey, Stéphane, Manlay, Luc, Rubin, David, Hebuterne, Xavier, Pariente, Benjamin, Fumery, Mathurin, Laharie, David, Roblin, Xavier, Bommelaer, Gilles, Pereira, Bruno, Peyrin‐biroulet, Laurent, Vuitton, Lucine, Post-Op Study Grp, Ustek, Service d'Hépatologie Gastro-entérologie [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Clermont Auvergne (UCA), Service d'Hépatogastroentérologie [CHU Lyon-Sud], Hospices Civils de Lyon (HCL), The University of Chicago Medicine [Chicago], Servcie Hépato-gastroentérolgie et Nutrition clinique [CHU Nice], Centre Hospitalier Universitaire de Nice (CHU Nice), Service Gastro-entérologie adulte – Maladies de l’appareil digestif [CHU Lille], CHU Lille, Service d'Hépato Gastroenterologie [CHU Amiens-Picardie], CHU Amiens-Picardie, Périnatalité et Risques Toxiques - UMR INERIS_I 1 (PERITOX), Institut National de l'Environnement Industriel et des Risques (INERIS)-Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Service Gastroentérologie [CHU Bordeaux], Centre Hospitalier Universitaire de Bordeaux (CHU Bordeaux), Service de Gastro-entérologie et Hépatologie [CHU Saint-Etienne], Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Unité de Biostatistiques [CHU Clermont-Ferrand], Direction de la recherche clinique et de l’innovation [CHU Clermont-Ferrand] (DRCI), Service d'Hépato-gastro-entérologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de Gastro-Entérologie [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), 'Francois Aupetit' Association (AFA CrohnRCH), CHU Clermont-Ferrand (DRCI), Centre Hospitalier Universitaire de Lille (CHU Lille), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de l'Environnement Industriel et des Risques, Service de gastroentérologie [CHU Saint-Etienne], and Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne)
Subjects: Adult, Male, medicine.medical_specialty, medicine.medical_treatment, Azathioprine, Antibodies, Monoclonal, Humanized, Gastroenterology, ustekinumab, law.invention, 03 medical and health sciences, 0302 clinical medicine, Crohn Disease, Gastrointestinal Agents, Randomized controlled trial, Recurrence, law, Internal medicine, Ustekinumab, Secondary Prevention, medicine, Clinical endpoint, Humans, postoperative recurrence, Propensity Score, Retrospective Studies, Crohn's disease, azathioprine, business.industry, Inflammatory Bowel Disease, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Bowel resection, medicine.disease, Control Groups, 3. Good health, Oncology, 030220 oncology & carcinogenesis, Cohort, Propensity score matching, Original Article, Female, 030211 gastroenterology & hepatology, business, Immunosuppressive Agents, medicine.drug
Abstract: International audience; Background: Preventing postoperative recurrence (POR) is a major concern in Crohn's disease (CD). While azathioprine is an option, no data is available on ustekinumab efficacy in this situation.Aims: We compared the effectiveness of ustekinumab versus azathioprine in preventing endoscopic POR in CD.Methods: We retrospectively collected data from all consecutive CD patients treated with ustekinumab after intestinal resection in 9 centers. The control group (azathioprine alone) was composed of patients who participated in a randomized controlled trial conducted in the same centers comparing azathioprine alone or in combination with curcumin. Propensity score analyses (inversed probability of treatment weighting = IPTW) were applied to compare the two groups. The primary endpoint was endoscopic POR (Rutgeerts' index ≥ i2) at 6 months.Results: Overall, 32 patients were included in the ustekinumab group and 31 in the azathioprine group. The propensity score analysis was adjusted on the main risk factors (smoking, fistulizing phenotype, prior bowel resection, resection length >30 cm and ≥2 biologics before surgery) and thiopurines or ustekinumab exposure prior to surgery making the two arms comparable (∣d∣ < 0.2). After IPTW, the rate of endoscopic POR at 6 months was lower in patients treated with ustekinumab compared to azathioprine (28.0% vs. 54.5%, p = 0.029). After IPTW, the rates of i2b-endoscopic POR (Rutgeerts' index ≥ i2b) and severe endoscopic POR (Rutgeerts' index ≥ i3) were 20.8% versus 42.5% (p = 0.066) and 16.9% versus 27.9% (p = 0.24), in the ustekinumab and azathioprine groups, respectively.Conclusion: Ustekinumab seemed to be more effective than azathioprine in preventing POR in this cohort of CD patients.
Published: 2021

11. Functional repertoire convergence of distantly related eukaryotic plankton lineages abundant in the sunlit ocean

Author: Tom O. Delmont, Morgan Gaia, Damien D. Hinsinger, Paul Frémont, Chiara Vanni, Antonio Fernandez-Guerra, A. Murat Eren, Artem Kourlaiev, Leo d'Agata, Quentin Clayssen, Emilie Villar, Karine Labadie, Corinne Cruaud, Julie Poulain, Corinne Da Silva, Marc Wessner, Benjamin Noel, Jean-Marc Aury, Colomban de Vargas, Chris Bowler, Eric Karsenti, Eric Pelletier, Patrick Wincker, Olivier Jaillon, Shinichi Sunagawa, Silvia G. Acinas, Peer Bork, Christian Sardet, Lars Stemmann, Magali Lescot, Marcel Babin, Gabriel Gorsky, Nigel Grimsley, Lionel Guidi, Pascal Hingamp, Stefanie Kandels, Daniele Iudicone, Hiroyuki Ogata, Stéphane Pesant, Matthew B. Sullivan, Fabrice Not, Karp-Boss Lee, Emmanuel Boss, Guy Cochrane, Michael Follows, Nicole Poulton, Jeroen Raes, Mike Sieracki, Sabrina Speich, Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), 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), Génomique Métabolique, Genoscope, Institut François Jacob, CEA, CNRS, Univ Evry, Université Paris-Saclay, Tara Oceans-GOSEE (FR2022), Centre for GeoGenetics, Natural History Museum of Denmark, Faculty of Science [Copenhagen], University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH)-Faculty of Science [Copenhagen], University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), The University of Chicago Medicine [Chicago], Life & Soft [Fontenay-aux-Roses], Génomique métabolique (UMR 8030), 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)-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), Station biologique de Roscoff (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie de l'ENS Paris (IBENS), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-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)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie physico-chimique (IBPC (FR_550)), BABIN, Marcel, Global Oceans Systems Ecology & Evolution - Tara Oceans (GOSEE), Université de Perpignan Via Domitia (UPVD)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Aix Marseille Université (AMU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Évry-Val-d'Essonne (UEVE)-Université de Toulon (UTLN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche pour le Développement (IRD [France-Nord])-Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay)-European Molecular Biology Laboratory (EMBL)-École Centrale de Nantes (Nantes Univ - ECN), Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Université australe du Chili, ANR-17-CE02-0012,ALGALVIRUS,Adaptations Génomique des Algues Marines aux Virus(2017), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Max Planck Institute for Marine Microbiology, Max-Planck-Gesellschaft, University of Copenhagen = Københavns Universitet (UCPH), Helmholtz Institute for Functional Marine Biodiversity at the University of Oldenburg (HIFMB), Carl Von Ossietzky Universität Oldenburg = Carl von Ossietzky University of Oldenburg (OFFIS), Tara Oceans Coordinators, Agencia Estatal de Investigación (España), Carl Von Ossietzky Universität Oldenburg, and Not, Fabrice
Subjects: [SDE] Environmental Sciences, functions, metagenomics, Tara Oceans, Planktonic eukaryotes, Genomics metagenomics, [SDE.BE] Environmental Sciences/Biodiversity and Ecology, anvi'o, evolution, [SDE]Environmental Sciences, genomics, anvi’o, ecology, [SDE.BE]Environmental Sciences/Biodiversity and Ecology, Conserve and sustainably use the oceans, seas and marine resources for sustainable development
Abstract: 18 pages, 4 figures, supplemental information https://doi.org/10.1016/j.xgen.2022.100123.-- Data and code availability: • All data our study generated are publicly available at http://www.genoscope.cns.fr/tara/. The link provides access to the 11 raw metagenomic co-assemblies, the FASTA files for 713 MAGs and SAGs, the ∼10 million protein-coding sequences (nucleotides, amino acids and gff format), and the curated DNA-dependent RNA polymerase genes (MAGs and SAGs and METdb transcriptomes). This link also provides access to the supplemental figures and the Supplemental material. Finally, code development within anvi’o for the BUSCO single copy core genes is available at https://github.com/merenlab/anvio. • Original code has been deposited at Zenodo and is publicly available. The accession number is listed in the key resources table. • Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request, Marine planktonic eukaryotes play critical roles in global biogeochemical cycles and climate. However, their poor representation in culture collections limits our understanding of the evolutionary history and genomic underpinnings of planktonic ecosystems. Here, we used 280 billion Tara Oceans metagenomic reads from polar, temperate, and tropical sunlit oceans to reconstruct and manually curate more than 700 abundant and widespread eukaryotic environmental genomes ranging from 10 Mbp to 1.3 Gbp. This genomic resource covers a wide range of poorly characterized eukaryotic lineages that complement long-standing contributions from culture collections while better representing plankton in the upper layer of the oceans. We performed the first, to our knowledge, comprehensive genome-wide functional classification of abundant unicellular eukaryotic plankton, revealing four major groups connecting distantly related lineages. Neither trophic modes of plankton nor its vertical evolutionary history could completely explain the functional repertoire convergence of major eukaryotic lineages that coexisted within oceanic currents for millions of years, Tara Oceans (which includes the Tara Oceans and Tara Oceans Polar Circle expeditions) would not exist without the leadership of the Tara Ocean Foundation and the continuous support of 23 institutes (https://oceans.taraexpeditions.org/). We thank the commitment of the following people and sponsors who made this singular expedition possible: CNRS (in particular Groupement de Recherche GDR3280 and the Research Federation for the Study of Global Ocean Systems Ecology and Evolution FR2022/Tara GOSEE), the European Molecular Biology Laboratory (EMBL), Genoscope/CEA, the French Ministry of Research and the French Governement ‘Investissement d’Avenir’ programs Oceanomics (ANR-11-BTBR-0008), FRANCE GENOMIQUE (ANR-10-INBS-09), ATIGE Genopole postdoctoral fellowship, HYDROGEN/ANR-14-CE23-0001, MEMO LIFE (ANR-10-LABX-54), PSL Research University (ANR-11-IDEX-0001-02) and EMBRC-France (ANR-10-INBS-02), Fund for Scientific Research—Flanders, VIB, Stazione Zoologica Anton Dohrn, UNIMIB, ANR (projects ALGALVIRUS ANR-17-CE02- 0012, PHYTBACK/ANR-2010-1709-01, POSEIDON/ANR-09-BLAN-0348, PROMETHEUS/ANR-09-PCS-GENM-217, TARA-GIRUS/ANR-09-PCS-GENM-218), EU FP7 (MicroB3/No. 287589, IHMS/HEALTH-F4-2010-261376), Genopole, CEA DRF Impulsion program, OCEANOMICS (project no. ANR-11-BTBR-0008), ERC Advanced Award Diatomic (grant agreement No 835067) to CB. The authors also thank Agnès B. and E. Bourgois, the Prince Albert II de Monaco Foundation, the Veolia Foundation, the EDF Foundation, Region Bretagne, Lorient Agglomeration, Worldcourier, Illumina, Serge Ferrari, and the Fonds Francais pour l'Environnement Mondial for support and commitment. [...] Part of the computations were performed using the platine, titane, and curie HPC machine provided through GENCI grants (t2011076389, t2012076389, t2013036389, t2014036389, t2015036389, and t2016036389, With the institutional support of the ‘Severo Ochoa Centre of Excellence’ accreditation (CEX2019-000928-S)
Published: 2022

12. Geographic Density and Uptake of Pre-exposure Prophylaxis (PrEP) Among Young Gay, Bisexual and Other Sexual Minority Men: A Global Positioning System (GPS) Study

Author: Yen Tyng Chen, Byoungjun Kim, Seann D. Regan, Denton Callander, Basile Chaix, Dustin T. Duncan, Columbia Mailman School of Public Health, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), The University of Chicago Medicine [Chicago], Columbia University [New York], Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), and HAL-SU, Gestionnaire
Subjects: Male, medicine.medical_specialty, Social Psychology, Sexual Behavior, HIV prevention, Gay bisexual, HIV Infections, Zip code, Sexual and Gender Minorities, 03 medical and health sciences, Pre-exposure prophylaxis, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Health care, medicine, Humans, 030212 general & internal medicine, Mobility, Original Paper, 030505 public health, business.industry, Public health, Spatial analysis, Public Health, Environmental and Occupational Health, 3. Good health, Sexual minority, Health psychology, Infectious Diseases, Geography, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Geographic Information Systems, Global Positioning System, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, 0305 other medical science, business, Geographic access, Demography
Abstract: The geographic availability of pre-exposure prophylaxis (PrEP) providers is one important factor that significantly affects PrEP uptake. While most previous studies have employed spatial accessibility in static residential neighborhood definitions or self-reported healthcare accessibility, we examined the associations of the objectively measured geographic density of PrEP services with current PrEP use, using global positioning system (GPS) among sexual minority men (SMM) in New York City. 250 HIV-negative SMM participated in a 2-week GPS monitoring (January 2017–January 2018). Geographic PrEP density was measured as total numbers of PrEP providers in (1) individual activity space defined as daily path area of GPS points, (2) residential street network buffers and (3) census tract and ZIP code of residential locations. Geographic PrEP density within GPS-based activity space was positively associated with current PrEP use (prevalence ratio for 50-m activity space = 1.10, 95% confidence interval: [1.02, 1.18]). PrEP provider counts in residential buffer areas and administrative neighborhoods were not associated with PrEP use. Although it is not generalizable beyond New York City, our finding suggests the importance of daily mobility pattern in HIV prevention and PrEP implementation strategies.
Published: 2021

13. Trained immunity, tolerance, priming and differentiation: distinct immunological processes

Author: Boris Novakovic, Andreas Schlitzer, Giuseppe Matarese, Zahi A. Fayad, Willem J. M. Mulder, Henk Stunnenberg, Andrew R. DiNardo, Niels P. Riksen, Joachim L. Schultze, Christine Stabell Benn, Joseph C. Sun, Eva Kaufmann, Shabaana A. Khader, Michael H. Sieweke, Siroon Bekkering, Stephanie Fanucchi, Luis B. Barreiro, Maziar Divangahi, Mihai G. Netea, Reinout van Crevel, Jordi Ochando, Peter Aaby, Shruti Naik, Leo A. B. Joosten, Triantafyllos Chavakis, Musa M. Mhlanga, Eicke Latz, David L. Williams, Jos W. M. van der Meer, Luke A. J. O'Neill, Ramnik J. Xavier, Nigel Curtis, Robert W. Sauerwein, Kate L. Jeffrey, Edward R. Sherwood, Elaine Fuchs, Sebastian Weis, Nargis Khan, Melanie Hamon, Raphael Duivenwoorden, Keiko Ozato, Simone J.C.F.M. Moorlag, Jorge Domínguez-Andrés, Frank L. van de Veerdonk, Precision Medicine, ICMS Core, McGill University Health Center [Montreal] (MUHC), Bandim Health Project, International Network for the Demographic Evaluation of Populations and Their Health (INDEPTH Network), Washington University in Saint Louis (WUSTL), The University of Chicago Medicine [Chicago], Radboud University Medical Center [Nijmegen], Technische Universität Dresden = Dresden University of Technology (TU Dresden), University of Melbourne, Baylor College of Medicine (BCM), Baylor University, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Eindhoven University of Technology [Eindhoven] (TU/e), University of Cape Town, Rockefeller University [New York], Chromatine et Infection - Chromatin and Infection, Institut Pasteur [Paris] (IP), Harvard Medical School [Boston] (HMS), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Institute of Experimental Endocrinology and Oncology (IEOS), National Research Council of Italy | Consiglio Nazionale delle Ricerche (CNR), New York University School of Medicine (NYU), New York University School of Medicine, NYU System (NYU)-NYU System (NYU), Trinity Biomedical Sciences Institute, School of Biochemistry & Immunology, National Institute of Child Health and Human Development [Bethesda], National Institutes of Health, Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], Universität Bonn = University of Bonn, 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), Biotechnology Center, and Center for Regenerative Therapies Dresden (CRTD), Max Delbrück Centrum für Molekulare Medizin (MDC), University of Southern Denmark (SDU), Radboud University [Nijmegen], Memorial Sloane Kettering Cancer Center [New York], Weill Medical College of Cornell University [New York], Jena University Hospital [Jena], East Tennessee State University (ETSU), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Massachusetts Institute of Technology (MIT), Divangahi, M., Aaby, P., Khader, S. A., Barreiro, L. B., Bekkering, S., Chavakis, T., van Crevel, R., Curtis, N., Dinardo, A. R., Dominguez-Andres, J., Duivenwoorden, R., Fanucchi, S., Fayad, Z., Fuchs, E., Hamon, M., Jeffrey, K. L., Khan, N., Joosten, L. A. B., Kaufmann, E., Latz, E., Matarese, G., van der Meer, J. W. M., Mhlanga, M., Moorlag, S. J. C. F. M., Mulder, W. J. M., Naik, S., Novakovic, B., O'Neill, L., Ochando, J., Ozato, K., Riksen, N. P., Sauerwein, R., Sherwood, E. R., Schlitzer, A., Schultze, J. L., Sieweke, M. H., Benn, C. S., Stunnenberg, H., Sun, J., van de Veerdonk, F. L., Weis, S., Williams, D. L., Xavier, R., Netea, M. G., Institut Pasteur [Paris], Consiglio Nazionale delle Ricerche (CNR), University of Bonn, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtzgemeinschaft, Radboud university [Nijmegen], Hamon, Melanie, and ACS - Atherosclerosis & ischemic syndromes
Subjects: 0301 basic medicine, [SDV]Life Sciences [q-bio], animal diseases, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Priming (immunology), Adaptive Immunity, 0302 clinical medicine, Immunology and Allergy, MESH: Animals, ComputingMilieux_MISCELLANEOUS, immunology [BCG Vaccine], Vaccination, Vascular damage Radboud Institute for Molecular Life Sciences [Radboudumc 16], Cell Differentiation, Common framework, [SDV] Life Sciences [q-bio], MESH: BCG Vaccine, BCG Vaccine, MESH: Immunologic Memory, MESH: Immunity, Innate, MESH: Cell Differentiation, MESH: Immune Tolerance, Immunology, education, immunology [Adaptive Immunity], chemical and pharmacologic phenomena, Biology, Article, 03 medical and health sciences, Immune system, Immunity, Immune Tolerance, Animals, Humans, ddc:610, Molecular Biology, MESH: Humans, immunology [Immune Tolerance], Cell Biology, MESH: Vaccination, biochemical phenomena, metabolism, and nutrition, Immunity, Innate, immunology [Immunologic Memory], immunology [Immunity, Innate], Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], 030104 developmental biology, bacteria, Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19], Neuroscience, Immunologic Memory, MESH: Adaptive Immunity, 030215 immunology
Abstract: The similarities and differences between trained immunity and other immune processes are the subject of intense interrogation. Therefore, a consensus on the definition of trained immunity in both in vitro and in vivo settings, as well as in experimental models and human subjects, is necessary for advancing this field of research. Here we aim to establish a common framework that describes the experimental standards for defining trained immunity.
Published: 2021

14. SU-F-J-19: Robust Region-Of-Interest (ROI) for Consistent Registration On Deteriorated Surface Images

Author: Al-Hallaq, H [The Department of Radiation and Cellular Oncology, The University of Chicago Medicine, Chicago, IL (United States)]
Published: 2016
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15. Steroidal and non-steroidal mineralocorticoid receptor antagonists in cardiorenal medicine

Author: Agarwal, Rajiv, Kolkhof, Peter, Bakris, George, Bauersachs, Johann, Haller, Hermann, Wada, Takashi, Zannad, Faiez, BOZEC, Erwan, Indiana University School of Medicine and VA Medical Center, Bayer Pharma AG [Berlin], American Society of Hypertension's Comprehensive Hypertension Center at the University of Chicago Medicine, Department of Cardiology and Angiology, Hannover Medical School, Department of Nephrology and Hypertension, Hannover Medical School, Department of Nephrology and Laboratory Medicine, Kanazawa University, Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), and Bayer AG, the manufacturer of finerenone
Subjects: Finerenone, medicine.drug_class, Spironolactone, 030204 cardiovascular system & hematology, Pharmacology, Mineralocorticoid receptor antagonists, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Mineralocorticoid receptor, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Chronic kidney disease, Mineralocorticoids, State of the Art Review, Humans, Medicine, AcademicSubjects/MED00200, 030212 general & internal medicine, Heart Failure and Cardiomyopathies, Heart Failure, Kidney, business.industry, Cardiorenal, medicine.disease, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Eplerenone, medicine.anatomical_structure, Diabetes Mellitus, Type 2, chemistry, Mineralocorticoid, Cardiology and Cardiovascular Medicine, business, MRAS, medicine.drug, Kidney disease
Abstract: This review covers the last 80 years of remarkable progress in the development of mineralocorticoid receptor (MR) antagonists (MRAs) from synthesis of the first mineralocorticoid to trials of nonsteroidal MRAs. The MR is a nuclear receptor expressed in many tissues/cell types including the kidney, heart, immune cells, and fibroblasts. The MR directly affects target gene expression—primarily fluid, electrolyte and haemodynamic homeostasis, and also, but less appreciated, tissue remodelling. Pathophysiological overactivation of the MR leads to inflammation and fibrosis in cardiorenal disease. We discuss the mechanisms of action of nonsteroidal MRAs and how they differ from steroidal MRAs. Nonsteroidal MRAs have demonstrated important differences in their distribution, binding mode to the MR and subsequent gene expression. For example, the novel nonsteroidal MRA finerenone has a balanced distribution between the heart and kidney compared with spironolactone, which is preferentially concentrated in the kidneys. Compared with eplerenone, equinatriuretic doses of finerenone show more potent anti-inflammatory and anti-fibrotic effects on the kidney in rodent models. Overall, nonsteroidal MRAs appear to demonstrate a better benefit–risk ratio than steroidal MRAs, where risk is measured as the propensity for hyperkalaemia. Among patients with Type 2 diabetes, several Phase II studies of finerenone show promising results, supporting benefits on the heart and kidneys. Furthermore, finerenone significantly reduced the combined primary endpoint (chronic kidney disease progression, kidney failure, or kidney death) vs. placebo when added to the standard of care in a large Phase III trial.
Published: 2020

16. Reionization with galaxies and active galactic nuclei

Author: Tirthankar Roy Choudhury, Maxime Trebitsch, Amy E. Reines, Raffaella Schneider, Marta Volonteri, Michaela Hirschmann, Pratika Dayal, Nickolay Y. Gnedin, Hakim Atek, University of Groningen [Groningen], Institut d'Astrophysique de Paris (IAP), Institut national des sciences de l'Univers (INSU - CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Tata Institute for Fundamental Research (TIFR), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Max-Planck-Institut für Astronomie (MPIA), Max-Planck-Gesellschaft, Institut fur Theoretische Physik und Astrophysik [Kiel], Christian-Albrechts-Universität zu Kiel (CAU), Fermi National Accelerator Laboratory (Fermilab), The University of Chicago Medicine [Chicago], IT University of Copenhagen, Montana State University (MSU), and Astronomy
Subjects: Active galactic nucleus, Stellar mass, Astrophysics::High Energy Astrophysical Phenomena, IONIZING PHOTON BUDGET, FOS: Physical sciences, DARK-AGES REIONIZATION, Astrophysics, Astrophysics::Cosmology and Extragalactic Astrophysics, 01 natural sciences, STAR-FORMATION, galaxies: evolution, galaxies: high-redshift, intergalactic medium, quasars: general, reionization, RADIATIVE-TRANSFER, 0103 physical sciences, Astrophysics::Solar and Stellar Astrophysics, AGN, BLACK-HOLES, 010303 astronomy & astrophysics, Reionization, evolution [galaxies], Astrophysics::Galaxy Astrophysics, Physics, quasars:general, general [quasars], 010308 nuclear & particles physics, Star formation, FORMATION SIMULATION, Astronomy and Astrophysics, Astrophysics - Astrophysics of Galaxies, EVOLUTION, Galaxy, Redshift, Black hole, Supernova, QUASARS, LUMINOSITY FUNCTION, Space and Planetary Science, Astrophysics of Galaxies (astro-ph.GA), Astrophysics::Earth and Planetary Astrophysics, [PHYS.ASTR]Physics [physics]/Astrophysics [astro-ph], high-redshift [galaxies]
Abstract: In this work we investigate the properties of the sources that reionized the intergalactic medium (IGM) in the high-redshift Universe. Using a semi-analytical model aimed at reproducing galaxies and black holes in the first 1.5 Gyr of the Universe, we revisit the relative role of star formation and black hole accretion in producing ionizing photons that can escape into the IGM. Both star formation and black hole accretion are regulated by supernova feedback, resulting in black hole accretion being stunted in low-mass halos. We explore a wide range of combinations for the escape fraction of ionizing photons (redshift-dependent, constant and scaling with stellar mass) from both star formation ($\langle f_{\rm esc}^{\rm sf} \rangle$) and AGN ($f_{\rm esc}^{\rm bh}$) to find: (i) the ionizing budget is dominated by stellar radiation from low stellar mass ($M_*6$ with the AGN contribution (driven by $M_{bh}>10^6 {\rm M_\odot}$ black holes in $M_* > 10^9 {\rm M_\odot}$ galaxies) dominating at lower redshifts; (ii) AGN only contribute $10-25\%$ to the cumulative ionizing emissivity by $z=4$ for the models that match the observed reionization constraints; (iii) if the stellar mass dependence of $\langle f_{\rm esc}^{\rm sf} \rangle$ is shallower than $f_{\rm esc}^{\rm bh}$, at $z, Accepted to MNRAS
Published: 2020

17. Efficacy and safety of finerenone in patients with chronic kidney disease and type 2 diabetes by GLP-1RA treatment:A subgroup analysis from the FIDELIO-DKD trial

Author: Stefan D. Anker, Aslam Amod, Luis M. Ruilope, Gerasimos Filippatos, Amer Joseph, Michel Marre, Bertram Pitt, Charlie Scott, Andrea Lage, Rajiv Agarwal, George L. Bakris, Peter Rossing, IT University of Copenhagen, Indiana University School of Medicine, Indiana University System, Charité Campus Virchow-Klinikum (CVK), National and Kapodistrian University of Athens (NKUA), University of Michigan [Ann Arbor], University of Michigan System, University of KwaZulu-Natal (UKZN), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Bayer Pharma AG [Berlin], The University of Chicago Medicine [Chicago], IT University of Copenhagen (ITU), University of KwaZulu-Natal [Durban, Afrique du Sud] (UKZN), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), and Gestionnaire, HAL Sorbonne Université 5
Subjects: medicine.medical_specialty, Finerenone, Endocrinology, Diabetes and Metabolism, Enfermedad cardiovascular, glucagon-like peptide-1 receptor agonist, Urology, Renal function, Subgroup analysis, Type 2 diabetes, 030204 cardiovascular system & hematology, Placebo, Tratamiento médico, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Internal Medicine, medicine, Humans, 030212 general & internal medicine, Myocardial infarction, mineralocorticoid receptor antagonist, Naphthyridines, Renal Insufficiency, Chronic, finerenone, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Fallo renal crónico, business.industry, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, 3. Good health, Diabetes mellitus tipo 2, Sistema endocrino, Diabetes Mellitus, Type 2, Heart failure, type 2 diabetes, business, chronic kidney disease, Glomerular Filtration Rate, Kidney disease
Abstract: Aims Finerenone significantly reduced the risk of kidney and cardiovascular (CV) outcomes in patients with chronic kidney disease and type 2 diabetes in the FIDELIO-DKD trial (NCT02540993). This exploratory subgroup analysis investigates the effect of glucagon-like peptide-1 receptor agonist (GLP-1RA) use on the treatment effect of finerenone. Materials and Methods Patients with type 2 diabetes, urine albumin-to-creatinine ratio (UACR) 30-5000 mg/g and estimated glomerular filtration rate 25
Published: 2022

18. Comparison of the risk of Crohn's disease postoperative recurrence between modified Rutgeerts score i2a and i2b categories: an individual patient data meta-analysis

Author: Pauline Rivière, Joel Pekow, Nassim Hammoudi, Pauline Wils, Peter De Cruz, Christina Pu Wang, Míriam Mañosa, Jacob Ollech, Matthieu Allez, Maria Nachury, Michael A Kamm, Maya Ahanori, Marc Ferrante, Anthony Buisson, Siddarth Singh, David Laharie, Momar Diouf, Mathurin Fumery, Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], The University of Chicago Medicine [Chicago], Ecotaxie, microenvironnement et développement lymphocytaire (EMily (UMR_S_1160 / U1160)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institute for Translational Research in Inflammation - U 1286 (INFINITE (Ex-Liric)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Austin Health, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Hospital Universitari Germans Trias I Pujol, University of Chicago, St. Vincent's Hospital, Melbourne, University of Melbourne, University Hospitals Leuven [Leuven], Service d'Hépatologie Gastro-entérologie [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Infection Inflammation et Interaction Hôtes Pathogènes [CHU Clermont-Ferrand] (3IHP ), Direction de la recherche clinique et de l’innovation [CHU Clermont-Ferrand] (DRCI), Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Clermont Auvergne (UCA), University of California [San Diego] (UC San Diego), University of California (UC), CHU Amiens-Picardie, Périnatalité et Risques Toxiques - UMR INERIS_I 1 (PERITOX), Institut National de l'Environnement Industriel et des Risques (INERIS)-Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, and University of California
Subjects: Crohn’s disease, Crohn's disease, Gastroenterology, postoperative recurrence, General Medicine, Original Articles, endoscopy, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Background The modified Rutgeerts’ score [RS] differentiates i2a—lesions confined to the anastomosis—and i2b—more than five aphthous ulcers in the neoterminal ileum with normal intervening mucosa, with or without anastomotic lesions—categories. Its relevance for the therapeutic management of Crohn’s disease [CD] patients after ileocolic resection is still debated. Our objective was to compare the postoperative recurrence risk in patients with an i2a or i2b score, using an individual patient data meta-analysis. Methods We conducted a systematic literature search until July 2020, to identify all relevant studies reporting the i2a/i2b status in the year following ileocolic resection and clinical and/or surgical postoperative CD recurrence in their follow-up. Individual patient-level data were obtained from the corresponding authors. The association between the modified RS and time-to-event was evaluated using a mixed Cox model with the centre as the random effect. Results Seven studies published between 2008 and 2019 were included, corresponding to 400 patients: 189 [47%] i2a and 211 [53%] i2b. Median [interquartile range, IQR] time from ileocolic resection to ileocolonoscopy was 6.2 [5.5, 7.9] months and median [IQR] follow-up time after ileocolonoscopy was 4.5 [2.9, 7.3] years. The risk of clinical postoperative recurrence at 1 and 3 years was 11% [6–15%], and 25% [18–32%] in the i2a group versus 9% [5–13%] and 33% [26–41%] in the i2b group [p = 0.63 and p = 0.12, respectively]. No significant difference was observed in terms of time to clinical postoperative recurrence [p = 0.16] or surgical postoperative recurrence [p = 0.87]. Results did not change after excluding patients having initiated an immunosuppressant or a biologic in the 3 months after endoscopy [remaining cohort, n = 361]. Conclusions In this individual patient data meta-analysis, no difference was observed between i2a and i2b subcategories with regards to clinical or surgical postoperative recurrence. As we wait for prospective trials, the same treatment strategy could be applied to all patients classified as i2 on the Rutgeerts score.
Published: 2022

19. Functional repertoire convergence of distantly related eukaryotic plankton lineages revealed by genome-resolved metagenomics

Author: Emilie Villar, Corinne Cruaud, de Vargas C, Patrick Wincker, Chiara Vanni, Da Silva C, Chris Bowler, Karine Labadie, Julie Poulain, Clayssen Q, Eric Karsenti, Leo d’Agata, Guerra Af, Eric Pelletier, Olivier Jaillon, Eren Am, Kourlaiev A, Paul Frémont, Jean-Marc Aury, Morgan Gaia, Damien Daniel Hinsinger, Tom O. Delmont, Bernard Noël, Wessner M, Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), 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), The Globe Institute, The University of Chicago Medicine [Chicago], Station biologique de Roscoff, Centre National de la Recherche Scientifique (CNRS), Institut de biologie de l'ENS Paris (IBENS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), European Molecular Biology Laboratory (EMBL), ANR-11-BTBR-0008,OCEANOMICS,Biotechnologies et bioressources pour la valorisation des écosystèmes marins planctoniques(2011), ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), ANR-09-GENM-0032,TARA-GIRUS,Inventaire et ressources génétiques de virus géants à ADN dans les milieux marins sur Tara-Oceans(2009), ANR-14-CE23-0001,HydroGen,Metagenomique comparative comme instrument de mesure pour la biodiversité. Application à l'étude de la vie dans les océans(2014), ANR-10-LABX-0054,MEMOLIFE,Memory in living systems: an integrated approach(2010), ANR-11-IDEX-0001,Amidex,INITIATIVE D'EXCELLENCE AIX MARSEILLE UNIVERSITE(2011), ANR-10-INBS-0002,EMBRC-France,CENTRE NATIONAL DE RESSOURCES BIOLOGIQUES MARINES(2010), ANR-17-CE02-0012,ALGALVIRUS,Adaptations Génomique des Algues Marines aux Virus(2017), ANR-10-BLAN-1709,PHYTBACK,Rétroactions écologie-climat dues à l'évolution de la taille et de la forme du phytoplancton(2010), ANR-09-BLAN-0348,POSEIDON(2009), ANR-09-GENM-0031,PROMETHEUS,Approches génomiques pour l?analyse de la biodiversité fonctionnelle des protistes océaniques de l?expédition Tara-Oceans.(2009), European Project: 287589,EC:FP7:KBBE,FP7-OCEAN-2011,MICRO B3(2012), European Project: 261376,EC:FP7:HEALTH,FP7-HEALTH-2010-single-stage,IHMS(2011), Station biologique de Roscoff (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-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)-Centre National de la Recherche Scientifique (CNRS), and Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS)
Subjects: Marine eukaryotes, Tara Oceans, single-cellgenomics, Marine life, Genomics, Biology, phylogeny, Genome, 03 medical and health sciences, 0302 clinical medicine, Phylogenetics, evolution, genomics, 14. Life underwater, 030304 developmental biology, open ocean, functions, 0303 health sciences, metagenomics, Phylogenetic tree, fungi, plankton, 15. Life on land, Plankton, Multicellular organism, Metagenomics, Evolutionary biology, [SDE]Environmental Sciences, anvi’o, ecology, 030217 neurology & neurosurgery
Abstract: Marine planktonic eukaryotes play a critical role in global biogeochemical cycles and climate. However, their poor representation in culture collections limits our understanding of the evolutionary history and genomic underpinnings of planktonic ecosystems. Here, we used 280 billion metagenomic reads from 143 Tara Oceans stations to reconstruct and manually curate more than 700 abundant and widespread eukaryotic metagenome-assembled genomes ranging from 10 Mbp to up to 1.3 Gbp. The resulting non-redundant genomic resource of 25 billion nucleotides that describe 10 million genes covers a wide range of poorly characterized unicellular and multicellular eukaryotic lineages that complement the long-standing contributions of culture efforts to survey the tree of marine life while better representing plankton from the open ocean. Phylogeny of the DNA-dependent RNA polymerase placed this genomic resource in a comprehensive evolutionary framework that provided insights into the relationships of eukaryotic supergroups. From there, classification of unicellular eukaryotic plankton based on functions encoded in their genes revealed four major groups connecting distantly related lineages such as the diatoms and green algae. There has been a recurrent problem in understanding the interplay between eukaryotes’ vertical evolution and their phenotype. By disentangling phylogenetic signals from functional trends with genomics, we found that neither the classical trophic mode of plankton nor its vertical evolutionary history could fully explain the genomic functional landscape of marine eukaryotes that coexisted for millions of years. Cover Navigating on the map of plankton genomics with Tara Oceans and anvi’o: a comprehensive genome-resolved metagenomic survey dedicated to eukaryotic plankton.
Published: 2021

20. Heterotrophic bacterial diazotrophs are more abundant than their cyanobacterial counterparts in metagenomes covering most of the sunlit ocean

Author: Eric Pelletier, A. Murat Eren, Patrick Wincker, Rachel A. Foster, Tom O. Delmont, Juan José Pierella Karlusich, Jessika Fuessel, Iva Veseli, Chris Bowler, Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), 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 de biologie de l'ENS Paris (IBENS), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-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)-Centre National de la Recherche Scientifique (CNRS), The University of Chicago Medicine [Chicago], Stockholm University, ANR-11-BTBR-0008,OCEANOMICS,Biotechnologies et bioressources pour la valorisation des écosystèmes marins planctoniques(2011), ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), ANR-10-LABX-0054,MEMOLIFE,Memory in living systems: an integrated approach(2010), ANR-11-IDEX-0001,Amidex,INITIATIVE D'EXCELLENCE AIX MARSEILLE UNIVERSITE(2011), ANR-16-CE01-0008,PHYTOMET,Étude métallomique du phytoplancton: effet de l'acidification des océans sur la séquestration du fer(2016), European Project: 835067,DIATOMIC, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS), delmont, tom, Biotech - Bioressources - Biotechnologies et bioressources pour la valorisation des écosystèmes marins planctoniques - - OCEANOMICS2011 - ANR-11-BTBR-0008 - BTBR - VALID, Organisation et montée en puissance d'une Infrastructure Nationale de Génomique - - France-Génomique2010 - ANR-10-INBS-0009 - INBS - VALID, Memory in living systems: an integrated approach - - MEMOLIFE2010 - ANR-10-LABX-0054 - LABX - VALID, INITIATIVE D'EXCELLENCE AIX MARSEILLE UNIVERSITE - - Amidex2011 - ANR-11-IDEX-0001 - IDEX - VALID, Étude métallomique du phytoplancton: effet de l'acidification des océans sur la séquestration du fer - - PHYTOMET2016 - ANR-16-CE01-0008 - AAPG2016 - VALID, and Untangling eco-evolutionary impacts on diatom genomes over timescales relevant to current climate change - DIATOMIC - 835067 - INCOMING
Subjects: [SDE] Environmental Sciences, Nitrogen balance, Nitrogen, Oceans and Seas, Population, Biodiversity, Heterotroph, Cyanobacteria, Microbiology, Article, 03 medical and health sciences, Microbial ecology, Nitrogen Fixation, Seawater, 14. Life underwater, education, Phylogeny, Ecology, Evolution, Behavior and Systematics, Primary productivity, 030304 developmental biology, 0303 health sciences, education.field_of_study, biology, 030306 microbiology, Ecology, Correction, Pelagic zone, Plankton, biology.organism_classification, Trichodesmium, Metagenomics, [SDE]Environmental Sciences, Nitrogen fixation, Metagenome, Diazotroph
Abstract: Biological nitrogen fixation is a major factor contributing to microbial primary productivity in the open ocean. The current view depicts a few cyanobacterial diazotrophs as the most relevant marine nitrogen fixers, whereas heterotrophic diazotrophs are more diverse and considered to have lower impacts on the nitrogen balance. Here, we used 891 Tara Oceans metagenomes to create a manually curated, non-redundant genomic database corresponding to free-living, as well as filamentous, colony-forming, particle-attached and symbiotic bacterial and archaeal populations occurring in the surface of five oceans and two seas. Notably, the database provided the genomic content of eight cyanobacterial diazotrophs including Trichodesmium populations and a newly discovered population similar to Richelia, as well as 40 heterotrophic bacterial diazotrophs organized into three main functional groups that considerably expand the known diversity of abundant marine nitrogen fixers compared to previous genomic surveys. Critically, these 48 populations may account for more than 90% of cells containing known nifH genes and occurring in the sunlit ocean, suggesting that the genomic characterization of the most abundant marine diazotrophs may be nearing completion. The newly identified heterotrophic bacterial diazotrophs are widespread, express their nifH genes in situ, and co-occur under nitrate-depleted conditions in large size fractions where they might form aggregates providing the low-oxygen microenvironments required for nitrogen fixation. Most significantly, we found heterotrophic bacterial diazotrophs to be more abundant than cyanobacterial diazotrophs in most metagenomes from the open oceans and seas. This large-scale environmental genomic survey emphasizes the considerable potential of heterotrophs in the marine nitrogen balance.
Published: 2021

21. Economic Analyses in Squamous Cell Carcinoma of the Head and Neck: A Review of the Literature From a Clinical Perspective

Author: Tina Shih, Ya-Chen [The University of Chicago Medicine, Chicago, Illinois (United States)]
Published: 2014
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22. Saffron and Its Major Ingredients’ Effect on Colon Cancer Cells with Mismatch Repair Deficiency and Microsatellite Instability

Author: Amr Amin, Hassan Brim, Françoise Praz, Aaminah Farrukh, Akbar Soleimani, Chandraprabha Murali, Hassan Ashktorab, Grazia Graziani, United Arab Emirates University (UAEU), The University of Chicago Medicine [Chicago], Howard University College of Medicine [Washington, DC, USA], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Department of System Medicine, Università degli Studi di Roma Tor Vergata [Roma], Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), and Gestionnaire, HAL Sorbonne Université 5
Subjects: Colorectal cancer, Pharmaceutical Science, Organic chemistry, DNA Mismatch Repair, Analytical Chemistry, Crocin, chemistry.chemical_compound, 0302 clinical medicine, QD241-441, Drug Discovery, 0303 health sciences, DNA damage and repair, Settore BIO/14, MLH1, apoptosis, safranal, 3. Good health, Safranal, Chemistry (miscellaneous), 030220 oncology & carcinogenesis, Colonic Neoplasms, Molecular Medicine, Microsatellite Instability, saffron, Context (language use), [SDV.CAN]Life Sciences [q-bio]/Cancer, colorectal cancer, Biology, HCT116, Article, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Humans, Physical and Theoretical Chemistry, neoplasms, 030304 developmental biology, Plant Extracts, Microsatellite instability, medicine.disease, Crocus, HCT116 Cells, MSH3, digestive system diseases, crocin, chemistry, Apoptosis, Cancer research
Abstract: Background: Colorectal cancer (CRC) is one of the most common cancers worldwide. One of its subtypes is associated with defective mismatch repair (dMMR) genes. Saffron has many potentially protective roles against colon malignancy. However, these roles in the context of dMMR tumors have not been explored. In this study, we aimed to investigate the effects of saffron and its constituents in CRC cell lines with dMMR. Methods: Saffron crude extracts and specific compounds (safranal and crocin) were used in the human colorectal cancer cell lines HCT116, HCT116+3 (inserted MLH1), HCT116+5 (inserted MSH3), and HCT116+3+5 (inserted MLH1 and MSH3). CDC25b, p-H2AX, TPDP1, and GAPDH were analyzed by Western blot. Proliferation and cytotoxicity were analyzed by MTT. The scratch wound assay was also performed. Results: Saffron crude extracts restricted (up to 70%) the proliferation in colon cells with deficient MMR (HCT116) compared to proficient MMR. The wound healing assay indicates that deficient MMR cells are doing better (up to 90%) than proficient MMR cells when treated with saffron. CDC25b and TDP1 downregulated (up to 20-fold) in proficient MMR cells compared to deficient MMR cells, while p.H2AX was significantly upregulated in both cell types, particularly at &gt, 10 mg/mL saffron in a concentration-dependent manner. The reduction in cellular proliferation was accompanied with upregulation of caspase 3 and 7. The major active saffron compounds, safranal and crocin reproduced most of the saffron crude extracts’ effects. Conclusions: Saffron’s anti-proliferative effect is significant in cells with deficient MMR. This novel effect may have therapeutic implications and benefits for MSI CRC patients who are generally not recommended for the 5-fluorouracil-based treatment.
Published: 2021
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23. Hemodynamic impact of coronary stenosis using computed tomography: comparison between noninvasive fractional flow reserve and 3D fusion of coronary angiography with stress myocardial perfusion

Author: Nadjia Kachenoura, S. Javed Zaidi, Francesco Maffessanti, Anuj Mediratta, Diego Medvedofsky, Akhil Narang, Amita Singh, Neha Goyal, Roberto M. Lang, Victor Mor-Avi, Amit R. Patel, Mita Patel, Kalie Kebed, The University of Chicago Medicine [Chicago], Università della Svizzera italiana = University of Italian Switzerland (USI), Laboratoire d'Imagerie Biomédicale (LIB), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Time Factors, Computed Tomography Angiography, [SDV]Life Sciences [q-bio], Vasodilator Agents, medicine.medical_treatment, Cardiovascular CT, Perfusion scanning, Coronary Artery Disease, Fractional flow reserve, 030204 cardiovascular system & hematology, Coronary Angiography, Multimodal Imaging, Severity of Illness Index, 030218 nuclear medicine & medical imaging, 0302 clinical medicine, Vasodilator stress, Risk Factors, Prospective Studies, Myocardial infarction, Cardiac imaging, Myocardial Perfusion Imaging, Middle Aged, Prognosis, 3. Good health, Fractional Flow Reserve, Myocardial, medicine.anatomical_structure, Disease Progression, Cardiology, Radiographic Image Interpretation, Computer-Assisted, Female, Cardiology and Cardiovascular Medicine, medicine.drug, Adult, medicine.medical_specialty, Revascularization, Risk Assessment, Article, Myocardial perfusion, 03 medical and health sciences, Imaging, Three-Dimensional, Predictive Value of Tests, Internal medicine, medicine, Humans, Radiology, Nuclear Medicine and imaging, Aged, business.industry, Coronary Stenosis, Hemodynamics, Reproducibility of Results, Fusion imaging, medicine.disease, Regadenoson, Coronary arteries, Stenosis, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Vasodilator-stress CT perfusion imaging in addition to CT coronary angiography (CTCA) may provide a single-test alternative to nuclear stress testing, commonly used to assess hemodynamic significance of stenosis. Another alternative is fractional flow reserve (FFR) calculated from cardiac CT images. We studied the concordance between these two approaches and their relationship to outcomes. We prospectively studied 150 patients with chest pain, who underwent CTCA and regadenoson CT. CTCA images were interpreted for presence and severity of stenosis. Fused 3D displays of subendocardial X-ray attenuation with coronary arteries were created to detect stress perfusion defects (SPD) in each coronary territory. In patients with stenosis > 25%, CT-FFR was quantified. Significant stenosis was determined by: (1) combination of stenosis > 50% with an SPD, (2) CT-FFR ≤ 0.80. Patients were followed-up for 36 ± 25 months for death, myocardial infarction or revascularization. After excluding patients with normal arteries and technical/quality issues, in final analysis of 76 patients, CTCA depicted stenosis > 70% in 13/224 arteries, 50-70% in 24, and < 50% in 187. CT-FFR ≤ 0.80 was found in 41/224 arteries, and combination of SPD with > 50% stenosis in 31/224 arteries. Inter-technique agreement was 89%. Despite high incidence of abnormal CT-FFR (30/76 patients), only 7 patients experienced adverse outcomes; 6/7 also had SPDs. Only 1/9 patients with CT-FFR ≤ 0.80 but normal perfusion had an event. Fusion of CTCA and stress perfusion can help determine the hemodynamic impact of stenosis in one test, in good agreement with CT-FFR. Adding stress CT perfusion analysis may help risk-stratify patients with abnormal CT-FFR.
Published: 2019

24. STRIDE-II: An Update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) Initiative of the International Organization for the Study of IBD (IOIBD): Determining Therapeutic Goals for Treat-to-Target strategies in IBD

Author: Ferdinando D'Amico, Iris Dotan, Maria T. Abreu, Axel Dignass, Jasbir Dhaliwal, Anne M. Griffiths, William J. Sandborn, Dan Turner, Amanda Ricciuto, Dominik Bettenworth, David T. Rubin, Silvio Danese, Jean Yves Mary, Jürgen Schölmerich, Ayanna Lewis, Laurent Peyrin-Biroulet, Willem A. Bemelman, Walter Reinisch, Jean-Frederic Colombel, Bruce E. Sands, Surgery, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, The Hebrew University of Jerusalem (HUJ), The Hospital for sick children [Toronto] (SickKids), University of Miami Leonard M. Miller School of Medicine (UMMSM), Humanitas Clinical and Research Center [Rozzano, Milan, Italy], University of Cincinnati (UC), University Hospital Münster - Universitaetsklinikum Muenster [Germany] (UKM), University of California [San Diego] (UC San Diego), University of California, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Medizinische Universität Wien = Medical University of Vienna, University of Amsterdam [Amsterdam] (UvA), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), The University of Chicago Medicine [Chicago], Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Tel Aviv University [Tel Aviv], and Goethe-University Frankfurt am Main
Subjects: 0301 basic medicine, Adult, medicine.medical_specialty, Consensus, Adolescent, Delphi Technique, Patient-Reported Outcomes, Endpoint Determination, [SDV]Life Sciences [q-bio], Disease, Biologics, Endoscopic Healing, Inflammatory bowel disease, 03 medical and health sciences, 0302 clinical medicine, Child Development, Crohn Disease, Internal medicine, medicine, Humans, Child, Crohn's disease, Wound Healing, Hepatology, business.industry, Remission Induction, Gastroenterology, Age Factors, Adolescent Development, medicine.disease, Ulcerative colitis, Symptomatic relief, Crohn's Disease Activity Index, 3. Good health, 030104 developmental biology, Treatment Outcome, Research Design, Quality of Life, 030211 gastroenterology & hepatology, Patient-reported outcome, Colitis, Ulcerative, Treat-to-Target, Calprotectin, business, Biomarkers
Abstract: International audience; Background: The Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) initiative of the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) has proposed treatment targets in 2015 for adult patients with inflammatory bowel disease (IBD). We aimed to update the original STRIDE statements for incorporating treatment targets in both adult and pediatric IBD.Methods: Based on a systematic review of the literature and iterative surveys of 89 IOIBD members, recommendations were drafted and modified in 2 surveys and 2 voting rounds. Consensus was reached if ≥75% of participants scored the recommendation as 7 to 10 on a 10-point rating scale.Results: In the systematic review, 11,278 manuscripts were screened, of which 435 were included. The first IOIBD survey identified the following targets as most important: clinical response and remission, endoscopic healing, and normalization of C-reactive protein/erythrocyte sedimentation rate and calprotectin. Fifteen recommendations were identified, of which 13 were endorsed. STRIDE-II confirmed STRIDE-I long-term targets of clinical remission and endoscopic healing and added absence of disability, restoration of quality of life, and normal growth in children. Symptomatic relief and normalization of serum and fecal markers have been determined as short-term targets. Transmural healing in Crohn's disease and histological healing in ulcerative colitis are not formal targets but should be assessed as measures of the remission depth.Conclusions: STRIDE-II encompasses evidence- and consensus-based recommendations for treat-to-target strategies in adults and children with IBD. This frameworkshould be adapted to individual patients and local resources to improve outcomes.
Published: 2021

25. Factors associated with anti-tumor necrosis factor effectiveness to prevent postoperative recurrence in Crohn's disease

Author: Neil Hyman, Russell D. Cohen, Bruno Pereira, Sushila Dalal, Roger D. Hurst, Lisa M. Cannon, Joel Pekow, Konstantin Umanskiy, David T. Rubin, Anthony Buisson, Atsushi Sakuraba, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Clermont Auvergne (UCA), Infection Inflammation et Interaction Hôtes Pathogènes [CHU Clermont-Ferrand] (3IHP ), Direction de la recherche clinique et de l’innovation [CHU Clermont-Ferrand] (DRCI), CHU Clermont-Ferrand-CHU Clermont-Ferrand, The University of Chicago Medicine [Chicago], Unité de Biostatistiques [CHU Clermont-Ferrand], United States Department of Health & Human Services, United States Department of Health & Human Services [P30 DK042086], NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK), Inflammatory Bowel Disease Center, Department of Surgery, and Molé, Christine
Subjects: medicine.medical_specialty, Combination therapy, ileocolonic resection, medicine.medical_treatment, Disease, Gastroenterology, Inflammatory bowel disease, combination therapy, surgery, 03 medical and health sciences, 0302 clinical medicine, inflammatory bowel disease, Internal medicine, medicine, Crohn's disease, business.industry, Hazard ratio, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Odds ratio, medicine.disease, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Confidence interval, 3. Good health, Immunosuppressive drug, 030220 oncology & carcinogenesis, 030211 gastroenterology & hepatology, business
Abstract: Background/Aims: We assessed the effectiveness of anti-TNF agents and its associated factors to prevent endoscopic and clinical postoperative recurrence (POR) in Crohn’s disease (CD). Methods: From a prospectively-maintained database, we retrieved 316 CD patients who underwent intestinal resection (2011–2017). Endoscopic (Rutgeerts index ≥ i2 at 6 months) and clinical (recurrence of symptoms leading to hospitalization or therapeutic escalation) POR were assessed. Results: In 117 anti-TNF-naïve patients, anti-TNF therapy was more effective than immunosuppressive agents (odds ratio [OR], 8.8; 95% confidence interval [CI], 1.8–43.9; P= 0.008) and no medication/5-aminosalicylates (OR, 5.2; 95% CI, 1.0–27.9; P= 0.05) to prevent endoscopic POR. In 199 patients exposed to anti-TNF prior to the surgery, combination with anti-TNF and immunosuppressive agents was more effective than anti-TNF monotherapy (OR, 2.32; 95% CI, 1.02–5.31; P= 0.046) to prevent endoscopic POR. Primary failure to anti-TNF agent prior to surgery was predictive of anti-TNF failure to prevent endoscopic POR (OR, 2.41; 95% CI, 1.10–5.32; P= 0.03). When endoscopic POR despite anti-TNF prophylactic medication (n = 55), optimizing anti-TNF and adding an immunosuppressive drug was the most effective option to prevent clinical POR (hazard ratio, 7.38; 95% CI, 1.54–35.30; P= 0.012). Anti-TNF therapy was the best option to prevent clinical POR (hazard ratio, 3.10; 95% CI, 1.09–8.83; P= 0.034) in patients with endoscopic POR who did not receive any biologic to prevent endoscopic POR (n = 55). Conclusions: Anti-TNF was the most effective medication to prevent endoscopic and clinical POR. Combination with anti-TNF and immunosuppressive agents should be considered in patients previously exposed to anti-TNF.
Published: 2021

26. TOI-1296b and TOI-1298b observed with TESS and SOPHIE: Two hot Saturn-mass exoplanets with different densities around metal-rich stars

Author: T. Lopez, Isabelle Boisse, S. Deheuvels, Zahra Essack, David Baker, F. Debras, P. C. König, T. Forveille, J. Villasenor, Sergio Hoyer, X. Delfosse, Keivan G. Stassun, Patricia T. Boyd, Nuno C. Santos, George R. Ricker, Guillaume Hébrard, Olivier Demangeon, C. Moutou, H. P. Osborn, C. Ziegler, P. Guerra, D. Laloum, S. C. C. Barros, Michael Vezie, R. Vanderspek, X. Bonfils, Flavien Kiefer, Joshua N. Winn, Katharine Hesse, D. W. Latham, S. Dalal, Magali Deleuil, Sara Seager, Jose-Manuel Almenara, P. Cortés-Zuleta, E. Girardin, Eder Martioli, Jon M. Jenkins, Paul Benni, Allyson Bieryla, Karen A. Collins, N. Heidari, Bill Wohler, Laboratoire d'Astrophysique de Marseille (LAM), Aix Marseille Université (AMU)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS), Canada-France-Hawaii Telescope Corporation (CFHT), National Research Council of Canada (NRC)-Centre National de la Recherche Scientifique (CNRS)-University of Hawai'i [Honolulu] (UH), Toulouse Biotechnology Institute (TBI), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centro de Astrofísica da Universidade do Porto (CAUP), Universidade do Porto, Departamento de Física e Astronomia [Porto] (DFA/FCUP), Faculdade de Ciências da Universidade do Porto (FCUP), Universidade do Porto-Universidade do Porto, Observatoire des Sciences de l'Univers de Grenoble (OSUG ), Institut national des sciences de l'Univers (INSU - CNRS)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA), Institute for Marine and Antarctic Studies [Horbat] (IMAS), University of Tasmania [Hobart, Australia] (UTAS), Inflammatory Bowel Disease Center, The University of Chicago Medicine [Chicago], Institut de Planétologie et d'Astrophysique de Grenoble (IPAG), Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Observatoire des Sciences de l'Univers de Grenoble (OSUG ), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut national des sciences de l'Univers (INSU - CNRS)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Commissariat à l'énergie atomique et aux énergies alternatives - Laboratoire d'Electronique et de Technologie de l'Information (CEA-LETI), Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut d'Astrophysique de Paris (IAP), Institut national des sciences de l'Univers (INSU - CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Center for Space Research [Cambridge] (CSR), Massachusetts Institute of Technology (MIT), Stephen F. Austin State University, Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Universidade do Porto = University of Porto, Universidade do Porto = University of Porto-Universidade do Porto = University of Porto, Institut national des sciences de l'Univers (INSU - CNRS)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA)-Météo-France, Institute for Marine and Antarctic Studies [Hobart] (IMAS), Centre National d'Études Spatiales [Toulouse] (CNES)-Observatoire des Sciences de l'Univers de Grenoble (OSUG ), Institut national des sciences de l'Univers (INSU - CNRS)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA)-Météo-France -Institut national des sciences de l'Univers (INSU - CNRS)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA)-Météo-France, and ANR-18-CE31-0019,SPlaSH,Recherche de planètes habitables avec SPIRou(2018)
Subjects: 010504 meteorology & atmospheric sciences, FOS: Physical sciences, Astrophysics, 01 natural sciences, techniques: photometric, Planet, Saturn, 0103 physical sciences, techniques: radial velocities, 010303 astronomy & astrophysics, Spectrograph, planetary systems, 0105 earth and related environmental sciences, Physics, Earth and Planetary Astrophysics (astro-ph.EP), Subgiant, Astronomy and Astrophysics, Radius, Exoplanet, planets and satellites: gaseous planets, Radial velocity, Stars, Space and Planetary Science, methods: observational, [PHYS.ASTR]Physics [physics]/Astrophysics [astro-ph], Astrophysics - Earth and Planetary Astrophysics
Abstract: We present the discovery of two new transiting extrasolar planet candidates identified as TOI-1296.01 and TOI-1298.01 by the Transiting Exoplanet Survey Satellite (TESS). The planetary nature of these candidates has been secured with the SOPHIE high-precision spectrograph through the measurement of the companion’s mass with the radial velocity method. Both planets are similar to Saturn in mass and have similar orbital periods of a few days. They, however, show discrepant radii and therefore different densities. The radius discrepancy might be explained by the different levels of irradiation by the host stars. The subgiant star TOI-1296 hosts a low-density planet with 1.2 RJup while the less luminous, lower-size star TOI-1298 hosts a much denser planet with a 0.84 RJup radius, resulting in bulk densities of 0.198 and 0.743 g cm−3, respectively.In addition, both stars are strongly enriched in heavy elements, having metallicities of +0.44 and +0.49 dex, respectively. The planet masses and orbital periods are 0.298 ± 0.039 MJup and 3.9443715 ± 5.8 ± 10−6 days for TOI-1296b, and 0.356 ± 0.032 MJup and 4.537164 ± 1.2 ± 10−5 days for TOI-1298b. The mass measurements have a relative precision of better than 13%.
Published: 2021
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27. Superior survival with pediatric-style chemotherapy compared to myeloablative allogeneic hematopoietic cell transplantation in older adolescents and young adults with Ph-negative acute lymphoblastic leukemia in first complete remission : analysis from CALGB 10403 and the CIBMTR

Author: Selina M. Luger, David A. Rizzieri, Martin S. Tallman, Partow Kebriaei, Mehdi Hamadani, Mark R. Litzow, Khalid Bo-Subait, Brenda M. Sandmaier, Anjali S. Advani, Richard A. Larson, Omer Jamy, Mary Eapen, Hai-Lin Wang, Wendy Stock, Bhagirathbhai Dholaria, Pere Barba, Matthew J. Wieduwilt, Wael Saber, David Ritchie, Daniel J. Weisdorf, Akshay Sharma, Vijaya Raj Bhatt, Tim Prestidge, Michael A. Pulsipher, Frederick R. Appelbaum, Mei-Jie Zhang, Marcos de Lima, Institut Català de la Salut, [Wieduwilt MJ] University of California, San Diego Medical Center, La Jolla, CA, USA. [Stock W, Larson RA] University of Chicago Medicine, Chicago, IL, USA. [Advani A] Cleveland Clinic, Taussig Cancer Institute, Cleveland, OH, USA. [Luger S] Abramson Cancer Center, University of Pennsylvania Medical Center, Philadelphia, PA, USA. [Tallman M] Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. [Barba P] Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Cancer Research, medicine.medical_specialty, medicine.medical_treatment, Medicaments antineoplàstics - Ús terapèutic, Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], Hematopoietic stem cell transplantation, Other subheadings::Other subheadings::/drug therapy [Other subheadings], Gastroenterology, Internal medicine, hemic and lymphatic diseases, neoplasias::neoplasias por tipo histológico::leucemia::leucemia linfoide::leucemia-linfoma linfoblástico de células precursoras [ENFERMEDADES], medicine, Young adult, Diagnosis::Prognosis::Treatment Outcome::Disease-Free Survival [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Chemotherapy, Univariate analysis, Neoplasms::Neoplasms by Histologic Type::Leukemia::Leukemia, Lymphoid::Precursor Cell Lymphoblastic Leukemia-Lymphoma [DISEASES], Hematology, Acute lymphocytic leukaemia, business.industry, Incidence (epidemiology), acciones y usos químicos::acciones farmacológicas::usos terapéuticos::antineoplásicos [COMPUESTOS QUÍMICOS Y DROGAS], diagnóstico::pronóstico::resultado del tratamiento::supervivencia sin enfermedad [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Transplantation, Leucèmia limfoblàstica - Quimioteràpia, Oncology, Cohort, Avaluació de resultats (Assistència sanitària), Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Antineoplastic Agents [CHEMICALS AND DRUGS], business
Abstract: Optimal post-remission therapy for adolescents and young adults (AYAs) with Ph-negative acute lymphoblastic leukemia (ALL) in first complete remission (CR1) is not established. We compared overall survival (OS), disease-free survival (DFS), relapse, and non-relapse mortality (NRM) for patients receiving post-remission therapy on CALGB 10403 to a cohort undergoing myeloablative (MA) allogeneic hematopoietic cell transplantation (HCT) in CR1. In univariate analysis, OS was superior with chemotherapy compared to MA allogeneic HCT (3-year OS 77% vs. 53%, P P P P P = 0.011). Obesity was independently associated with inferior OS (HR 2.17, 95% CI 1.63–2.89, P P P P
Published: 2021

28. Metabolically controlled histone H4K5 acylation/acetylation ratio drives BRD4 genomic distribution

Author: Gao, Mengqing, Wang, Jin, Rousseaux, Sophie, Tan, Minjia, Pan, Lulu, Peng, Lijun, Wang, Sisi, Xu, Wenqian, Ren, Jiayi, Liu, Yuanfang, Spinck, Martin, Barral, Sophie, Wang, Tao, Chuffart, Florent, Bourova-Flin, Ekaterina, Puthier, Denis, Curtet, Sandrine, Bargier, Lisa, Cheng, Zhongyi, Neumann, Heinz, Li, Jian, Zhao, Yingming, Mi, Jian-Qing, Khochbin, Saadi, Shanghai Institute of Hematology, Shanghai Jiao Tong University School of Medicine-Shanghai Rui Jin Hospital, Chinese Academy of Sciences [Xi’an], Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Shanghai Institute of Materia Medica, Chinese Academy of Sciences [Changchun Branch] (CAS), Chinese Academy of Sciences [Beijing] (CAS), Max Planck Institute of Molecular Physiology, Max-Planck-Gesellschaft, Transscriptomics and Genomics of Marseille-Luminy (TGML), Theories and Approaches of Genomic Complexity (TAGC), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Chongqing Jiaotong University, The University of Chicago Medicine [Chicago], Shanghai Jiao Tong University School of Medicine, Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), jingjie PTM Biolab, Hangzhou Dianzi University (HDU), University of Chicago, and Bargier, Lisa
Subjects: QH301-705.5, Acylation, [SDV]Life Sciences [q-bio], Cell Cycle Proteins, Models, Biological, Histones, Mitochondrial Proteins, Cell Line, Tumor, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Humans, Biology (General), Gene Expression Regulation, Leukemic, Genome, Human, Lysine, Fatty Acids, RNA-Binding Proteins, Acetylation, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Chromatin, Mitochondria, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, lipids (amino acids, peptides, and proteins), Oxidation-Reduction, Protein Processing, Post-Translational, Protein Binding, Transcription Factors
Abstract: International audience; In addition to acetylation, histones are modified by a series of competing longer-chain acylations. Most of these acylation marks are enriched and co-exist with acetylation on active gene regulatory elements. Their seemingly redundant functions hinder our understanding of histone acylations’ specific roles. Here, by using an acute lymphoblastic leukemia (ALL) cell model and blasts from individuals with B-precusor ALL (B-ALL), we demonstrate a role of mitochondrial activity in controlling the histone acylation/acetylation ratio, especially at histone H4 lysine 5 (H4K5). An increase in the ratio of non-acetyl acylations (crotonylation or butyrylation) over acetylation on H4K5 weakens bromodomain containing protein 4 (BRD4) bromodomain-dependent chromatin interaction and enhances BRD4 nuclear mobility and availability for binding transcription start site regions of active genes. Our data suggest that the metabolism-driven control of the histone acetylation/longer-chain acylation(s) ratio could be a common mechanism regulating the bromodomain factors’ functional genomic distribution.
Published: 2021

29. Venetoclax plus bendamustine-rituximab or bendamustine-obinutuzumab in chronic lymphocytic leukemia: final results of a phase 1b study (GO28440)

Author: Stilgenbauer, Stephan, Morschhauser, Franck, Wendtner, Clemens-Martin, Cartron, Guillaume, Hallek, Michael, Eichhorst, Barbara, Kozloff, Mark, Giever, Thomas, Lozanski, Gerard, Jiang, Yanwen, Huang, Huang, Pignataro, Daniela, Schary, William, Humphrey, Kathryn, Mobasher, Mehrdad, Salles, Gilles, Universität Ulm - Ulm University [Ulm, Allemagne], Groupe de Recherche sur les formes Injectables et les Technologies Associées - ULR 7365 (GRITA), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Ludwig-Maximilians-Universität München (LMU), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Montpellier (UM), University Hospital of Cologne [Cologne], The University of Chicago Medicine [Chicago], Medical College of Wisconsin [Milwaukee] (MCW), Ohio State University [Columbus] (OSU), Genentech, Inc. [San Francisco], F. Hoffmann-La Roche [Basel], Roche Products Ltd, Abbvie Inc. [North Chicago], Hospices Civils de Lyon (HCL), and Université de Lyon
Subjects: MESH: Antineoplastic Combined Chemotherapy Protocols, MESH: Bendamustine Hydrochloride, MESH: Humans, MESH: Antibodies, Monoclonal, Humanized, MESH: Sulfonamides, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Bridged Bicyclo Compounds, Heterocyclic, MESH: Rituximab, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, MESH: Leukemia, Lymphocytic, Chronic, B-Cell
Abstract: International audience; Venetoclax (Ven), an orally administered, potent BCL-2 inhibitor, has demonstrated efficacy in chronic lymphocytic leukaemia (CLL) in combination with rituximab (R) or obinutuzumab (G). Our aim was to investigate the addition of bendamustine (B) to these Ven-containing regimens in relapsed/refractory (R/R) or first-line (1L) CLL. This multi-arm, non-randomized, open-label, phase 1b study was designed to evaluate the maximum tolerated dose (MTD) and safety/tolerability of Ven with BR/BG, with 3+3 dose-escalation followed by safety expansion. Patients received Ven (schedule A) or BR/BG first (schedule B) to compare safety and determine dose/schedule for expansion. Six Ven-BR/-BG cycles were to be administered, then Ven monotherapy until disease progression (R/R) or fixed-duration 1-year treatment (1L). Overall, 33 R/R and 50 1L patients were enrolled. No dose-limiting toxicities were observed (doses 100–400-mg), and the MTD was not reached. Safety was similar between schedules; no tumour lysis syndrome (TLS) occurred during dose-finding. Schedule B and Ven 400-mg were chosen for expansion. The most frequent grade 3–4 toxicity was neutropenia: R/R 64%, 1L Ven-BR 85%, 1L Ven-BG 55%. Grade 3–4 infection rate was: R/R 27%, 1L Ven-BR 0%, 1L Ven-BG 27%. During expansion, one clinical and two laboratory TLS cases occurred. Fewer than half the patients completed six combination therapy cycles with all study drugs; rates of bendamustine discontinuation were high. Overall response rate was 91% in R/R and 100% in 1L patients (16/49 1L patients received Ven for >1 year). In conclusion, addition of bendamustine to Ven-R/-G increased toxicity without apparent efficacy benefit.
Published: 2021

30. Red Cell Distribution Width in Patients with Diabetes and Myocardial Infarction: an analysis from the EXAMINE trial

Author: João Pedro Ferreira, Zohra Lamiral, Cyrus R. Mehta, Faiez Zannad, George L. Bakris, William B. White, BOZEC, Erwan, Combattre l'insuffisance cardiaque - - FIGHT-HF2015 - ANR-15-RHUS-0004 - RHUS - VALID, Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), The University of Chicago Medicine [Chicago], Cytel Corportation, Calhoun Cardiology Center [University of Connecticut], School of Medicine [University of Connecticut], University of Connecticut (UCONN)-University of Connecticut (UCONN), EXAMINE is a clinical trial sponsored by Takeda Global Research and Development Center, Inc., Deerfield, IL. JPF, PR, FZ are supported by a public grant overseen by the French National Research Agency (ANR) as part of the second 'Investissements d’Avenir' programme (ANR-15-RHU-0004), and ANR-15-RHUS-0004,FIGHT-HF,Combattre l'insuffisance cardiaque(2015)
Subjects: Erythrocyte Indices, Acute coronary syndrome, medicine.medical_specialty, Erythrocytes, Endocrinology, Diabetes and Metabolism, Myocardial Infarction, alogliptin, red cell distribution width, 030209 endocrinology & metabolism, Type 2 diabetes, 030204 cardiovascular system & hematology, outcomes, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Risk Factors, Internal medicine, Diabetes mellitus, Internal Medicine, medicine, Humans, Myocardial infarction, Proportional hazards model, business.industry, Red blood cell distribution width, Middle Aged, medicine.disease, Prognosis, 3. Good health, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Diabetes Mellitus, Type 2, Cardiology, Anisocytosis, Female, type 2 diabetes, business, Alogliptin
Abstract: International audience; Background: Red blood cell distribution width (RDW) is a measure of size variability in the red blood cell population (anisocytosis). Increased RDW may arise from any condition that affects erythropoiesis or the survival of erythrocytes. RDW has been associated with poor prognosis in patients with type 2 diabetes (T2D). Whether RDW is a risk marker for adverse cardiovascular outcomes or also a marker of non-cardiovascular health concerns is of clinical importance.Aims: To determine the clinical correlates of increased RDW, its potential mechanistic association with multiple circulating biomarkers, and its prognostic value, in patients with (T2D) who had a recent acute coronary syndrome.Methods: We used time-updated Cox models applied to patients enrolled in the EXAMINE (Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care) trial.Results: A total of 5380 patients were included, the median age was 61 years and 32% were women. Patients with higher RDW were older, more frequently women, with longer duration of diabetes duration, and increased comorbidities. An RDW >16.1% (both baseline and time-updated) was independently associated with the study primary composite outcome of nonfatal myocardial infarction, nonfatal stroke or cardiovascular death (time-updated adjusted HR =1.36, 95%CI =1.16-1.61, p < 0.001), all-cause death (time-updated adjusted HR =2.01, 95%CI =1.60-2.53, p < 0.001), as well as mortality from non-CV causes (time-updated adjusted HR =2.67, 95%CI =1.72-4.15, p < 0.001). RDW had a weak-to-moderate correlation with hemoglobin and circulating markers that reflected inflammation, apoptosis, fibrosis and congestion. Alogliptin did not alter RDW values.Conclusions: RDW is a marker of disease severity associated with a multitude of poor outcomes, including both cardiovascular and non-cardiovascular death. RDW correlated modestly with inflammatory, pro-apoptotic, pro-fibrotic, and congestion markers, and its levels were not affected by alogliptin during the course of the trial. This article is protected by copyright. All rights reserved.
Published: 2021

31. Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants

Author: Daniel R. Barnes, Matti A. Rookus, Lesley McGuffog, Goska Leslie, Thea M. Mooij, Joe Dennis, Nasim Mavaddat, Julian Adlard, Munaza Ahmed, Kristiina Aittomäki, Nadine Andrieu, Irene L. Andrulis, Norbert Arnold, Banu K. Arun, Jacopo Azzollini, Judith Balmaña, Rosa B. Barkardottir, Daniel Barrowdale, Javier Benitez, Pascaline Berthet, Katarzyna Białkowska, Amie M. Blanco, Marinus J. Blok, Bernardo Bonanni, Susanne E. Boonen, Åke Borg, Aniko Bozsik, Angela R. Bradbury, Paul Brennan, Carole Brewer, Joan Brunet, Saundra S. Buys, Trinidad Caldés, Maria A. Caligo, Ian Campbell, Lise Lotte Christensen, Wendy K. Chung, Kathleen B.M. Claes, Chrystelle Colas, Marie-Agnès Collonge-Rame, Capucine Delnatte, Laurence Faivre, Sophie Giraud, Christine Lasset, Véronique Mari, Noura Mebirouk, Emmanuelle Mouret-Fourme, Hélène Schuster, Dominique Stoppa-Lyonnet, Antonis Antoniou, Jackie Cook, Rosemarie Davidson, Douglas Easton, Ros Eeles, D. Gareth Evans, Debra Frost, Helen Hanson, Louise Izatt, Kai-ren Ong, Lucy Side, Aoife O’Shaughnessy-Kirwan, Marc Tischkowitz, Lisa Walker, Mary B. Daly, Miguel de la Hoya, Robin de Putter, Peter Devilee, Orland Diez, Yuan Chun Ding, Susan M. Domchek, Cecilia M. Dorfling, Martine Dumont, Bent Ejlertsen, Christoph Engel, Lenka Foretova, Florentia Fostira, Michael Friedlander, Eitan Friedman, Patricia A. Ganz, Judy Garber, Andrea Gehrig, Anne-Marie Gerdes, Paul Gesta, Gord Glendon, Andrew K. Godwin, David E. Goldgar, Anna González-Neira, Mark H. Greene, Daphne Gschwantler-Kaulich, Eric Hahnen, Ute Hamann, Julia Hentschel, Frans B.L. Hogervorst, Maartje J. Hooning, Judit Horvath, Chunling Hu, Peter J. Hulick, Evgeny N. Imyanitov, Georgia Chenevix-Trench, Kelly-Anne Phillips, Amanda Spurdle, Marinus Blok, Frans Hogervorst, Maartje Hooning, Marco Koudijs, Arjen Mensenkamp, Hanne Meijers-Heijboer, Matti Rookus, Klaartje van Engelen, Catherine Noguès, Claudine Isaacs, Angel Izquierdo, Anna Jakubowska, Paul A. James, Ramunas Janavicius, Esther M. John, Vijai Joseph, Beth Y. Karlan, Karin Kast, Torben A. Kruse, Ava Kwong, Yael Laitman, Conxi Lazaro, Jenny Lester, Fabienne Lesueur, Annelie Liljegren, Jennifer T. Loud, Jan Lubiński, Phuong L. Mai, Siranoush Manoukian, Hanne E.J. Meijers-Heijboer, Alfons Meindl, Arjen R. Mensenkamp, Austin Miller, Marco Montagna, Semanti Mukherjee, Anna Marie Mulligan, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Dieter Niederacher, Finn Cilius Nielsen, Liene Nikitina-Zake, Edith Olah, Olufunmilayo I. Olopade, Ana Osorio, Claus-Eric Ott, Laura Papi, Sue K. Park, Michael T. Parsons, Inge Sokilde Pedersen, Bernard Peissel, Ana Peixoto, Paolo Peterlongo, Georg Pfeiler, Karolina Prajzendanc, Miquel Angel Pujana, Paolo Radice, Juliane Ramser, Susan J. Ramus, Johanna Rantala, Gad Rennert, Harvey A. Risch, Mark Robson, Karina Rønlund, Ritu Salani, Leigha Senter, Payal D. Shah, Priyanka Sharma, Lucy E. Side, Christian F. Singer, Thomas P. Slavin, Penny Soucy, Melissa C. Southey, Amanda B. Spurdle, Doris Steinemann, Zoe Steinsnyder, Christian Sutter, Yen Yen Tan, Manuel R. Teixeira, Soo Hwang Teo, Darcy L. Thull, Silvia Tognazzo, Amanda E. Toland, Alison H. Trainer, Nadine Tung, Elizabeth J. van Rensburg, Ana Vega, Jeroen Vierstraete, Gabriel Wagner, Shan Wang-Gohrke, Barbara Wappenschmidt, Jeffrey N. Weitzel, Siddhartha Yadav, Xin Yang, Drakoulis Yannoukakos, Dario Zimbalatti, Kenneth Offit, Mads Thomassen, Fergus J. Couch, Rita K. Schmutzler, Jacques Simard, Douglas F. Easton, Antonis C. Antoniou, Pediatric surgery, Human genetics, CCA - Cancer biology and immunology, CCA - Cancer Treatment and quality of life, Amsterdam Reproduction & Development (AR&D), Apollo - University of Cambridge Repository, University of Cambridge [UK] (CAM), Netherlands Cancer Institute (NKI), Antoni van Leeuwenhoek Hospital, Chapel Allerton Hospital, Great Ormond Street Hospital for Children [London] (GOSH), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], Université Paris sciences et lettres (PSL), Mount Sinai Hospital [Toronto, Canada] (MSH), University of Toronto (University of Toronto), Christian-Albrechts University of Kiel, The University of Texas M.D. Anderson Cancer Center [Houston], Fondazione IRCCS Istituto Nazionale Tumori - National Cancer Institute [Milan], Vall d'Hebron Institute of Oncology [Barcelone] (VHIO), Vall d'Hebron University Hospital [Barcelona], Landspitali National University Hospital of Iceland, University of Iceland [Reykjavik], CIBER de Enfermedades Raras (CIBERER), Spanish National Cancer Research Center (CNIO), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Pomeranian Medical University [Szczecin] (PUM), University of California (UC), Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], European Institute of Oncology IRCCS [Milan, Italy] (EIO), Zealand University Hospital [Roskilde, Denmark], Lund University [Lund], National Institute of Oncology [Budapest, Hungary], Abramson Cancer Center [philadelphia], University of Pennsylvania-Perelman School of Medicine, University of Pennsylvania, Institute of Genetic Medicine [Newcastle], Newcastle University [Newcastle], Royal Devon & Exeter Hospital, Exeter, UK, Catalan Institute of Oncology [Barcelone, Espagne], Huntsman Cancer Institute [Salt Lake City], University of Utah, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos [Madrid, Spain] (IdISSC), Pisa University Hospital, Peter MacCallum Cancer Centre [Melbourne, Australie], University of Melbourne, Aarhus University Hospital, Columbia University [New York], Ghent University Hospital, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Sheffield Children's NHS Foundation Trust, Fox Chase Cancer Center, Queen Elizabeth University Hospital (Glasgow), Centre hospitalier universitaire de Nantes (CHU Nantes), Leiden University Medical Center (LUMC), Beckman Research Institute of the City of Hope, Abramson Cancer Center, University of Pretoria [South Africa], Centre Hospitalier Universitaire de Québec Research Center [Canada], Royal Marsden NHS Foundation Trust, Copenhagen University Hospital, Leipzig University, University of Manchester [Manchester], Manchester Academic Health Science Centre (MAHSC), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Masaryk Memorial Cancer Institute (MMCI), Institute of Nuclear and Radiological Sciences and Technology, Energy and Safety (INRASTES), National Center for Scientific Research 'Demokritos' (NCSR), NHMRC Clinical Trials Centre [Camperdown NSW 2050, Australie], Chaim Sheba Medical Center, Tel Aviv University (TAU), Jonsson Comprehensive Cancer Center, University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), Dana-Farber Cancer Institute [Boston], University of Würzburg, Rigshospitalet [Copenhagen], Centre Hospitalier Georges Renon [Niort] (CH Georges Renon Niort), Hospices Civils de Lyon (HCL), University of Kansas [Kansas City], National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Medizinische Universität Wien = Medical University of Vienna, University of Cologne, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Lancashire NHS Foundation Trust, University Hospital Leipzig, Department of Medical Oncology, Family Cancer Clinic, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Mayo Clinic, NorthShore University HealthSystem [Evanston, IL, USA], The University of Chicago Medicine [Chicago], N. N. Petrov Institute of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Guy's and St Thomas' NHS Foundation Trust [London, UK], Peter MacCallum Cancer Center, East Melbourne, Peter MacCallum Cancer Center, Vilnius University [Vilnius], The State Scientific Research Institute Nature Research Centre, Vilnius, Lithuania, Stanford University School of Medicine [CA, USA], Memorial Sloane Kettering Cancer Center [New York], Cedars-Sinai Medical Center, Technische Universität Dresden = Dresden University of Technology (TU Dresden), University Medical Center [Utrecht], Odense University Hospital [Odense, Denmark], The Hong Kong Hereditary Breast Cancer Family Registry, The University of Hong Kong (HKU), Hong Kong Sanatorium and Hospital [Hong Kong] (HKSH), Equipe de prévention et épidémiologie génétique, Centre Léon Bérard [Lyon], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), David Geffen School of Medicine [Los Angeles], Fondation MINES ParisTech, Karolinska Institutet [Stockholm], University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Amsterdam UMC - Amsterdam University Medical Center, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Radboud University Medical Center [Nijmegen], Roswell Park Cancer Institute [Buffalo], Veneto Institute of Oncology IOV-IRCCS [Padua, Italy], University of Toronto, University Health Network, University Hospital Düsseldorf, Latvian Biomedical Research and Study Centre [Rīga], Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), University of Chicago, Birmingham Women's and Children's NHS Foundation Trust, Cambridge University Hospitals - NHS (CUH), Charité Campus Virchow-Klinikum (CVK), Università degli Studi di Firenze = University of Florence (UniFI), Seoul National University College of Medicine [Séoul, Corée du Sud] (SNUCM), Seoul National University [Seoul] (SNU), QIMR Berghofer Medical Research Institute, Aalborg University [Denmark] (AAU), IRCCS Istituto Nazionale dei Tumori [Milano], Instituto Português de Oncologia do Porto / Portuguese Oncology Institute of Porto (IPO Porto), IFOM, Istituto FIRC di Oncologia Molecolare (IFOM), Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), Klinikum rechts der Isar [Munich, Germany], University of New South Wales [Sydney] (UNSW), Garvan Institute of medical research, Technion Faculty of Medicine [Haifa, Israel], Yale School of Medicine [New Haven, Connecticut] (YSM), Vejle Hospital [Danemark], Ohio State University [Columbus] (OSU), Centre de lutte contre le cancer Paul-Strauss, Institut de Cancérologie de Strasbourg Europe (ICANS), Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Kansas Medical Center [Kansas City, KS, USA], Princess Anne Hospital, City of Hope Comprehensive Cancer Center [Duarte], Monash University [Clayton], Cancer Council Victoria [Melbourne, VIC, Australia], Hannover Medical School [Hannover] (MHH), Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Heidelberg University Hospital [Heidelberg], Institute of Biomedical Sciences Abel Salazar - ICBAS [Porto, Portugal], Malaysia and University Malaya Cancer Research Institute, Faculty of Medicine, University of Malaya [Kuala Lumpur, Malaisie], University of Malaya = Universiti Malaya [Kuala Lumpur, Malaisie] (UM), McGill University = Université McGill [Montréal, Canada], Beth Israel Deaconess Medical Center [Boston] (BIDMC), Harvard Medical School [Boston] (HMS), Fundación Pública Galega Medicina Xenómica - SERGAS [Santiago de Compostela, Spain] (Grupo de Medicina Xenómica), CIBER de Enfermedades Raras (CIBERER)-Universidade de Santiago de Compostela [Spain] (USC ), Instituto de Investigaciones Sanitarias, Universidade de Santiago de Compostela [Spain] (USC ), Universiteit Gent = Ghent University (UGENT), Oxford University Hospitals NHS Trust, University of Oxford, Universitätsklinikum Ulm - University Hospital of Ulm, University Hospital of Cologne [Cologne], Mayo Clinic [Rochester], Collaborators : Pascaline Berthet, Chrystelle Colas, Marie-Agnès Collonge-Rame, Capucine Delnatte, Laurence Faivre, Sophie Giraud, Christine Lasset, Véronique Mari, Noura Mebirouk, Emmanuelle Mouret-Fourme, Hélène Schuster, Dominique Stoppa-Lyonnet, Julian Adlard, Munaza Ahmed, Antonis Antoniou, Daniel Barrowdale, Paul Brennan, Carole Brewer, Jackie Cook, Rosemarie Davidson, Douglas Easton, Ros Eeles, D Gareth Evans, Debra Frost, Helen Hanson, Louise Izatt, Kai-Ren Ong, Lucy Side, Aoife O'Shaughnessy-Kirwan, Marc Tischkowitz, Lisa Walker, Georgia Chenevix-Trench, Kelly-Anne Phillips, Amanda Spurdle, Marinus Blok, Peter Devilee, Frans Hogervorst, Maartje Hooning, Marco Koudijs, Arjen Mensenkamp, Hanne Meijers-Heijboer, Matti Rookus, Klaartje van Engelen, Nadine Andrieu, Catherine Noguès, Dupuis, Christine, Institut Català de la Salut, [Barnes DR, McGuffog L, Leslie G, Dennis J] Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. [Rookus MA, Mooij TM] The Netherlands Cancer Institute, Department of Epidemiology (PSOE), Amsterdam, The Netherlands. [Balmaña J] High Risk and Cancer Prevention Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Diez O] Oncogenetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Àrea de Genètica Clínica i Molecular, Vall d’Hebron Hospital Universitari, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Barnes, Daniel [0000-0002-3781-7570], Leslie, Goska [0000-0001-5756-6222], Dennis, Joe [0000-0003-4591-1214], Mavaddat, Nasim [0000-0003-0307-055X], RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Lab Centraal Lab (9), Universiteit Leiden, Roswell Park Cancer Institute [Buffalo] (RPCI), Medical Oncology, Medicum, Kristiina Aittomäki / Principal Investigator, HUSLAB, Department of Medical and Clinical Genetics, Helsinki University Hospital Area, Department of Obstetrics and Gynecology, Biosciences, HUS Gynecology and Obstetrics, University of Helsinki, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), MINES ParisTech - École nationale supérieure des mines de Paris, UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Pomeranian Medical University, University of California, University of Pennsylvania [Philadelphia]-Perelman School of Medicine, University of Pennsylvania [Philadelphia], University of Leipzig [Leipzig, Allemagne], Masaryk Memorial Cancer Institute (RECAMO), Tel Aviv University [Tel Aviv], University of California-University of California, University of Münster, Amsterdam UMC, Technical University of Munich (TUM), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Garvan Institute of Medical Research [Sydney, Australia], Yale University School of Medicine, Vejle Hospital, University of Kansas Medical Center [Lawrence], Université Paris Descartes (Paris 5), University of Malaya [Kuala Lumpur, Malaisie], Universiteit Gent = Ghent University [Belgium] (UGENT), and University of Oxford [Oxford]
Subjects: 0301 basic medicine, Oncology, endocrine system diseases, Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES], [SDV]Life Sciences [q-bio], Càncer d'ovari, Genetic Phenomena::Genotype::Genetic Predisposition to Disease [PHENOMENA AND PROCESSES], MODIFIERS, Diàtesi, SUSCEPTIBILITY, Carcinoma, Ovarian Epithelial, PRS, 0302 clinical medicine, Breast cancer, 3123 Gynaecology and paediatrics, Risk Factors, Medicine and Health Sciences, Medicine, Genetics(clinical), genetics, Prospective Studies, Prospective cohort study, skin and connective tissue diseases, Genetics (clinical), Ovarian Neoplasms, education.field_of_study, neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES], Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], BRCA1 Protein, Hazard ratio, Absolute risk reduction, 1184 Genetics, developmental biology, physiology, article, ASSOCIATION, neoplasias::neoplasias::neoplasias por localización::neoplasias de las glándulas endocrinas::neoplasias ováricas::carcinoma epitelial de ovario [ENFERMEDADES], ddc, 3. Good health, [SDV] Life Sciences [q-bio], ovarian cancer, 030220 oncology & carcinogenesis, Female, Cohort study, medicine.medical_specialty, Heterozygote, Population, 3122 Cancers, Single-nucleotide polymorphism, Breast Neoplasms, MUTATION CARRIERS, Ovaris - Càncer - Aspectes genètics, Càncer de mama, 03 medical and health sciences, breast cancer, SDG 3 - Good Health and Well-being, Ovarian cancer, BRCA1/2, Internal medicine, Humans, Genetic Predisposition to Disease, education, Retrospective Studies, fenómenos genéticos::genotipo::predisposición genética a la enfermedad [FENÓMENOS Y PROCESOS], BRCA2 Protein, IDENTIFICATION, business.industry, Neoplasms::Neoplasms::Neoplasms by Site::Endocrine Gland Neoplasms::Ovarian Neoplasms::Carcinoma, Ovarian Epithelial [DISEASES], Retrospective cohort study, ALLELES, medicine.disease, BRCA1, BRCA2, MODEL, PATHOLOGY, 030104 developmental biology, Mutation, Mama - Càncer - Aspectes genètics, 3111 Biomedicine, business
Abstract: Contains fulltext : 229292.pdf (Publisher’s version ) (Open Access) PURPOSE: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers. METHODS: Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort. RESULTS: The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33], P = 3×10(-72)). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36], P = 7×10(-50)). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25-1.40], P = 3×10(-22)) and BRCA2 (HR = 1.44 [95% CI 1.30-1.60], P = 4×10(-12)) carriers. The associations in the prospective cohort were similar. CONCLUSION: Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.
Published: 2020

32. Improved Delineation of Cardiac Pathology Using a Novel Three-Dimensional Echocardiographic Tissue Transparency Tool

Author: Karima Addetia, Eric Kruse, Lydia Rivera, Laurie Soulat-Dufour, Amita Singh, Roberto M. Lang, Jeanne M. DeCara, Megan Yamat, Victor Mor-Avi, Alasdair Dow, Atman P. Shah, Ilya Karagodin, The University of Chicago Medicine [Chicago], Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: medicine.medical_specialty, [SDV]Life Sciences [q-bio], Cardiac pathology, Echocardiography, Three-Dimensional, Transillumination, 030204 cardiovascular system & hematology, Three-dimensional echocardiography, Article, 3D rendering, 030218 nuclear medicine & medical imaging, Rendering (computer graphics), Random Allocation, 03 medical and health sciences, 0302 clinical medicine, Light source, Cardiac valve, Humans, Medicine, Radiology, Nuclear Medicine and imaging, business.industry, Heart, Valvular heart disease, Visualization, Echocardiography, Radiology, Cardiology and Cardiovascular Medicine, Depth perception, business, Echocardiography, Transesophageal
Abstract: BACKGROUND: Accurate visualization of cardiac valves and lesions by three-dimensional (3D) echocardiography is integral for optimal guidance of structural procedures and appropriate selection of closure devices. A new 3D rendering tool known as transillumination (TI), which integrates a virtual light source into the data set, was recently reported to effectively enhance depth perception and orifice definition. We hypothesized that adding the ability to adjust transparency to this tool would result in improved visualization and delineation of anatomy and pathology and improved localization of regurgitant jets compared with TI without transparency and standard 3D rendering. METHODS: We prospectively studied 30 patients with a spectrum of structural heart disease who underwent 3D transesophageal imaging (EPIQ system, Philips) with standard acquisition and TI with and without the transparency feature. Six experienced cardiologists and sonographers were shown randomized images of all three display types in a blinded fashion. Each image was scored independently by all experts using a Likert scale from 1 to 5, while assessing each of the following aspects: (1) ability to recognize anatomy, (2) ability to identify pathology, including regurgitant jet origin, (3) depth perception, and (4) quality of border delineation. RESULTS: TI images with transparency were successfully obtained in all cases. All experts perceived an incremental value of the transparency mode, compared with TI without transparency and standard 3D rendering, in terms of ability to recognize anatomy (respective scores: 4.5 ± 1.1 vs 4.1 ± 1.1 vs 3.6 ± 1.1, P < .05), ability to identify pathology (4.1 ± 1.1 vs 3.9 ± 1.2 vs 3.3 ± 1, P < .05), depth perception (4.6 ± 0.7 vs 4.1 ± 0.8 vs 3.2 ± 1.0, P < .05), and border delineation (4.6 ± 0.8 vs 4.1 ± 1.0 vs 3.1 ± 1.1, P < .05). CONCLUSIONS: The addition of the transparency mode to TI rendering significantly improves the diagnostic and clinical utility of 3D echocardiography and has the potential to markedly enhance echocardiographic guidance of cardiac structural interventions. (J Am Soc Echocardiogr 2020;33:1316–23.)
Published: 2020

33. Sexology as a profession in France: Preliminary results of a national survey (2019)

Author: S. Michaels, Alain Giami, 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, The University of Chicago Medicine [Chicago], and CCSD, Accord Elsevier
Subjects: 050103 clinical psychology, medicine.medical_specialty, education.field_of_study, Sexology, business.industry, education, 05 social sciences, Population, Obstetrics and Gynecology, Identity (social science), 050109 social psychology, Human sexuality, Professional activity, [SHS]Humanities and Social Sciences, Family medicine, medicine, 0501 psychology and cognitive sciences, Psychology (miscellaneous), [SHS] Humanities and Social Sciences, Psychology, business, Reproductive health
Abstract: Summary The article aims to identify the sociodemographic characteristics of the population of sexologists practicing in France and in particular the distribution between the different initial professions (doctors, psychologists, nurses, midwives, other professions), the sex ratio and the adhesion to the professional identity of sexologist. It was also a question of examining the training and diplomas in sexology obtained, the framework of practice (private or salaried), the different clinical practices used by sexologists as well as their degree of participation in the sexology apparatus (membership of an association, participation in congresses). A cross-sectional survey was carried out between December 2018 and March 2019 using a self-administered questionnaire distributed electronically to persons who had participated in the Assises de sexologie in previous years (2014–2018). This is the questionnaire that was already used in the surveys conducted in 1999 and 2009 and adapted to recent developments. The results show a significant change in the population of sexologists (compared to the 1999 data) with, in particular, the inversion of the sex ratio (83% of women) and the relative proportion of doctors and non-physicians (67% of non-physicians). The majority of participants have a degree in sexology or sexual health (62%). More than 60% of the participants do not devote more than 50% to sexology as part of their overall professional activity. In spite of their minority presence among sexologists, physicians continue to exert a strong influence in that they are more frequent speakers at sexology congresses. The survey has thus revealed a change in the profile of persons working in the field of sexology and sexual health as well as a change in the missions assigned to sexologists and to all persons who intervene in matters related to sexuality and sexual health. This evolution is parallel to the creation of new sexology associations focusing on specific themes.
Published: 2020

34. Abnormalities of Potassium in Heart Failure JACC State-of-the-Art Review

Author: Ferreira, João Pedro, Butler, Javed, Rossignol, Patrick, Pitt, Bertram, Anker, Stefan D., Kosiborod, Mikhail, Lund, Lars H., Bakris, George L., Weir, Matthew R., Zannad, Faiez, Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Department of Medicine, University of Washington [Seattle], Department of Internal Medicine (DIM - Cartagena), Hospital Universitario Santa Maria de Rosell, German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), University of Missouri [Kansas City] (UMKC), University of Missouri System, The George Institute for Global Health [Sydney] (GIGH), The University of Sydney, The University of Chicago Medicine [Chicago], and CCSD, Accord Elsevier
Subjects: [SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio]
Published: 2020

35. Evolutionary and population (epi)genetics of immunity to infection

Author: Lluis Quintana-Murci, Luis B. Barreiro, The University of Chicago Medicine [Chicago], Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), This work has been supported by grants NIH R01-GM115656 and R01-GM134376 to L.B.B, and by the Institut Pasteur, the French Government’s Investissement d’Avenir program, Laboratoires d’Excellence 'Integrative Biology of Emerging Infec-tious Diseases' (ANR-10- LABX-62-IBEID) and 'Milieu Intérieur' (ANR-10-LABX-69-01), and the Fondation pour la Recherche Médi-cale (Equipe FRM DEQ20180339214) to L.Q.-M, ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Collège de France - Chaire Génomique humaine et évolution, and Collège de France (CdF (institution))
Subjects: MESH: Selection, Genetic, Population, Population genetics, MESH: Genetics, Population, MESH: Biological Evolution, Biology, Infections, Article, Epigenesis, Genetic, 03 medical and health sciences, Immune system, Genetics, Animals, Humans, MESH: Animals, MESH: Epigenesis, Genetic, MESH: Genetic Variation, Selection, Genetic, education, Genetics (clinical), MESH: Genome, Human, 030304 developmental biology, 0303 health sciences, education.field_of_study, Natural selection, MESH: Humans, Genome, Human, 030305 genetics & heredity, MESH: Infections, Genetic Variation, Biological Evolution, Human genetics, Genetics, Population, Human evolution, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Adaptation, Functional genomics
Abstract: International audience; Immune response is one of the functions that have been more strongly targeted by natural selection during human evolution. The evolutionary genetic dissection of the immune system has greatly helped to distinguish genes and functions that are essential, redundant or advantageous for human survival. It is also becoming increasingly clear that admixture between early Eurasians with now-extinct hominins such as Neanderthals or Denisovans, or admixture between modern human populations, can be beneficial for human adaptation to pathogen pressures. In this review, we discuss how the integration of population genetics with functional genomics in diverse human populations can inform about the changes in immune functions related to major lifestyle transitions (e.g., from hunting and gathering to farming), the action of natural selection to the evolution of the immune system, and the history of past epidemics. We also highlight the need of expanding the characterization of the immune system to a larger array of human populations-particularly neglected human groups historically exposed to different pathogen pressures-to fully capture the relative contribution of genetic, epigenetic, and environmental factors to immune response variation in humans.
Published: 2020

36. Timing of randomization after an acute coronary syndrome in patients with type 2 diabetes mellitus

Author: George L. Bakris, Abhinav Sharma, Patrick Rossignol, Malik Elharram, Cyrus R. Mehta, João Pedro Ferreira, Faiez Zannad, William B. White, McGill University Health Center [Montreal] (MUHC), University of Connecticut (UCONN), The University of Chicago Medicine [Chicago], Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), Harvard T.H. Chan School of Public Health, Cytel Corporation, Cambridge, IMPACT GEENAGE, ANR-15-RHUS-0004,FIGHT-HF,Combattre l'insuffisance cardiaque(2015), and ANR-15-IDEX-0004,LUE (ISITE),Lorraine Université d'Excellence(2016)
Subjects: Male, Acute coronary syndrome, medicine.medical_specialty, Time Factors, [SDV]Life Sciences [q-bio], Myocardial Infarction, Comorbidity, 030204 cardiovascular system & hematology, Risk Assessment, law.invention, 03 medical and health sciences, Random Allocation, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Randomized controlled trial, Piperidines, law, Internal medicine, medicine, Humans, Hypoglycemic Agents, 030212 general & internal medicine, Myocardial infarction, Acute Coronary Syndrome, Uracil, business.industry, Patient Selection, Hazard ratio, Middle Aged, medicine.disease, 3. Good health, Clinical trial, Stroke, Outcome and Process Assessment, Health Care, Diabetes Mellitus, Type 2, Heart Disease Risk Factors, Evidence-Based Practice, Cohort, Female, Cardiology and Cardiovascular Medicine, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Alogliptin
Abstract: International audience; Background: The timing of enrolment following an acute coronary syndrome (ACS) may influence cardiovascular (CV) outcomes and potentially treatment effect in clinical trials. Understanding the timing and type of clinical events after an ACS will allow for clinicians to better tailor evidence-based treatments to optimize therapeutic effect. Using a large contemporary trial in patients with type 2 diabetes mellitus (T2DM) post-ACS, we examined the impact of timing of enrolment on subsequent CV outcomes.Methods: EXAMINE was a randomized trial of alogliptin versus placebo in 5,380 patients with T2DM and a recent ACS from October 2009 to March 2013. The primary outcome was a composite of CV death, nonfatal myocardial infarction (MI), or nonfatal stroke. The median follow-up was 18 months. In this post hoc analysis, we examined the occurrence of subsequent CV events by timing of enrollment divided by tertiles of time from ACS to randomization: 8-34, 35-56, and 57-141 days.Results: Patients randomized early (compared to the latest times) had less comorbidities at baseline including a history of heart failure (HF; 24.7% vs 33.0%), prior coronary artery bypass graft (9.6% vs 15.9%), or atrial fibrillation (5.9% vs 9.4%). Despite the reduced comorbidity burden, the risk of the primary outcome was highest in patients randomized early compared to the latest time (adjusted hazard ratio 1.47; 95% CI 1.21-1.74). Similarly, patients randomized early had an increased risk of recurrent MI (adjusted hazard ratio 1.51; 95% CI 1.17-1.96) and HF hospitalization (1.49; 95% CI 1.05-2.10).Conclusions: In a contemporary cohort of T2DM with a recent ACS, the risk for recurrent CV events including MI and HF hospitalization is elevated early after an ACS. Given the emergence of antihyperglycemic therapies that reduce the risk of MI and HF among patients with T2DM at high CV risk, future studies evaluating the initiation of these therapies in the early period following an ACS are warranted given the large burden of potentially modifiable CV events.Copyright © 2020 Elsevier Inc. All rights reserved.
Published: 2020

37. CoMPARA: Collaborative Modeling Project for Androgen Receptor Activity

Author: Geven Piir, Paola Gramatica, Vinicius M. Alves, Uko Maran, Xianliang Qiao, Michel Petitjean, Christopher M. Grulke, Karl-Werner Schramm, Giuseppe Felice Mangiatordi, Antony J. Williams, Barun Bhhatarai, Sherif Farag, Alexey V. Zakharov, Chetan Rupakheti, Emilio Benfenati, Weida Tong, Chandrabose Selvaraj, Eva Bay Wedebye, Fang Bai, Sugunadevi Sakkiah, Nicole Kleinstreuer, Ann M. Richard, Orazio Nicolotti, Huixiao Hong, George Van Den Driessche, Ilya A. Balabin, Eugene N. Muratov, Imran Shah, Ulf Norinder, Jiazhong Li, Huanxiang Liu, Viviana Consonni, Igor V. Tetko, Pavel V. Pogodin, Ruili Huang, Ester Papa, Ahmed Abdelaziz, Dragos Horvath, Alexandre Varnek, Patricia Ruiz, Carolina Horta Andrade, Domenico Alberga, Ziye Zheng, Roberto Todeschini, Daniela Trisciuzzi, Nina Jeliazkova, Xuehua Li, Dac-Trung Nguyen, Gilles Marcou, Zhongyu Wang, Kamel Mansouri, Alexander Tropsha, Yun Tang, Alessandro Sangion, Todd M. Martin, Xin Hu, Scott Boyer, Hongbin Xie, Serena Manganelli, Richard S. Judson, Nikolai Georgiev Nikolov, Jingwen Chen, Denis Fourches, Vladimir Poroikov, Alfonso T. García-Sosa, Alessandra Roncaglioni, Davide Ballabio, Patrik L. Andersson, Sulev Sild, Francesca Grisoni, Lixia Sun, Olivier Taboureau, US Environmental Protection Agency (EPA), University of Insubria, Varese, Laboratoire de Chémoinformatique, Chimie de la matière complexe (CMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Università degli studi di Bari, Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Mansouri, K, Kleinstreuer, N, Abdelaziz, A, Alberga, D, Alves, V, Andersson, P, Andrade, C, Bai, F, Balabin, I, Ballabio, D, Benfenati, E, Bhhatarai, B, Boyer, S, Chen, J, Consonni, V, Farag, S, Fourches, D, García-Sosa, A, Gramatica, P, Grisoni, F, Grulke, C, Hong, H, Horvath, D, Hu, X, Huang, R, Jeliazkova, N, Li, J, Li, X, Liu, H, Manganelli, S, Mangiatordi, G, Maran, U, Marcou, G, Martin, T, Muratov, E, Nguyen, D, Nicolotti, O, Nikolov, N, Norinder, U, Papa, E, Petitjean, M, Piir, G, Pogodin, P, Poroikov, V, Qiao, X, Richard, A, Roncaglioni, A, Ruiz, P, Rupakheti, C, Sakkiah, S, Sangion, A, Schramm, K, Selvaraj, C, Shah, I, Sild, S, Sun, L, Taboureau, O, Tang, Y, Tetko, I, Todeschini, R, Tong, W, Trisciuzzi, D, Tropsha, A, Van Den Driessche, G, Varnek, A, Wang, Z, Wedebye, E, Williams, A, Xie, H, Zakharov, A, Zheng, Z, Judson, R, National Institute of Environmental Health Sciences, National Institutes of Health, University of Bari Aldo Moro (UNIBA), Federal University of Goiás [Jataí], Dept. of Statistics - University of North Carolina - Chapel Hill, University of North Carolina System (UNC)-University of North Carolina System (UNC), Umeå University, Lanzhou University, Università degli Studi di Milano-Bicocca [Milano] (UNIMIB), Istituto di Ricerche Farmacologiche 'Mario Negri', Karolinska Institutet [Stockholm], Dalian University of Technology, Department of Statistics University of Milano Bicocca, University of North Carolina at Chapel Hill (UNC), North Carolina State University [Raleigh] (NC State), Institute of Computer Science [University of Tartu, Estonie], University of Tartu, U.S. ENVIRONMENTAL PROTECTION AGENCY USA, Partenaires IRSTEA, Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA), U.S. Food and Drug Administration (FDA), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), National Institutes of Health [Bethesda] (NIH), Università degli studi di Bari Aldo Moro (UNIBA), Technical University of Denmark [Lyngby] (DTU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institute of Biomedical Chemistry [Moscou] (IBMC), Centers for Disease Control and Prevention, The University of Chicago Medicine [Chicago], East China University of Science and Technology, and German Research Center for Environmental Health - Helmholtz Center München (GmbH)
Subjects: Databases, Factual, Health, Toxicology and Mutagenesis, Computational biology, Pharmacology and Toxicology, 010501 environmental sciences, Biology, Endocrine Disruptors, 01 natural sciences, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, CHIM/01 - CHIMICA ANALITICA, High-Throughput Screening Assays, consensu, Endocrine system, Humans, Computer Simulation, 030212 general & internal medicine, United States Environmental Protection Agency, 0105 earth and related environmental sciences, QSAR, Research, Public Health, Environmental and Occupational Health, Farmakologi och toxikologi, United States, 3. Good health, Metabolic pathway, machine learning, chemistry, 13. Climate action, Receptors, Androgen, chemical modelling, Androgen Receptor, Androgens, Xenobiotic, Androgen receptor activity, [CHIM.CHEM]Chemical Sciences/Cheminformatics, Hormone
Abstract: Background:Endocrine disrupting chemicals (EDCs) are xenobiotics that mimic the interaction of natural hormones and alter synthesis, transport, or metabolic pathways. The prospect of EDCs causing adverse health effects in humans and wildlife has led to the development of scientific and regulatory approaches for evaluating bioactivity. This need is being addressed using high-throughput screening (HTS) in vitro approaches and computational modeling.Objectives:In support of the Endocrine Disruptor Screening Program, the U.S. Environmental Protection Agency (EPA) led two worldwide consortiums to virtually screen chemicals for their potential estrogenic and androgenic activities. Here, we describe the Collaborative Modeling Project for Androgen Receptor Activity (CoMPARA) efforts, which follows the steps of the Collaborative Estrogen Receptor Activity Prediction Project (CERAPP).Methods:The CoMPARA list of screened chemicals built on CERAPP’s list of 32,464 chemicals to include additional chemicals of interest, as well as simulated ToxCast™ metabolites, totaling 55,450 chemical structures. Computational toxicology scientists from 25 international groups contributed 91 predictive models for binding, agonist, and antagonist activity predictions. Models were underpinned by a common training set of 1,746 chemicals compiled from a combined data set of 11 ToxCast™/Tox21 HTS in vitro assays.Results:The resulting models were evaluated using curated literature data extracted from different sources. To overcome the limitations of single-model approaches, CoMPARA predictions were combined into consensus models that provided averaged predictive accuracy of approximately 80% for the evaluation set.Discussion:The strengths and limitations of the consensus predictions were discussed with example chemicals; then, the models were implemented into the free and open-source OPERA application to enable screening of new chemicals with a defined applicability domain and accuracy assessment. This implementation was used to screen the entire EPA DSSTox database of ∼875,000 chemicals, and their predicted AR activities have been made available on the EPA CompTox Chemicals dashboard and National Toxicology Program’s Integrated Chemical Environment. https://doi.org/10.1289/EHP5580
Published: 2020

38. Clinical and Biomarker Predictors of Expanded Heart Failure Outcomes in Patients With Type 2 Diabetes Mellitus After a Recent Acute Coronary Syndrome: Insights From the EXAMINE Trial

Author: Abhinav Sharma, Muthiah Vaduganathan, George L. Bakris, William B. White, João Pedro Ferreira, Faiez Zannad, Yuyin Liu, Christopher P. Cannon, Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), Division of Cardiology Stanford University Palo Alto, McGill University Health Center [Montreal] (MUHC), Brigham and Women's Hospital Heart and Vascular Center Harvard Medical School Boston MA, Department of Physiology University of Porto, Baim Institute for Clinical Research Boston MA, The University of Chicago Medicine [Chicago], University of Connecticut School of Medicine Farmington CT, EXAMINE is a clinical trial sponsored by Takeda Global Research and Development Center, Inc, Deerfield, IL., Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), and BOZEC, Erwan
Subjects: Male, Galectin 3, Myocardial Infarction, heart failure, risk stratification, 030204 cardiovascular system & hematology, 0302 clinical medicine, Piperidines, Natriuretic Peptide, Brain, Natriuretic peptide, Original Research, Blood Proteins, Middle Aged, Prognosis, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3. Good health, Hospitalization, Risk stratification, Biomarker (medicine), Female, Cardiology and Cardiovascular Medicine, Acute coronary syndrome, medicine.medical_specialty, Growth Differentiation Factor 15, medicine.drug_class, Galectins, MEDLINE, 030209 endocrinology & metabolism, Risk Assessment, 03 medical and health sciences, Double-Blind Method, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, medicine, Humans, In patient, Acute Coronary Syndrome, Uracil, Aged, Dipeptidyl-Peptidase IV Inhibitors, natriuretic peptide, business.industry, Troponin I, biomarkers, Type 2 Diabetes Mellitus, medicine.disease, Peptide Fragments, Diabetes Mellitus, Type 2, Heart Disease Risk Factors, Heart failure, business
Abstract: Background Improved heart failure ( HF ) risk stratification after a recent acute coronary syndrome may identify those who can benefit from therapies that reduce HF risk. We aimed to identify clinical and biomarker predictors for expanded HF outcomes in patients with type 2 diabetes mellitus after recent acute coronary syndrome. Methods and Results The EXAMINE ( Ex amination of Cardiovascular Outcomes with Alogliptin versus Standard of Care) trial was a multicenter, non‐inferiority, double‐masked, placebo‐controlled study which randomized 5380 patients with type 2 diabetes mellitus after recent acute coronary syndrome to alogliptin or placebo. Baseline biomarkers were measured in 5154 patients: NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide), high‐sensitivity troponin I, adiponectin, growth‐differentiation‐factor‐15, and galectin‐3. Our primary outcome was cardiovascular) death, HF hospitalization, elevated NT‐proBNP during follow‐up, or loop diuretics initiation. The association between clinical variables, biomarkers, and outcomes were assessed using Cox regression models. In the study population, the median age was 61.0 years, 67.7% were men, and 28.0% had baseline HF (median follow‐up was 18 months). In multivariable analyses, NT‐proBNP had the strongest association with the primary outcome (per log 2 , hazard ratio 1.24; Wald χ 2 67.4; P HF history (hazard ratio 1.42; Wald χ 2 20.8; P HF outcomes (C‐statistic=0.72). Discrimination results were similar for cardiovascular death or HF hospitalization. Conclusions Among patients with type 2 diabetes mellitus after recent acute coronary syndrome, the use biomarkers such as N‐terminal pro‐B‐type natriuretic peptide and clinical variables enables risk stratification for expanded HF outcomes. Clinical Trial Registration URL : https://www.clinicaltrials.gov/ . Unique identifier: NCT 00968708.
Published: 2020

39. Degenerative mitral regurgitation

Author: Karima Addetia, Laurie Soulat-Dufour, The University of Chicago Medicine [Chicago], Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), 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], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: medicine.medical_specialty, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Severe disease, Disease, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Mitral valve, Humans, Medicine, 030212 general & internal medicine, Cardiac Surgical Procedures, Therapeutic strategy, Mitral regurgitation, Mitral valve repair, Arrhythmic risk, business.industry, Mitral Valve Insufficiency, Prognosis, 3. Good health, medicine.anatomical_structure, Echocardiography, embryonic structures, Cardiology, Mitral Valve, Cardiology and Cardiovascular Medicine, business
Abstract: International audience; Purpose of review: Degenerative mitral regurgitation (DMR) continues to be an important cause of morbidity and mortality with surgical mitral valve repair remaining the gold standard for the treatment of severe disease. The purpose of this review is to summarize recent advances in the understanding of DMR as well as the progress made in its assessment with a focus on imaging techniques.Recent findings: Recent insights into the anatomy and physiology of DMR challenge the assumption that fibroelastic deficiency and Barlow disease are part of a single DMR spectrum. Advances in echocardiography and cardiovascular MRI have the potential to improve quantification of mitral regurgitation, provide unique information on prognosis and impact of DMR, further the association between DMR and arrhythmic risk and aide in decision-making for DMR treatment.Summary: With growing interest in the use of noninvasive transcatheter therapies in the mitral valve space, comprehensive assessment of the mitral valve is critical to instruct decision-making and guide therapeutic strategy.
Published: 2020

40. Lung- and Diaphragm-Protective Ventilation

Author: Robinder G. Khemani, Eddy Fan, Samir Jaber, Giacomo Grasselli, Alexandre Demoule, Sarina K. Sahetya, Jose Dianti, Dimitrios Georgopoulos, Francesco Mojoli, Tommaso Mauri, Laurent Brochard, Katerina Vaporidi, Claude Guérin, Coen A.C. Ottenheijm, Jeremy R. Beitler, Tom Schepens, Savino Spadaro, Takeshi Yoshida, Antonio Pesenti, Franco Laghi, Marcelo B. P. Amato, Ewan C. Goligher, Alain Mercat, Domenico Luca Grieco, Giacomo Bellani, L.M.A. Heunks, Irene Telias, Niall D. Ferguson, Martin Dres, Jordi Mancebo, Bhakti K. Patel, Physiology, ACS - Pulmonary hypertension & thrombosis, Intensive care medicine, University Health Network, Toronto General Hospital Research Institute [Canada] (TGHRI), Neurophysiologie Respiratoire Expérimentale et Clinique (UMRS 1158), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Chicago, Johns Hopkins University (JHU), Columbia University [New York], St. Michael's Hospital, Osaka University, University of Crete [Heraklion] (UOC), Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Antwerp University Hospital [Edegem] (UZA), Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Università degli Studi di Milano = University of Milan (UNIMI), Università degli Studi di Ferrara = University of Ferrara (UniFE), Italian Hospital of Buenos Aires, Universidade de São Paulo = University of São Paulo (USP), Università degli Studi di Milano-Bicocca = University of Milano-Bicocca (UNIMIB), University of Toronto, Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Molecular virology and immunology – Physiopathology and therapeutic of chronic viral hepatitis (Team 18) (Inserm U955), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Children’s Hospital Los Angeles [Los Angeles], University of Southern California (USC), Loyola University [Chicago], Endocrinologie pédiatrique[CHU Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Università degli Studi di Pavia = University of Pavia (UNIPV), Amsterdam UMC - Amsterdam University Medical Center, Hôpital Saint Eloi (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Hospital de la Santa Creu i Sant Pau, dres, martin, Interdepartmental Division of Critical Care Medicine, Biomécanique cellulaire et respiratoire (BCR), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), VU University Medical Center [Amsterdam], European Soc Intensive Care Med, Goligher, E, Dres, M, Patel, B, Sahetya, S, Beitler, J, Telias, I, Yoshida, T, Vaporidi, K, Grieco, D, Schepens, T, Grasselli, G, Spadaro, S, Dianti, J, Amato, M, Bellani, G, Demoule, A, Fan, E, Ferguson, N, Georgopoulos, D, Guérin, C, Khemani, R, Laghi, F, Mercat, A, Mojoli, F, Ottenheijm, C, Jaber, S, Heunks, L, Mancebo, J, Mauri, T, Pesenti, A, Brochard, L, Sorbonne Université - Faculté de médecine [CHU Pitié Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), The University of Chicago Medicine [Chicago], Johns Hopkins University School of Medicine [Baltimore], Columbia University College of Physicians and Surgeons, Keenan Research Centre of the Li Ka Shing Knowledge Institute [Toronto], Graduate School of Medicine [Osaka], Osaka University [Osaka], Department of Physiopatology and Transplantation, University of Milan (DEPT), Universidade de São Paulo Medical School (FMUSP), Service de Pneumologie - R3S [CHU Pitié-Salpêtrière] (SPMIR-R3S), IMRB - 'Biomechanics and Respiratory Apparatus' [Créteil] (U955 Inserm - UPEC), Stritch School of Medicine, Edward Hines, Jr. VA Hospital, and Fondazione IRCCS Policlinico San Matteo [Pavia]
Subjects: Pulmonary and Respiratory Medicine, Artificial ventilation, medicine.medical_specialty, Consensus, Critical Care, Ventilator-Induced Lung Injury, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Diaphragm, Electric Stimulation Therapy, Lung injury, Critical Care and Intensive Care Medicine, Artificial respiration, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, NO, 03 medical and health sciences, Extracorporeal Membrane Oxygenation, 0302 clinical medicine, Mechanical ventilation, Intensive care, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], medicine, Extracorporeal membrane oxygenation, Humans, Myotrauma, 030212 general & internal medicine, Intensive care medicine, business.industry, Decision Support Systems, Clinical, Respiration, Artificial, 3. Good health, Diaphragm (structural system), Phrenic Nerve, [SDV] Life Sciences [q-bio], Muscular Atrophy, 030228 respiratory system, Breathing, Human medicine, business, Critical Care Perspective
Abstract: International audience; Mechanical ventilation can cause acute diaphragm atrophy and injury, and this is associated with poor clinical outcomes. Although the importance and impact of lung-protective ventilation is widely appreciated and well established, the concept of diaphragm-protective ventilation has recently emerged as a potential complementary therapeutic strategy. This Perspective, developed from discussions at a meeting of international experts convened by PLUG (the Pleural Pressure Working Group) of the European Society of Intensive Care Medicine, outlines a conceptual framework for an integrated lung- and diaphragm-protective approach to mechanical ventilation on the basis of growing evidence about mechanisms of injury. We propose targets for diaphragm protection based on respiratory effort and patient–ventilator synchrony. The potential for conflict between diaphragm protection and lung protection under certain conditions is discussed; we emphasize that when conflicts arise, lung protection must be prioritized over diaphragm protection. Monitoring respiratory effort is essential to concomitantly protect both the diaphragm and the lung during mechanical ventilation. To implement lung- and diaphragm-protective ventilation, new approaches to monitoring, to setting the ventilator, and to titrating sedation will be required. Adjunctive interventions, including extracorporeal life support techniques, phrenic nerve stimulation, and clinical decision-support systems, may also play an important role in selected patients in the future. Evaluating the clinical impact of this new paradigm will be challenging, owing to the complexity of the intervention. The concept of lung- and diaphragm-protective ventilation presents a new opportunity to potentially improve clinical outcomes for critically ill patients.
Published: 2020

41. DYRK1A Is Regulated By Oncogenic KMT2A and Required for Survival of KMT2A-Rearranged Acute Lymphoblastic Leukemia

Author: Gerald Wertheim, Anne Lehman, John D. Crispino, Thierry Besson, Christian Hurtz, Martin Carroll, Rahul S. Bhansali, Sarah K. Tasian, Grace R. Jeschke, University of Pennsylvania [Philadelphia], Children’s Hospital of Philadelphia (CHOP ), University of Illinois College of Medicine, University of Illinois System, The University of Chicago Medicine [Chicago], Chimie Organique et Bioorganique : Réactivité et Analyse (COBRA), Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie Organique Fine (IRCOF), Université de Rouen Normandie (UNIROUEN), and Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Cell signaling, Immunology, achilles tendon, cell lines, acute lymphocytic leukemia, Biochemistry, burkitt's lymphoma, chemotherapy regimen, 03 medical and health sciences, 0302 clinical medicine, Acute lymphocytic leukemia, b-lymphocytes, medicine, Transcriptional regulation, [CHIM]Chemical Sciences, 030304 developmental biology, 0303 health sciences, acute megakaryocytic leukemias, Oncogene, biology, business.industry, Cell Biology, Hematology, DOT1L, medicine.disease, Fusion protein, 3. Good health, binding (molecular function), Leukemia, KMT2A, biological products, Cancer research, biology.protein, adverse effects, business, 030215 immunology
Abstract: Background: Research efforts have focused upon uncovering critical leukemia-associated genetic alterations that may be amenable to therapeutic targeting with new drugs. Targeting the oncogenic BCR-ABL1 fusion protein in Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia (B-ALL) with tyrosine kinase inhibitors to shut down constitutive signaling activation and induce leukemia cell cytotoxicity has remarkably improved patients' survival and has established a precision medicine paradigm for kinase-driven leukemias. However, multiple subtypes of B-ALL are driven through non-tyrosine fusion proteins, including the high-risk KMT2A-rearranged (KMT2A-R) subtype common in infants with B-ALL, leaving many patients with insufficient treatment options. Objectives: KMT2A-R B-ALL is associated with chemoresistance, relapse, and poor survival with a frequency of 75% in infants and 10% in older children/adults with B-ALL. Current intensive multiagent chemotherapy regimens induce significant side effects yet fail to cure the majority of patients, demonstrating continued need for novel therapeutic approaches. The goals of our study were to i) identify signaling molecules required for KMT2A-R B-ALL cell survival, ii) select ALL-associated targets that are not essential in normal tissues, and iii) develop new treatment strategies that may benefit patients with KMT2A-R ALL. Results: We performed a genome-wide kinome CRISPR screen using the pediatric KMT2A-R cell line SEM and identified DYRK1A among other signaling molecules as required for leukemia cell survival. DYRK1A is a member of the dual-specificity tyrosine phosphorylation-regulated kinase family and has been reported as a critical oncogene in a murine Down syndrome (DS) model of megakaryoblastic leukemia. In normal hematopoiesis, DYRK1A controls the transition from proliferation to quiescence during lymphoid development. Deletion of DYRK1A results in increased numbers of B cells in S-G2-M phase, yet also significantly reduces cell proliferation. Meta-analysis of ChIP-Seq data from two KMT2A-AFF1 cell lines (SEM and RS4;11) and a human KMT2A-Aff1-FLAG-transduced ALL model demonstrates that both N-terminal (KMT2AN) and C-terminal (AFF1C) and the FLAG-tagged KMT2A-Aff1 fusion directly bind to the DYRK1A promoter. Gene expression and RT-PCR analyses of SEM cells treated with inhibitors against two important KMT2A fusion complex proteins, DOT1L (histone methyltransferase) and menin (tumor suppressor), demonstrate that only menin inhibition induced DYRK1A downregulation. Interestingly, deletion of germline KMT2A in murine B-cells did not decrease DYRK1A expression. Taken together, these results suggest direct transcriptional regulation through the KMT2A fusion complex. Surprisingly, RNA and protein expression of DYRK1A was reduced in KMT2A-R ALL compared to other B-ALL subtypes. We then identified MYC as a potential negative regulator of DYRK1A that could explain the lower RNA and protein expression levels observed. A gain-of-function experiment showed marked downregulation of DYRK1A when MYC was ectopically expressed in murine B-cells, while loss of MYC resulted in DYRK1A upregulation. Parallel analysis of publicly available gene expression data from children with high-risk B-ALL (NCI TARGET database) showed significantly higher MYC RNA expression levels in KMT2A-R ALL as compared to other ALL subtypes, further validating our findings that MYC acts as a negative regulator of DYRK1A. Finally, to assess pharmacologic inhibition, we treated multiple KMT2A-rearranged ALL cell lines with the novel DYRK1A inhibitor EHT 1610 and identified sensitivity to DYRK1A inhibition. We then queried the Achilles database and identified that DYRK1A is not a common essential gene in normal tissues, suggesting minimal potential for on-target/off-tumor effects of DYRK1A inhibition. Conclusions: We identified a novel mechanism in KMT2A-R ALL in which DYRK1A is positively regulated by the KMT2A fusion protein and negatively regulated by MYC. Genetic deletion and pharmacologic inhibition of DYRK1A resulted in significant growth disadvantage of KMT2A-R ALL cells. While further studies are needed, we predict that combining DYRK1A inhibitors with chemotherapy could decrease relapse risk and improve long-term survival of patients with KMT2A-R B-ALL. Disclosures Crispino: MPN Research Foundation: Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy; Scholar Rock: Research Funding; Forma Therapeutics: Research Funding. Tasian:Incyte Corportation: Research Funding; Gilead Sciences: Research Funding; Aleta Biotherapeutics: Membership on an entity's Board of Directors or advisory committees. Carroll:Astellas Pharmaceuticals: Research Funding; Incyte: Research Funding; Janssen Pharmaceuticals: Consultancy.
Published: 2019

42. Fusion of Three-Dimensional Echocardiographic Regional Myocardial Strain with Cardiac Computed Tomography for Noninvasive Evaluation of the Hemodynamic Impact of Coronary Stenosis in Patients with Chest Pain

Author: Diego Medvedofsky, Victor Mor-Avi, Francesco Maffessanti, Akhil Narang, Noreen Nazir, Amita Singh, Anuj Mediratta, S. Javed Zaidi, Amit R. Patel, Roberto M. Lang, Mita Patel, Nadjia Kachenoura, Gestionnaire, Hal Sorbonne Université, The University of Chicago Medicine [Chicago], Università della Svizzera italiana = University of Italian Switzerland (USI), Laboratoire d'Imagerie Biomédicale (LIB), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, [SDV]Life Sciences [q-bio], Stress testing, Echocardiography, Three-Dimensional, Hemodynamics, Cardiovascular CT, Fractional flow reserve, 030204 cardiovascular system & hematology, Coronary Angiography, Chest pain, 030218 nuclear medicine & medical imaging, 0302 clinical medicine, Vasodilator stress, Prospective Studies, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Middle Aged, Myocardial strain, Prognosis, Coronary Vessels, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Cardiology, Female, medicine.symptom, Cardiology and Cardiovascular Medicine, medicine.drug, Artery, Chest Pain, medicine.medical_specialty, Article, 03 medical and health sciences, Internal medicine, medicine, Humans, Radiology, Nuclear Medicine and imaging, 3D echocardiography, business.industry, Coronary Stenosis, Myocardium perfusion, Fusion imaging, medicine.disease, Myocardial Contraction, Regadenoson, Coronary arteries, Stenosis, Tomography, X-Ray Computed, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Follow-Up Studies
Abstract: International audience; Background: Combined evaluation of coronary stenosis and the extent of ischemia is essential in patients with chest pain. Intermediate-grade stenosis on computed tomographic coronary angiography (CTCA) frequently triggers downstream nuclear stress testing. Alternative approaches without stress and/or radiation may have important implications. Myocardial strain measured from echocardiographic images can be used to detect subclinical dysfunction. The authors recently tested the feasibility of fusion of three-dimensional (3D) echocardiography-derived regional resting longitudinal strain with coronary arteries from CTCA to determine the hemodynamic significance of stenosis. The aim of the present study was to validate this approach against accepted reference techniques.Methods: Seventy-eight patients with chest pain referred for CTCA who also underwent 3D echocardiography and regadenoson stress computed tomography were prospectively studied. Left ventricular longitudinal strain data (TomTec) were used to generate fused 3D displays and detect resting strain abnormalities (RSAs) in each coronary territory. Computed tomographic coronary angiographic images were interpreted for the presence and severity of stenosis. Fused 3D displays of subendocardial x-ray attenuation were created to detect stress perfusion defects (SPDs). In patients with stenosis >25% in at least one artery, fractional flow reserve was quantified (HeartFlow). RSA as a marker of significant stenosis was validated against two different combined references: stenosis >50% on CTCA and SPDs seen in the same territory (reference standard A) and fractional flow reserve < 0.80 and SPDs in the same territory (reference standard B).Results: Of the 99 arteries with no stenosis >50% and no SPDs, considered as normal, 19 (19%) had RSAs. Conversely, with stenosis >50% and SPDs, RSAs were considerably more frequent (17 of 24 [71%]). The sensitivity, specificity, and accuracy of RSA were 0.71, 0.81, and 0.79, respectively, against reference standard A and 0.83, 0.81, and 0.82 against reference standard B.Conclusions: Fusion of CTCA and 3D echocardiography-derived resting myocardial strain provides combined displays, which may be useful in determination of the hemodynamic or functional impact of coronary abnormalities, without additional ionizing radiation or stress testing.
Published: 2018

43. THREE-DIMENSIONAL CARDIAC REMODELLING AFTER RESTORATION TO SINUS RHYTHM IN ATRIAL FIBRILLATION: ONE YEAR FOLLOW UP

Author: Ariel Cohen, Rim Ben Said, Franck Boccara, Sylvie Lang, Laurie Soulat-Dufour, P Nhan, Iris Kamami, Marion Chauvet-Droit, P. Issaurat, Stéphane Ederhy, Victor Mor-Avi, Karima Addetia, Saroumadi Adavane-Scheuble, Roberto M. Lang, Marie-Liesse Jean, The University of Chicago Medicine [Chicago], Service de Cardiologie [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), 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], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: medicine.medical_specialty, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, One year follow up, business.industry, Internal medicine, cardiovascular system, Cardiology, Medicine, Sinus rhythm, Atrial fibrillation, Cardiology and Cardiovascular Medicine, business, medicine.disease
Abstract: International audience; Background: The long-term four-chamber cardiac remodelling after sinus rhythm restoration in atrial fibrillation is unknown.Methods: We prospectively evaluated 86 consecutive patients hospitalized for atrial fibrillation. Three-dimensional indexed volumes (3D Vi) and ejection fraction of the right (RA) left atria (LA) right (RV) and left ventricle (LV) were measured using transthoracic echocardiography at admission and at 12 months follow-up. Patients were divided into two groups according to restoration of sinus rhythm (n=47) or persistence of atrial fibrillation (n=39) post cardioversion, ablation or pharmacological therapy.Results: Compared to baseline values at one year the 3D Vi of both atria were smaller at ED and ES. in the sinus group. Interestingly, the RV was significantly smaller only in ES and unchanged in ED whereas the LV was larger in ED and unchanged is ES (Figure A). At one year the 3D ejection fraction of all cardiac chambers were improved (Figure C). In contrast, in the atrial fibrillation group at 12 months, there were no significant differences in 3D Vi of RA, LV and LA end-systolic Vi together with a significant increase of 3D RV Vi and LA end-diastolic Vi (Figure B). No significant changes in ejection fraction were noted in the RA, RV and LV but with a significant decrease LA ejection fraction (Figure D).Conclusion: The management of atrial fibrillation should be focused on restoration of sinus rhythm to improve cardiac remodelling and both atrial and ventricular ejection fractions.
Published: 2021

44. The PARADIGHM (physicians advancing disease knowledge in hypoparathyroidism) registry for patients with chronic hypoparathyroidism: study protocol and interim baseline patient characteristics

Author: Bart L. Clarke, Claudio Marelli, Maria Luisa Brandi, Michael A. Levine, Sigridur Bjornsdottir, John Germak, Lars Rejnmark, Steven W. Ing, Michael Mannstadt, Dolores M. Shoback, Stefanie Hahner, Lorenz C. Hofbauer, Pinggao Zhang, Neil Gittoes, Tamara Vokes, Aliya Khan, Pascal Houillier, Queens Elizabeth Hospital [Birmingham], Aarhus University Hospital, Ohio State University [Columbus] (OSU), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Karolinska University Hospital [Solna, Sweden] (KUH), University Hospital of Würzburg, Technische Universität Dresden = Dresden University of Technology (TU Dresden), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), McMaster University [Hamilton, Ontario], University of Pennsylvania School of Medicine, University of Pennsylvania [Philadelphia], Harvard Medical School [Boston] (HMS), University of California [San Francisco] (UCSF), University of California, The University of Chicago Medicine [Chicago], Takeda company, Takeda Pharmaceuticals International GmbH, and Mayo Clinic [Rochester]
Subjects: Male, Endocrinology, Diabetes and Metabolism, Disease, chemistry.chemical_compound, 0302 clinical medicine, patient registry, Clinical Protocols, Quality of life, Prospective Studies, Registries, Vitamin D, quality of life, rhPTH(1-84), General Medicine, Middle Aged, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Recombinant Proteins, 3. Good health, Treatment Outcome, 030220 oncology & carcinogenesis, Cohort, Female, rhPTH(1-84), Chronic hypoparathyroidism, Adult, medicine.medical_specialty, Hormone Replacement Therapy, Hypoparathyroidism, Renal function, 030209 endocrinology & metabolism, Diseases of the endocrine glands. Clinical endocrinology, 03 medical and health sciences, Physicians, Internal medicine, Diabetes mellitus, medicine, Humans, parathyroid hormone, parathyroid hormone, patient registry, Aged, Creatinine, business.industry, Research, medicine.disease, RC648-665, chemistry, quality of life, Chronic Disease, symptoms, Calcium, Observational study, business
Abstract: Background The PARADIGHM registry of adult and pediatric patients with chronic hypoparathyroidism evaluates the long-term safety and effectiveness of treatment with recombinant human parathyroid hormone, rhPTH(1-84), and describes the clinical disease course under conditions of routine clinical practice. In this first report, we detail the registry protocol and describe the baseline characteristics of two adult patient cohorts from an interim database analysis. One cohort after study entry were prescribed rhPTH(1-84), and the other cohort received conventional therapy of calcium and active vitamin D. Methods An observational study of patients with chronic hypoparathyroidism in North America and Europe, collecting data for ≥10 years per patient. Main outcome measures were baseline patient demographics, clinical characteristics, medications, and disease outcome variables of symptoms, biochemical parameters, and health assessments. Baseline is the enrollment assessment for all variables except biochemical measurements in patients treated with rhPTH(1-84); those measurements were the most recent value before the first rhPTH(1-84) dose. Exclusion criteria applied to the analysis of specified outcomes included pediatric patients, patients who initiated rhPTH(1-84) prior to enrollment, and those who received rhPTH(1-34). Clinically implausible biochemical outlier data were excluded. Results As of 30 June 2019, data of 737 patients were analyzed from 64 centers; 587 (80%) were women, mean ± SD age 49.1±16.45 years. At enrollment, symptoms reported for patients later prescribed rhPTH(1-84) (n=60) and those who received conventional therapy (n=571), respectively, included fatigue (51.7%, 40.1%), paresthesia (51.7%, 29.6%), muscle twitching (48.3%, 21.9%), and muscle cramping (41.7%, 33.8%). Mean serum total calcium, serum phosphate, creatinine, and estimated glomerular filtration rate were similar between cohorts. Health-related quality of life (HRQoL) 36-item Short Form Health Survey questionnaire scores for those later prescribed rhPTH(1-84) were generally lower than those for patients in the conventional therapy cohort. Conclusions At enrollment, based on symptoms and HRQoL, a greater percentage of patients subsequently prescribed rhPTH(1-84) appeared to have an increased burden of disease than those who received conventional therapy despite having normal biochemistry measurements. PARADIGHM will provide valuable real-world insights on the clinical course of hypoparathyroidism in patients treated with rhPTH(1-84) or conventional therapy in routine clinical practice. Trial registration EUPAS16927, NCT01922440
Published: 2019

45. Carfilzomib with immunomodulatory drugs for the treatment of newly diagnosed multiple myeloma

Author: Mohamad Mohty, Ola Landgren, David S. Siegel, Pieter Sonneveld, Andrzej Jakubowiak, Khalid Mezzi, Karim Iskander, Memorial Sloane Kettering Cancer Center [New York], Erasmus University Medical Center [Rotterdam] (Erasmus MC), The University of Chicago Medicine [Chicago], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Amgen Inc. [Thousand Oaks, CA, USA], John Theurer Cancer Center [Hackensack, NJ, USA], Hackensack University Medical Center [Hackensack], Hematology, Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), and Gestionnaire, Hal Sorbonne Université
Subjects: 0301 basic medicine, Oncology, Drug, [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Cancer Research, medicine.medical_specialty, media_common.quotation_subject, [SDV.CAN]Life Sciences [q-bio]/Cancer, Review Article, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Medical research, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Immunologic Factors, Multiple myeloma, media_common, Lenalidomide, Cancer, Hematology, business.industry, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, medicine.disease, Carfilzomib, Minimal residual disease, 3. Good health, Clinical trial, 030104 developmental biology, chemistry, 030220 oncology & carcinogenesis, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Proteasome inhibitor, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, business, Multiple Myeloma, Oligopeptides, Proteasome Inhibitors, medicine.drug
Abstract: International audience; Carfilzomib, a selective proteasome inhibitor (PI), is approved for the treatment of patients with relapsed or refractory multiple myeloma (MM). Combination regimens incorporating a PI and immunomodulatory drug (IMiD) have been associated with deep responses and extended survival in patients with newly diagnosed MM (NDMM). Carfilzomib-based combinations with immunomodulators are being extensively studied in the frontline setting. The objective of this review was to describe efficacy and safety data for carfilzomib-based, PI/immunomodulatory combinations in NDMM. Information sources were articles indexed in PubMed and abstracts from key hematology/oncology congresses published between January 2012 and December 2018. PubMed and congresses were searched for prospective clinical studies assessing the combination of carfilzomib with an IMiD for NDMM treatment. Retrospective and preclinical reports, case reports/series, reviews, and clinical studies not evaluating carfilzomib–immunomodulator combinations in NDMM were excluded based on review of titles and abstracts. A total of nine articles and 72 abstracts were deemed relevant and included in the review. A total of six distinct carfilzomib-based, PI/immunomodulator combination regimens have been evaluated in 12 clinical trials. Overall, treatment with these regimens has resulted in deep responses, including high rates of negativity for minimal residual disease. These deep responses have translated to long progression-free survival and overall survival rates. Efficacy results for these regimens have generally been consistent across subgroups defined by age, transplant eligibility, and cytogenetic risk. The safety profile of carfilzomib in NDMM is consistent with that observed in the relapsed-refractory MM setting. Clinical studies have found that carfilzomib-based combinations with immunomodulators are highly active with a favorable safety profile in NDMM. The carfilzomib, lenalidomide, and dexamethasone (KRd) drug backbone is a promising foundation for treatment strategies aimed at achieving long-term, deep responses (functional cures) in the frontline setting. Several ongoing studies are evaluating KRd, with or without anti-CD38 monoclonal antibodies.
Published: 2019

46. Faecal Calprotectin Is a Very Reliable Tool to Predict and Monitor the Risk of Relapse After Therapeutic De-escalation in Patients With Inflammatory Bowel Diseases

Author: Joel Pekow, Bruno Pereira, Anthony Buisson, Wing Yan Mak, Michael J. Andersen, Donald Lei, R Cohen, Nada Zmeter, Stacy A. Kahn, David T. Rubin, The University of Chicago Medicine [Chicago], CHU Clermont-Ferrand, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne), Queen Elizabeth Hospital [Hong Kong] (QEH), Unité de Biostatistiques [CHU Clermont-Ferrand], Direction de la recherche clinique et de l’innovation [CHU Clermont-Ferrand] (DRCI), CHU Clermont-Ferrand-CHU Clermont-Ferrand, United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) P30 DK042086, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte - Clermont Auvergne (M2iSH), and Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne)
Subjects: Adult, Male, medicine.medical_specialty, Multivariate analysis, Databases, Factual, Medication Therapy Management, faecal calprotectin, Gastroenterology, Inflammatory bowel disease, 03 medical and health sciences, Feces, 0302 clinical medicine, Predictive Value of Tests, Risk Factors, Internal medicine, medicine, Secondary Prevention, Humans, therapeutic de-escalation, Biological Products, Receiver operating characteristic, business.industry, Hazard ratio, Area under the curve, Reproducibility of Results, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, General Medicine, Original Articles, medicine.disease, Inflammatory Bowel Diseases, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Ulcerative colitis, Faecal calprotectin, 3. Good health, 030220 oncology & carcinogenesis, 030211 gastroenterology & hepatology, Female, Risk Adjustment, Tumor Necrosis Factor Inhibitors, France, business, Leukocyte L1 Antigen Complex, De-escalation
Abstract: Aims To assess faecal calprotectin [Fcal] levels before and after therapeutic de-escalation, to predict clinical relapse in patients with inflammatory bowel disease [IBD]. Methods From a prospectively maintained database, we enrolled 160 IBD patients [112 Crohn’s disease/48 ulcerative colitis] in clinical remission, with Fcal measured within 8 weeks before therapeutic de-escalation. Clinical relapse was defined using the Harvey-Bradshaw index or Simple Clinical Colitis Activity Index. Results Using a receiver operating characteristic [ROC] curve, Fcal >100 µg/g was the best threshold to predict clinical relapse after therapeutic de-escalation (area under the curve [AUC] = 0.84). In multivariate analysis, clinical remission >6 months before therapeutic de-escalation (hazard ratio [HR] = 0.57 [0.33–0.99]; p = 0.044) was associated with decreased risk of relapse, whereas current steroid medication ( = 1.67[1.00–2.79]; p 100 µg/g was predictive of clinical relapse (HR = 3.96 [2.47–6.35]; p < 0.0001) in the whole cohort but also in patients receiving anti-tumour necrosis factor [TNF] agents [n = 85 patients; p 200 µg/g [ROC curve with AUC = 0.96] was highly predictive of clinical relapse in multivariate analysis ([HR = 31.8 [3.5–289.4], p = 0.002). Only two relapses [2/45, 4.4%] occurred within 6 months while Fcal Conclusions Fcal level is highly accurate to predict and monitor the risk of relapse after therapeutic de-escalation in IBD patients and could be used in daily practice.
Published: 2019

47. Biological Characterization of 8-Cyclopropyl-2-(pyridin-3-yl)thiazolo[5,4-f]quinazolin-9(8H)-one, a Promising Inhibitor of DYRK1A

Author: Mattias F. Lindberg, Malini Rammohan, John D. Crispino, Corinne Fruit, Florence Couly, Rahul S. Bhansali, Thierry Besson, Laurent Meijer, Chimie Organique et Bioorganique : Réactivité et Analyse (COBRA), Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie Organique Fine (IRCOF), Université de Rouen Normandie (UNIROUEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), The University of Chicago Medicine [Chicago], ManRos Therapeutics, and Northwestern University Feinberg School of Medicine
Subjects: DYRK1A, pre-B cells, Pharmaceutical Science, SH-SY5Y-Tau-4R cells, Pre-B-Cells, 01 natural sciences, Flow cytometry, 03 medical and health sciences, Drug Discovery, medicine, [CHIM]Chemical Sciences, quiescence, Tyrosine, 030304 developmental biology, DYRK family kinases, 0303 health sciences, thiazolo[5, medicine.diagnostic_test, 010405 organic chemistry, Chemistry, Kinase, 4-f]quinazolin-9(8H)-one, 0104 chemical sciences, 3. Good health, Family member, Leucettine L41, Biochemistry, CMGC kinases, Molecular Medicine
Abstract: International audience; Dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs) hyperactivity has been linked to the development of a number of human malignancies. DYRK1A is the most studied family member, and the discovery of novel specific inhibitors is attracting considerable interest. The 8-cyclopropyl-2(pyridin-3-yl)thiazolo[5,4-f]quinazolin-9(8H)-one (also called FC162) was found to be a promising inhibitor of DYRK1A and was characterized in biological experiments, by western transfer and flow cytometry on SH-SY5Y and pre-B cells. Here, the results obtained with FC162 are compared to well-characterized known DYRK1A inhibitors (e.g., Leucettine L41 and EHT1610).
Published: 2019

48. Duodenal bacterial proteolytic activity determines sensitivity to dietary antigen through protease-activated receptor-2

Author: Joseph A. Murray, Marco Constante, Xuechen B. Yu, Elena F. Verdu, Michael G. Surette, Bana Jabri, Wolfram Ruf, Premysl Bercik, Fernando Gabriel Chirdo, Justin L. McCarville, Carolyn M. Southward, Brian K. Coombes, Armin Alaedini, Céline Deraison, Alberto Caminero, Corinne Rolland, Javier Casqueiro, Marlies Meisel, Heather J. Galipeau, Steve P. Bernier, Nathalie Vergnolle, Farncombe Family Digestive Health Research Institute, McMaster University [Hamilton, Ontario], Institut de Recherche en Santé Digestive (IRSD ), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Chicago Medicine, University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE), Division of Gastroenterology and Hepatology, Department of Immunology, Mayo Clinic, Department of Medicine, Columbia University [New York], Department of Biochemistry and Biomedical Sciences, Johannes Gutenberg - Universität Mainz (JGU), Department of Immunology and Microbiology, Wayne State University [Detroit], Universidad Nacional de la Plata, Partenaires INRAE, Universidad de León [León], CIHR grant MOP#142773 and a Boris Family award to E.F.V, European Research Council (ERC- 310973 PIPE), European Research executive Agency (IOF-627487-EPIMACase), CCFA Research Fellowship Award (ID: 480735), ProdInra, Migration, and Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU)
Subjects: Male, 0301 basic medicine, Biopsy, Biología, General Physics and Astronomy, 02 engineering and technology, medicine.disease_cause, Cohort Studies, Mice, Mice, Inbred NOD, Intestinal Mucosa, lcsh:Science, Protease-activated receptor 2, chemistry.chemical_classification, Multidisciplinary, Microbiota, Elastase, Metalloendopeptidases, Colonoscopy, purl.org/becyt/ford/3.1 [https], Proteases, Middle Aged, 021001 nanoscience & nanotechnology, Food sensitivities, Up-Regulation, 3. Good health, Pseudomonas aeruginosa, Veterinary medicine and animal Health, Female, purl.org/becyt/ford/3 [https], Dietary Proteins, 0210 nano-technology, Adult, Celiac Dsease, Glutens, Duodenum, Science, Mice, Transgenic, Biology, Article, General Biochemistry, Genetics and Molecular Biology, Young Adult, 03 medical and health sciences, Immune system, Bacterial Proteins, Antigen, Downregulation and upregulation, HLA-DQ Antigens, medicine, Animals, Germ-Free Life, Humans, Receptor, PAR-2, Mucosal Immunity, Antigens, Aged, [SDV.BA.MVSA]Life Sciences [q-bio]/Animal biology/Veterinary medicine and animal Health, Host Microbial Interactions, [SDV.BA.MVSA] Life Sciences [q-bio]/Animal biology/Veterinary medicine and animal Health, Microbe-host interactions, nutritional and metabolic diseases, General Chemistry, Gluten, digestive system diseases, Gastrointestinal Microbiome, Mice, Inbred C57BL, Celiac Disease, Disease Models, Animal, Médecine vétérinaire et santé animal, 030104 developmental biology, chemistry, Case-Control Studies, Proteolysis, Immunology, lcsh:Q
Abstract: Microbe-host interactions are generally homeostatic, but when dysfunctional, they can incite food sensitivities and chronic diseases. Celiac disease (CeD) is a food sensitivity characterized by a breakdown of oral tolerance to gluten proteins in genetically predisposed individuals, although the underlying mechanisms are incompletely understood. Here we show that duodenal biopsies from patients with active CeD have increased proteolytic activity against gluten substrates that correlates with increased Proteobacteria abundance, including Pseudomonas. Using Pseudomonas aeruginosa producing elastase as a model, we show gluten-independent, PAR-2 mediated upregulation of inflammatory pathways in C57BL/6 mice without villus blunting. In mice expressing CeD risk genes, P. aeruginosa elastase synergizes with gluten to induce more severe inflammation that is associated with moderate villus blunting. These results demonstrate that proteases expressed by opportunistic pathogens impact host immune responses that are relevant to the development of food sensitivities, independently of the trigger antigen., Gluten triggers celiac disease in genetically predisposed individuals, but additional unknown mechanisms are required. Here, the authors show that proteases from Pseudomonas aeruginosa can modulate inflammatory pathways that are relevant to the development of food sensitivities, independently of the trigger antigen.
Published: 2019

49. The Chromosome 21 Kinase DYRK1A and Its Substrate FOXO1 Constitute a Novel Therapeutic Pathway in B-ALL

Author: Jean-Pierre Bourquin, John D. Crispino, Beat Bornhauser, Corinne Fruit, Ji Heon Paul Lee, Malini Rammohan, Yi-Chien Tsai, Rahul S. Bhansali, Thierry Besson, Sébastien Malinge, Nobuko Hijiya, University of Illinois College of Medicine, University of Illinois System, The University of Chicago Medicine [Chicago], Ann & Robert H. Lurie Children's Hospital of Chicago, University Children’s Hospital Zurich, Chimie Organique et Bioorganique : Réactivité et Analyse (COBRA), Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie Organique Fine (IRCOF), Université de Rouen Normandie (UNIROUEN), and Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: chromosomes, T cell, [SDV]Life Sciences [q-bio], Immunology, b-cell, Biochemistry, forkhead box protein o1, burkitt's lymphoma, chemotherapy regimen, pair 21, medicine, Kinase activity, Protein kinase B, PI3K/AKT/mTOR pathway, B cell, acute megakaryocytic leukemias, Cell growth, Chemistry, Kinase, leukemia, Cell Biology, Hematology, Cell cycle, 1-phosphatidylinositol 3-kinase, medicine.anatomical_structure, adult t-cell lymphoma/leukemia, Cancer research, phosphotransferases
Abstract: Dual Specificity Tyrosine-Phosphorylation-Regulated Kinase 1A (DYRK1A) is a serine/threonine kinase that regulates diverse pathways such as splicing, cell cycle, differentiation, apoptosis, and transcription. DYRK1A is encoded within the Down syndrome (DS) critical region of chromosome 21, underlying its importance in DS-related pathologies, such as Alzheimer's disease. Children with DS have an increased risk of developing hematologic malignancies, namely acute megakaryoblastic leukemia (DS-AMKL) and B-cell acute lymphoblastic leukemia (DS-ALL). We previously reported that DYRK1A promotes DS-AMKL by regulating subcellular localization of its substrate NFAT. In a subsequent study, we examined its role in normal hematopoiesis and found that DYRK1A is necessary for B and T cell development through phosphorylation and destabilization of Cyclin D3. Dyrk1a-deficient large pre-B cells and double negative thymocytes are unable to enter quiescence for maturation. Despite elevated levels of Cyclin D3, however, these cells lose proliferative capacity due to a block at the G2-M transition. This observation suggests that DYRK1A inhibition may exhibit anti-tumor activity in lymphocytes by first stimulating exit from quiescence but then blocking repeated rounds of cell division. Notably, DYRK1A is overexpressed in acute leukemias, including both T-ALL and B-ALL, relative to normal hematopoietic counterparts. Moreover, overexpression of dominant-negative DYRK1A-K188R impairs proliferation in human B-ALL cell lines, suggesting that DYRK1A kinase activity is required for B-ALL growth. In order to assess the physiologic relevance of targeting DYRK1A in vivo, we generated a murine model of B-ALL with a floxed Dyrk1a allele and observed significant survival advantages with homozygous (p=0.0045) and heterozygous deletion (p=0.0015). Additionally, both B-ALL cell lines and patient samples were sensitive to EHT1610, a potent and selective DYRK1 inhibitor. Relevant to the localization of DYRK1A on chromosome 21, DS-ALL samples were especially sensitive to kinase inhibition. EHT1610 also conferred synergistic growth inhibition of B-ALL cells when combined with cytotoxic chemotherapy drugs used in traditional ALL treatment regimens, such as dexamethasone, methotrexate and cytarabine. We next aimed to elucidate the mechanism by which DYRK1A inhibition cause a failure of G2-M progression. Using global and directed phosphoproteomic studies, we identified several DYRK1A substrates in pre-B cells that are involved in cell cycle, splicing, transcriptional regulation, and RNA metabolism. In addition to Cyclin D3, a notable substrate is FOXO1, an indispensable transcription factor in B lymphopoiesis. We observed that inhibition of DYRK1A led to an accumulation of FOXO1 in the nucleus of large pre-B cells despite intact PI3K/Akt signaling, which is the predominant negative regulator of FOXO1. Treatment of pre-B cells with AS1842856, an inhibitor of FOXO1 nuclear translocation, rescued the G2-M blockade and proliferative impairment induced by EHT1610 treatment. Despite FOXO1 acting as a tumor suppressor in normal lymphocytes, B-ALL cell lines and patient samples were paradoxically sensitive to FOXO1 inhibition, suggesting a unique requirement in the survival of B-ALL cells. This may be due to regulation of DNA damage, as DYRK1A inhibition alone led to negligible changes in gamma-H2AX foci, whereas FOXO1 inhibition increased DNA damage. When DYRK1A and FOXO1 were inhibited in combination, we observed a synergistic accumulation of DNA damage along with cell death in B-ALL cell lines. Finally, as both EHT1610 and AS1842856 are potent inhibitors of B-ALL cell growth in vitro, we assessed their in vivo efficacy. Both EHT1610 and AS1842856 significantly increased survival in xenograft models of B-ALL (p=0.0002 and p=0.001, respectively). We therefore conclude that both DYRK1A and its substrate FOXO1 are therapeutic targets in B-ALL. Importantly, EHT1610 represents the first selective DYRK1A inhibitor with suitable in vivo activity. Ultimately, we have determined that the DYRK1A pathway is integral to the maintenance of normal and malignant B-lymphopoiesis, the latter which can be effectively targeted through 1) a primary proliferative impairment, 2) sensitization to cell cycle-dependent chemotherapy, and 3) downstream inhibition of DYRK1A substrates such as FOXO1. Disclosures Lee: AbbVie: Employment. Bourquin:Amgen: Other: Travel Support. Crispino:Scholar Rock: Research Funding; Forma Therapeutics: Research Funding.
Published: 2018

50. Can secondary contact following range expansion be distinguished from barriers to gene flow?

Author: Bertl, Johanna, Ringbauer, Harald, Blum, Michael G.B., Aarhus University [Aarhus], Vetmeduni Vienna, The University of Chicago Medicine [Chicago], Institute of Science and Technology [Austria] (IST Austria), Biologie Computationnelle et Mathématique (TIMC-IMAG-BCM), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), and Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])
Subjects: 0106 biological sciences, Linkage disequilibrium, Hybrid zone, LINKAGE DISEQUILIBRIUM, Range (biology), [SDV]Life Sciences [q-bio], EFFECTIVE POPULATION-SIZE, SecondaryContact, author, lcsh:Medicine, Biology, F-STATISTICS, 010603 evolutionary biology, 01 natural sciences, Landscape genetics, Coalescent theory, Gene flow, 03 medical and health sciences, Quaternary glaciation, DIVERGENCE, Directionality, Allele frequency, HYBRID-ZONE, 030304 developmental biology, 0303 health sciences, Genetic diversity, Barrier of gene-flow, Isolation with migration models, Ecology, Population Biology, lcsh:R, Isolation-by-distance, Computational Biology, Evolutionary Studies, Genetic differentiation, ADMIXTURE, COALESCENT, Evolutionary biology, DISTANCE, PATTERNS, Secondary contact
Abstract: Secondary contact is the reestablishment of gene flow between sister populations that have diverged. For instance, at the end of the Quaternary glaciations in Europe, secondary contact occurred during the northward expansion of the populations which had found refugia in the southern peninsulas. With the advent of multi-locus markers, secondary contact can be investigated using various molecular signatures including gradients of allele frequency, admixture clines, and local increase of genetic differentiation. We use coalescent simulations to investigate if molecular data provide enough information to distinguish between secondary contact following range expansion and an alternative evolutionary scenario consisting of a barrier to gene flow in an isolation-by-distance model. We find that an excess of Linkage Disequilibrium and of genetic diversity at the suture zone is a unique signature of secondary contact. We also find that the directionality index Ψ, which was proposed to study range expansion, is informative to distinguish between the two hypotheses. However, although evidence for secondary contact is usually conveyed by statistics related to admixture coefficients, we find that they can be confounded by isolation-by-distance. We recommend to account for the spatial repartition of individuals when investigating secondary contact in order to better reflect the complex spatio-temporal evolution of populations and species.
Published: 2018

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