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1. Use of a novel microbiome modulator improves anticancer immunity in a murine model of malignant pleural mesotheliomaCentral MessagePerspective

Author

Christophe Gattlen, PhD, Kirby R. Frank, MSc, Damien N. Marie, MSc, Aurélien Trompette, MSc, Louis-Emmanuel Chriqui, MD, PhD, Yameng Hao, PhD, Etienne Abdelnour, MD, Michel Gonzalez, MD, Thorsten Krueger, MD, Paul J. Dyson, PhD, Sviatlana Siankevich, PhD, Christophe von Garnier, MD, Niki D.J. Ubags, PhD, Sabrina Cavin, PhD, and Jean Y. Perentes, MD, PhD

Subjects
malignant pleural mesothelioma, prebiotic, microbiome, antitumor immunity, microbiome modulator, Diseases of the circulatory (Cardiovascular) system, RC666-701, Surgery, RD1-811
Abstract

Objective: Malignant pleural mesothelioma is a fatal disease and a clinical challenge, as few effective treatment modalities are available. Previous evidence links the gut microbiome to the host immunoreactivity to tumors. We thus evaluated the impact of a novel microbiome modulator compound (MMC) on the gut microbiota composition, tumor immune microenvironment, and cancer control in a model of malignant pleural mesothelioma. Methods: Age- and weight-matched immunocompetent (n = 23) or athymic BALB/c mice (n = 15) were randomly assigned to MMC or no treatment (control) groups. MMC (31 ppm) was administered through the drinking water 14 days before AB12 malignant mesothelioma cell inoculation into the pleural cavity. The impact of MMC on tumor growth, animal survival, tumor-infiltrating leucocytes, gut microbiome, and fecal metabolome was evaluated and compared with those of control animals. Results: The MMC delayed tumor growth and significantly prolonged the survival of immunocompetent animals (P = .0015) but not that of athymic mice. The improved tumor control in immunocompetent mice correlated with increased infiltration of CD3+CD8+GRZB+ cytotoxic T lymphocytes in tumors. Gut microbiota analyses indicated an enrichment in producers of short chain fatty acids in MMC-treated animals. Finally, we observed a positive correlation between the level of fecal short chain fatty acids and abundance of tumor-infiltrating cytotoxic T cells in malignant pleural mesothelioma. Conclusions: MMC administration boosts antitumor immunity, which correlates with a change in gut microbiome and metabolome. MMC may represent a valuable treatment option to combine with immunotherapy in patients with cancer.

Published
2024
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3. Early real-life evaluation of the efficacy of esketamine in resistant depressive disorder

Author

S. Faisant, P. Crublet, R. Bellay, B. Langrée, N. Marie, and M. Rojo-Bouton

Subjects
esketamine, therapeutic strategy, resistant depressive disorder, antidepressant, Psychiatry, RC435-571
Abstract

Introduction The efficacy and of current antidepressants is insufficient. Esketamine, a new antidepressant administered by nasal route, is available since 2019 in the management of resistant characterized depressive episodes. Objectives To evaluate the response profile of patients to Esketamine in our institution specialized in mental health. Methods We included all patients treated with Esketamine in our institution from November 2019 to September 2021.We collected efficacy and tolerability data using the computerized and paper patient record, prescribing support software, and nursing staff. Results Since 2019, we treated 11 patients with Esketamine in combination with an antidepressant as indicated in the MA. Two patients from the 11 were found resistant, three discontinued due to adverse events, four relapsed after an initial clinical response, and two were still ongoing at the end of the study. Conclusions Despite an initial and rapid response, our study does not highlight any long-term efficacy of Esketamine in resistant depressive disorder. This highlight the fact that its use in the acute phase of depression or earlier in the management strategy could be a good alternative because of its rapid onset of action. Esketamine was initiated as a last line therapy, which may represent a bias in the evaluation of the molecule, as the later the depression is treated, the lower the response rate. The place of Esketamine in the therapeutic strategy is not yet well determined due to a lack of hindsight, and the question of pharmacological tolerance and dependence on the molecule arises. Disclosure No significant relationships.

Published
2022
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4. Late p65 nuclear translocation in glioblastoma cells indicates non-canonical TLR4 signaling and activation of DNA repair genes

Author

Isabele F. Moretti, Antonio M. Lerario, Marina Trombetta-Lima, Paula R. Sola, Roseli da Silva Soares, Sueli M. Oba-Shinjo, and Suely K. N. Marie

Subjects
Medicine, Science
Abstract

Abstract Glioblastoma (GBM) is the most aggressive brain primary malignancy. Toll-like receptor 4 (TLR4) has a dual role in cell fate, promoting cell survival or death depending on the context. Here, we analyzed TLR4 expression in different grades of astrocytoma, and observed increased expression in tumors, mainly in GBM, compared to non-neoplastic brain tissue. TLR4 role was investigated in U87MG, a GBM mesenchymal subtype cell line, upon LPS stimulation. p65 nuclear translocation was observed in late phase, suggesting TLR4-non-canonical pathway activation. In fact, components of ripoptosome and inflammasome cascades were upregulated and they were significantly correlated in GBMs of the TCGA-RNASeq dataset. Moreover, an increased apoptotic rate was observed when the GBM-derived U87MG cells were co-treated with LPS and Temozolomide (TMZ) in comparison to TMZ alone. Increased TLR4 immunostaining was detected in nuclei of U87MG cells 12 h after LPS treatment, concomitant to activation of DNA repair genes. Time-dependent increased RAD51, FEN1 and UNG expression levels were confirmed after LPS stimulation, which may contribute to tumor cell fitness. Moreover, the combined treatment with the RAD51 inhibitor, Amuvatinib in combination with, TMZ after LPS stimulation reduced tumor cell viability more than with each treatment alone. In conclusion, our results suggest that stimulation of TLR4 combined with pharmacological inhibition of the DNA repair pathway may be an alternative treatment for GBM patients.

Published
2021
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5. Reconfigurable Gradient Index using VO2 Memory Metamaterials

Author

Goldflam, M. D., Driscoll, T., Chapler, B., Khatib, O., Jokerst, N. Marie, Palit, S., Smith, D. R., Kim, Bong-Jun, Seo, Giwan, Kim, Hyun-Tak, Di Ventra, M., and Basov, D. N.

Subjects
Condensed Matter - Mesoscale and Nanoscale Physics
Abstract

We demonstrate tuning of a metamaterial device that incorporates a form of spatial gradient control. Electrical tuning of the metamaterial is achieved through a vanadium dioxide layer which interacts with an array of split ring resonators. We achieved a spatial gradient in the magnitude of permittivity, writeable using a single transient electrical pulse. This induced gradient in our device is observed on spatial sc ales on the order of one wavelength at 1 THz. Thus, we show the viability of elements for use in future devices with potential applications in beamforming and communications, Comment: 4 pages, 3 figures

Published
2011
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6. Difficulties in maintaining electroconvulsive treatment (ECT) in a psychiatric hospital during covid19 pandemic

Author

M. Rojo, M. Constantin, B. Langree, N. Marie, and R. Bellay

Subjects
ECT, Pharmacy, COVID-19, supply, Psychiatry, RC435-571
Abstract

Introduction ECT is an effective care with high level of recommendation. During the COVID19, new recommendations to protect patients and caregivers combined with the increasing use of medicines and medical devices (MD) for anesthesia, caused greater difficulties of supply. Even if vital for patients, it is challenging to maintain ECT in this environment. Objectives The aim of this study is to resume the measures implemented in order to maintain ECT during COVID19. Methods Retrospective analysis of measures implemented to maintain the ECT during COVID19. Results As FFP2 masks were restricted to intensive care units, our hospital were not supplied. After negotiations, the regional health agency (ARS) has granted us an allocation of 100 masks to maintain ECT. Our efficient stock management of personal protective equipment as well as our transparency on these stocks with ARS and sharing with other hospitals out of stock played a role in this agreement.We had to adapt our MDs references according to breaks of many ones and new recommendations. The university hospital helping us in supplying certain missing references. Considering the difficulties in supplying drugs and MDs, and limited availability of anesthetists, we have reduced the number of ECT. Prioritization of patients with vital indications had to be achieved. Conclusions The prioritization of some services by the regulatory agency causes many supply difficulties for the others. It would be important to reassess the priority of ECT in such crisis because most of the time other caregivers and regulatory agencies are not aware how they are vital for patients.

Published
2021
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7. Cellular Model of Malignant Transformation of Primary Human Astrocytes Induced by Deadhesion/Readhesion Cycles

Author

Roseli da S. Soares, Talita de S. Laurentino, Camila T. da Silva, Jéssica D. Gonçalves, Antonio M. Lerario, Suely K. N. Marie, Sueli M. Oba-Shinjo, and Miriam G. Jasiulionis

Subjects
malignant transformation, astrocytes, glioblastoma, anoikis resistance, tumor progression, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Astrocytoma is the most common and aggressive tumor of the central nervous system. Genetic and environmental factors, bacterial infection, and several other factors are known to be involved in gliomagenesis, although the complete underlying molecular mechanism is not fully understood. Tumorigenesis is a multistep process involving initiation, promotion, and progression. We present a human model of malignant astrocyte transformation established by subjecting primary astrocytes from healthy adults to four sequential cycles of forced anchorage impediment (deadhesion). After limiting dilution of the surviving cells obtained after the fourth deadhesion/readhesion cycle, three clones were randomly selected, and exhibited malignant characteristics, including increased proliferation rate and capacity for colony formation, migration, and anchorage-independent growth in soft agar. Functional assay results for these clonal cells, including response to temozolomide, were comparable to U87MG—a human glioblastoma-derived cell lineage—reinforcing malignant cell transformation. RNA-Seq analysis by next-generation sequencing of the transformed clones relative to the primary astrocytes revealed upregulation of genes involved in the PI3K/AKT and Wnt/β-catenin signaling pathways, in addition to upregulation of genes related to epithelial–mesenchymal transition, and downregulation of genes related to aerobic respiration. These findings, at a molecular level, corroborate the change in cell behavior towards mesenchymal-like cell dedifferentiation. This linear progressive model of malignant human astrocyte transformation is unique in that neither genetic manipulation nor treatment with carcinogens are used, representing a promising tool for testing combined therapeutic strategies for glioblastoma patients, and furthering knowledge of astrocytoma transformation and progression.

Published
2022
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10. Urinary Sediment Transcriptomic and Longitudinal Data to Investigate Renal Function Decline in Type 1 Diabetes

Author

Maria Beatriz Monteiro, Tatiana S. Pelaes, Daniele P. Santos-Bezerra, Karina Thieme, Antonio M. Lerario, Sueli M. Oba-Shinjo, Ubiratan F. Machado, Marisa Passarelli, Suely K. N. Marie, and Maria Lúcia Corrêa-Giannella

Subjects
diabetic kidney disease, transcriptomics, renal function decline, longitudinal data, type 1 diabetes, urine, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

Introduction: Using a discovery/validation approach we investigated associations between a panel of genes selected from a transcriptomic study and the estimated glomerular filtration rate (eGFR) decline across time in a cohort of type 1 diabetes (T1D) patients.Experimental: Urinary sediment transcriptomic was performed to select highly modulated genes in T1D patients with rapid eGFR decline (decliners) vs. patients with stable eGFR (non-decliners). The selected genes were validated in samples from a T1D cohort (n = 54, mean diabetes duration of 21 years, 61% women) followed longitudinally for a median of 12 years in a Diabetes Outpatient Clinic.Results: In the discovery phase, the transcriptomic study revealed 158 genes significantly different between decliners and non-decliners. Ten genes increasingly up or down-regulated according to renal function worsening were selected for validation by qRT-PCR; the genes CYP4F22, and PMP22 were confirmed as differentially expressed comparing decliners vs. non-decliners after adjustment for potential confounders. CYP4F22, LYPD3, PMP22, MAP1LC3C, HS3ST2, GPNMB, CDH6, and PKD2L1 significantly modified the slope of eGFR in T1D patients across time.Conclusions: Eight genes identified as differentially expressed in the urinary sediment of T1D patients presenting different eGFR decline rates significantly increased the accuracy of predicted renal function across time in the studied cohort. These genes may be a promising way of unveiling novel mechanisms associated with diabetic kidney disease progression.

Published
2020
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11. LOXL3 Silencing Affected Cell Adhesion and Invasion in U87MG Glioma Cells

Author

Talita de S. Laurentino, Roseli da S. Soares, Antonio M. Lerario, Suely K. N. Marie, and Sueli M. Oba-Shinjo

Subjects
LOXL3, lysyl oxidase, glioblastoma, cytoskeleton, extracellular matrix, cell death, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Lysyl oxidase-like 3 (LOXL3), belonging to the lysyl oxidase family, is responsible for the crosslinking in collagen or elastin. The cellular localization of LOXL3 is in the extracellular space by reason of its canonical function. In tumors, the presence of LOXL3 has been associated with genomic stability, cell proliferation, and metastasis. In silico analysis has shown that glioblastoma was among tumors with the highest LOXL3 expression levels. LOXL3 silencing of U87MG cells by siRNA led to the spreading of the tumor cell surface, and the transcriptome analysis of these cells revealed an upregulation of genes coding for extracellular matrix, cell adhesion, and cytoskeleton components, convergent to an increase in cell adhesion and a decrease in cell invasion observed in functional assays. Significant correlations of LOXL3 expression with genes coding for tubulins were observed in the mesenchymal subtype in the TCGA RNA-seq dataset of glioblastoma (GBM). Conversely, genes involved in endocytosis and lysosome formation, along with MAPK-binding proteins related to focal adhesion turnover, were downregulated, which may corroborate the observed decrease in cell viability and increase in the rate of cell death. Invasiveness is a major determinant of the recurrence and poor outcome of GBM patients, and downregulation of LOXL3 may contribute to halting the tumor cell invasion.

Published
2021
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12. Identification of HDAC4 as a potential therapeutic target and prognostic biomarker for ZFTA-fused ependymomas

Author

Graziella R. de Sousa, Karina B. Salomão, Luis F. P. Nagano, Kent A. Riemondy, Pablo S. Chagas, Luciana C. Veronez, Fabiano P. Saggioro, Suely K. N. Marie, José A. Yunes, Izilda A. Cardinalli, Silvia R. Brandalise, Rosane G. de Paula Queiroz, Carlos A. Scrideli, Andrew M. Donson, Nicholas K. Foreman, Luiz G. Tone, and Elvis T. Valera

Subjects
Cancer Research, Molecular Medicine, Molecular Biology
Published
2023

13. Supplementary Table S9 from Targeted Assessment of G0S2 Methylation Identifies a Rapidly Recurrent, Routinely Fatal Molecular Subtype of Adrenocortical Carcinoma

Author

Gary D. Hammer, Maria Candida B. V. Fragoso, Thomas J. Giordano, William E. Rainey, Suely K. N. Marie, Ana Claudia Latronico, Berenice B. Mendonca, Maria Claudia N. Zerbini, Beatriz M. P. Mariani, Juilee Rege, Michelle Vinco, Madson Q. Almeida, Bhramar Mukherjee, Tobias Else, Antonio Marcondes Lerario, and Dipika R. Mohan

Abstract

Complete clinical and molecular data of all samples used in this study.

Published
2023

14. Data from Targeted Assessment of G0S2 Methylation Identifies a Rapidly Recurrent, Routinely Fatal Molecular Subtype of Adrenocortical Carcinoma

Author

Gary D. Hammer, Maria Candida B. V. Fragoso, Thomas J. Giordano, William E. Rainey, Suely K. N. Marie, Ana Claudia Latronico, Berenice B. Mendonca, Maria Claudia N. Zerbini, Beatriz M. P. Mariani, Juilee Rege, Michelle Vinco, Madson Q. Almeida, Bhramar Mukherjee, Tobias Else, Antonio Marcondes Lerario, and Dipika R. Mohan

Abstract

Purpose:Adrenocortical carcinoma (ACC) is a rare, aggressive malignancy with few therapies; however, patients with locoregional disease have variable outcomes. The Cancer Genome Atlas project on ACC (ACC-TCGA) identified that cancers of patients with homogeneously rapidly recurrent or fatal disease bear a unique CpG island hypermethylation phenotype, “CIMP-high.” We sought to identify a biomarker that faithfully captures this subgroup.Experimental Design: We analyzed ACC-TCGA data to characterize differentially regulated biological processes, and identify a biomarker that is methylated and silenced exclusively in CIMP-high ACC. In an independent cohort of 114 adrenocortical tumors (80 treatment-naive primary ACC, 22 adrenocortical adenomas, and 12 non-naive/nonprimary ACC), we evaluated biomarker methylation by a restriction digest/qPCR-based approach, validated by targeted bisulfite sequencing. We evaluated expression of this biomarker and additional prognostic markers by qPCR.Results:We show that CIMP-high ACC is characterized by upregulation of cell cycle and DNA damage response programs, and identify that hypermethylation and silencing of G0S2 distinguishes this subgroup. We confirmed G0S2 hypermethylation and silencing is exclusive to 40% of ACC, and independently predicts shorter disease-free and overall survival (median 14 and 17 months, respectively). Finally, G0S2 methylation combined with validated molecular markers (BUB1B-PINK1) stratifies ACC into three groups, with uniformly favorable, intermediate, and uniformly dismal outcomes.Conclusions:G0S2 hypermethylation is a hallmark of rapidly recurrent or fatal ACC, amenable to targeted assessment using routine molecular diagnostics. Assessing G0S2 methylation is straightforward, feasible for clinical decision-making, and will enable the direction of efficacious adjuvant therapies for patients with aggressive ACC.

Published
2023

15. Supplementary Tables S3, S4, S6, S7, S8 from Targeted Assessment of G0S2 Methylation Identifies a Rapidly Recurrent, Routinely Fatal Molecular Subtype of Adrenocortical Carcinoma

Author

Gary D. Hammer, Maria Candida B. V. Fragoso, Thomas J. Giordano, William E. Rainey, Suely K. N. Marie, Ana Claudia Latronico, Berenice B. Mendonca, Maria Claudia N. Zerbini, Beatriz M. P. Mariani, Juilee Rege, Michelle Vinco, Madson Q. Almeida, Bhramar Mukherjee, Tobias Else, Antonio Marcondes Lerario, and Dipika R. Mohan

Abstract

This compiled PDF includes Supplementary Tables S3, S4, S6, S7, and S8, as follows: Supp. Table S3. G0S2 hypermethylation predicts CIMP-high. Supp. Table S4. Clinical characteristics of FMUSP+UM ACC and ACA Cohorts. Supp. Table S6. EpiTect accurately measures binary G0S2 methylation status. Supp. Table S7. Hypermethylation and silencing of G0S2 is heterogeneous in recurrent, metastatic, and non-treatment naive carcinomas. Supp. Table S8. BUB1B-PINK1 can predict any history of metastasis in patients with G0S2 Unmethylated ACC.

Published
2023

18. An integrated pipeline for comprehensive analysis of immune cells in human brain tumor clinical samples

Author

Robert L. Bowman, Monika E. Hegi, Damien N. Marie, Romain Bedel, Ángel F. Álvarez-Prado, Johanna A. Joyce, Danny Labes, Klara Soukup, Roy Thomas Daniel, Mara Kornete, Anne Wilson, Jean-Philippe Brouland, Roeltje R. Maas, and Florian Klemm

Subjects
Tumor microenvironment, Cell, Brain tumor, Human brain, Cell sorting, Biology, medicine.disease, General Biochemistry, Genetics and Molecular Biology, Cell biology, Transcriptome, Immune system, medicine.anatomical_structure, medicine, Macrophage
Abstract

Human tissue samples represent an invaluable source of information for the analysis of disease-specific cellular alterations and their variation between different pathologies. In cancer research, advancing a comprehensive understanding of the unique characteristics of individual tumor types and their microenvironment is of considerable importance for clinical translation. However, investigating human brain tumor tissue is challenging due to the often-limited availability of surgical specimens. Here we describe a multimodule integrated pipeline for the processing of freshly resected human brain tumor tissue and matched blood that enables analysis of the tumor microenvironment, with a particular focus on the tumor immune microenvironment (TIME). The protocol maximizes the information yield from limited tissue and includes both the preservation of bulk tissue, which can be performed within 1 h following surgical resection, as well as tissue dissociation for an in-depth characterization of individual TIME cell populations, which typically takes several hours depending on tissue quantity and further downstream processing. We also describe integrated modules for immunofluorescent staining of sectioned tissue, bulk tissue genomic analysis and fluorescence- or magnetic-activated cell sorting of digested tissue for subsequent culture or transcriptomic analysis by RNA sequencing. Applying this pipeline, we have previously described the overall TIME landscape across different human brain malignancies, and were able to delineate disease-specific alterations of tissue-resident versus recruited macrophage populations. This protocol will enable researchers to use this pipeline to address further research questions regarding the tumor microenvironment. Bulk tumor preservation and dissociation enable multiple analyses of the brain tumor immune microenvironment via immunofluorescent staining and cell sorting followed by transcriptomics, genomics or in vitro culture of specific cell populations.

Published
2021

19. N-acetylcysteine Counteracts Adipose Tissue Macrophage Infiltration and Insulin Resistance Elicited by Advanced Glycated Albumin in Healthy Rats

Author

Karolline S. da Silva, Paula R. Pinto, Nelly T. Fabre, Diego J. Gomes, Karina Thieme, Ligia S. Okuda, Rodrigo T. Iborra, Vanessa G. Freitas, Maria H. M. Shimizu, Walcy R. Teodoro, Suely K. N. Marie, Tom Woods, Margaret A. Brimble, Russell Pickford, Kerry-Anne Rye, Maristela Okamoto, Sergio Catanozi, Maria L. Correa-Giannela, Ubiratan F. Machado, and Marisa Passarelli

Subjects
advanced glycation, adipose tissue, advanced glycated albumin, insulin resistance, diabetes mellitus, macrophage differentiation, Physiology, QP1-981
Abstract

Background: Advanced glycation endproducts elicit inflammation. However, their role in adipocyte macrophage infiltration and in the development of insulin resistance, especially in the absence of the deleterious biochemical pathways that coexist in diabetes mellitus, remains unknown. We investigated the effect of chronic administration of advanced glycated albumin (AGE-albumin) in healthy rats, associated or not with N-acetylcysteine (NAC) treatment, on insulin sensitivity, adipose tissue transcriptome and macrophage infiltration and polarization.Methods: Male Wistar rats were intraperitoneally injected with control (C) or AGE-albumin alone, or, together with NAC in the drinking water. Biochemical parameters, lipid peroxidation, gene expression and protein contents were, respectively, determined by enzymatic techniques, reactive thiobarbituric acid substances, RT-qPCR and immunohistochemistry or immunoblot. Carboxymethyllysine (CML) and pyrraline (PYR) were determined by LC/mass spectrometry (LC-MS/MS) and ELISA.Results: CML and PYR were higher in AGE-albumin as compared to C. Food consumption, body weight, systolic blood pressure, plasma lipids, glucose, hepatic and renal function, adipose tissue relative weight and adipocyte number were similar among groups. In AGE-treated animals, insulin resistance, adipose macrophage infiltration and Col12a1 mRNA were increased with no changes in M1 and M2 phenotypes as compared to C-albumin-treated rats. Total GLUT4 content was reduced by AGE-albumin as compared to C-albumin. NAC improved insulin sensitivity, reduced urine TBARS, adipose macrophage number and Itgam and Mrc mRNA and increased Slc2a4 and Ppara. CD11b, CD206, Ager, Ddost, Cd36, Nfkb1, Il6, Tnf, Adipoq, Retn, Arg, and Il12 expressions were similar among groups.Conclusions: AGE-albumin sensitizes adipose tissue to inflammation due to macrophage infiltration and reduces GLUT4, contributing to insulin resistance in healthy rats. NAC antagonizes AGE-albumin and prevents insulin resistance. Therefore, it may be a useful tool in the prevention of AGE action on insulin resistance and long-term complications of DM.

Published
2017
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20. β-catenin programs a tissue-specific epigenetic vulnerability in aggressive adrenocortical carcinoma

Author

Dipika R. Mohan, Kleiton S. Borges, Isabella Finco, Christopher R. LaPensee, Juilee Rege, April L. Solon, Donald W. Little, Tobias Else, Madson Q. Almeida, Derek Dang, James Haggerty-Skeans, April A. Apfelbaum, Michelle Vinco, Alda Wakamatsu, Beatriz MP Mariani, Larissa Amorin, Ana Claudia Latronico, Berenice B. Mendonca, Maria Claudia N. Zerbini, Elizabeth R. Lawlor, Ryoma Ohi, Richard J. Auchus, William E. Rainey, Suely K. N. Marie, Thomas J. Giordano, Sriram Venneti, Maria Candida B. V. Fragoso, David T. Breault, Antonio Marcondes Lerario, and Gary D. Hammer

Abstract

Adrenocortical carcinoma (ACC) is a rare cancer in which tissue-specific differentiation is paradoxically associated with dismal outcomes. The differentiated ACC subtype CIMP-high is prevalent, incurable, and routinely fatal. CIMP-high ACC possess abnormal DNA methylation and frequent β-catenin activating mutations. Here, we demonstrate that ACC differentiation is maintained by a balance between nuclear, tissue-specific β-catenin-containing complexes and the epigenome. On chromatin, β-catenin binds master adrenal transcription factor SF1 and hijacks the adrenocortical super-enhancer landscape to maintain differentiation. Off chromatin, β-catenin binds histone methyltransferase EZH2, which is redistributed by the CIMP-high DNA methylation signature. SF1/β-catenin and EZH2/β-catenin complexes exist in normal adrenals and are selected for through all phases of ACC evolution. Pharmacologic EZH2 inhibition in CIMP-high ACC favors EZH2/β-catenin assembly and purges SF1/β-catenin from chromatin, erasing differentiation and restraining cancer growth in vitro and in vivo. Our studies illustrate how tissue-specific programs shape oncogene selection, surreptitiously encoding targetable therapeutic vulnerabilities.

Published
2022

21. LOXL3 Function Beyond Amino Oxidase and Role in Pathologies, Including Cancer

Author

Talita de S. Laurentino, Roseli da S. Soares, Suely K. N. Marie, and Sueli M. Oba-Shinjo

Subjects
LOXL3, lysyl oxidase, collagen, development, disease, cancer, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Lysyl oxidase like 3 (LOXL3) is a copper-dependent amine oxidase responsible for the crosslinking of collagen and elastin in the extracellular matrix. LOXL3 belongs to a family including other members: LOX, LOXL1, LOXL2, and LOXL4. Autosomal recessive mutations are rare and described in patients with Stickler syndrome, early-onset myopia and non-syndromic cleft palate. Along with an essential function in embryonic development, multiple biological functions have been attributed to LOXL3 in various pathologies related to amino oxidase activity. Additionally, various novel roles have been described for LOXL3, such as the oxidation of fibronectin in myotendinous junction formation, and of deacetylation and deacetylimination activities of STAT3 to control of inflammatory response. In tumors, three distinct roles were described: (1) LOXL3 interacts with SNAIL and contributes to proliferation and metastasis by inducing epithelial-mesenchymal transition in pancreatic ductal adenocarcinoma cells; (2) LOXL3 is localized predominantly in the nucleus associated with invasion and poor gastric cancer prognosis; (3) LOXL3 interacts with proteins involved in DNA stability and mitosis completion, contributing to melanoma progression and sustained proliferation. Here we review the structure, function and activity of LOXL3 in normal and pathological conditions and discuss the potential of LOXL3 as a therapeutic target in various diseases.

Published
2019
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22. CD99 Expression in Glioblastoma Molecular Subtypes and Role in Migration and Invasion

Author

Lais C. Cardoso, Roseli da S. Soares, Talita de S. Laurentino, Antonio M. Lerario, Suely K. N. Marie, and Sueli Mieko Oba-Shinjo

Subjects
glioblastoma, CD99, migration, cytoskeleton, transcriptome, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Glioblastoma (GBM) is the most aggressive type of brain tumor, with an overall survival of 17 months under the current standard of care therapy. CD99, an over-expressed transmembrane protein in several malignancies, has been considered a potential target for immunotherapy. To further understand this potentiality, we analyzed the differential expression of its two isoforms in human astrocytoma specimens, and the CD99 involved signaling pathways in glioma model U87MG cell line. CD99 was also analyzed in GBM molecular subtypes. Whole transcriptomes by RNA-Seq of CD99-siRNA, and functional in vitro assays in CD99-shRNA, that are found in U87MG cells, were performed. Astrocytoma of different malignant grades and U87MG cells only expressed CD99 isoform 1, which was higher in mesenchymal and classical than in proneural GBM subtypes. Genes related to actin dynamics, predominantly to focal adhesion, and lamellipodia/filopodia formation were down-regulated in the transcriptome analysis, when CD99 was silenced. A decrease in tumor cell migration/invasion, and dysfunction of focal adhesion, were observed in functional assays. In addition, a striking morphological change was detected in CD99-silenced U87MG cells, further corroborating CD99 involvement in actin cytoskeleton rearrangement. Inhibiting the overexpressed CD99 may improve resectability and decrease the recurrence rate of GBM by decreasing tumor cells migration and invasion.

Published
2019
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23. A novel program of infiltrative control in astrocytomas: ADAM23 depletion promotes cell invasion by activating γ-Secretase and NOTCH1 signaling pathway

Author

Elisa Helena Farias Jandrey, Gabriela Filoso Barnabé, Paula Fontes Asprino, Natália Cristina Santos, Lilian Tiemi Inoue, Andrei Rozanski, Marcos Maldaun, Pedro Alexandre Favoretto Galante, Suely Kazue N Marie, Sueli Mieko Oba-Shinjo, Tiago Góss Santos, Roger Chammas, Carmen Lucia Penteado Lancellotti, Frank B. Furnari, Anamaria Aranha Camargo, and Érico Tosoni Costa

Abstract

Background Diffuse infiltration is a life-threatening growth pattern in malignant astrocytomas and a significant cause of therapy resistance. This pattern is determined by the balance between proliferative and invasive genetic programs and is mainly recapitulated by glioma stem cells (GSCs) during astrocytoma progression. Infiltration results in the GSCs spreading deeply into the surrounding brain tissue, fostering tumor recurrence and making complete surgical resection impossible. We need to thoroughly understand the mechanisms underlying diffuse infiltration to develop effective therapies. Results We found that ADAM23 is downregulated in astrocytoma compared with the normal brain. Based on the clinical data and preclinical models, ADAM23 downregulation is associated with a favorable prognosis in lower-grade astrocytoma patients and correlated with the emergence of a pro-invasive tumor phenotype. The expression of ADAM23 in astrocytoma cells is inversely correlated with increased γ-secretase complex activity, consequently contributing to NOTCH1 pathway activation in GSCs and amyloid-β (Aβ) deposition in the mouse brain. Finally, epigenetic inhibition or administration of γ-secretase inhibitors (GSIs) induced a significant inhibitory effect on the invasive programs, specifically in ADAM23low astrocytoma cells. Conclusions Overall, our findings reveal ADAM23 expression levels as a new prognostic biomarker and a predictive factor of GSI efficacy for diffuse infiltration in ADAM23 low-expressing astrocytomas.

Published
2022

24. CTNNB1, AXIN1 and APC expression analysis of different medulloblastoma variants

Author

Roseli da Silva, Suely K. N. Marie, Miyuki Uno, Hamilton Matushita, Alda Wakamatsu, Sergio Rosemberg, and Sueli M. Oba-Shinjo

Subjects
Gene Expression, Immunohistochemistry, Medulloblastoma, Wnt Pathway, Medicine (General), R5-920
Abstract

OBJECTIVES: We investigated four components of the Wnt signaling pathway in medulloblastomas. Medulloblastoma is the most common type of malignant pediatric brain tumor, and the Wnt signaling pathway has been shown to be activated in this type of tumor. METHODS: Sixty-one medulloblastoma cases were analyzed for β-catenin gene (CTNNB1) mutations, β-catenin protein expression via immunostaining and Wnt signaling pathway-related gene expression. All data were correlated with histological subtypes and patient clinical information. RESULTS: CTNNB1 sequencing analysis revealed that 11 out of 61 medulloblastomas harbored missense mutations in residues 32, 33, 34 and 37, which are located in exon 3. These mutations alter the glycogen synthase kinase-3β phosphorylation sites, which participate in β-catenin degradation. No significant differences were observed between mutation status and histological medulloblastoma type, patient age and overall or progression-free survival times. Nuclear β-catenin accumulation, which was observed in 27.9% of the cases, was not associated with the histological type, CTNNB1 mutation status or tumor cell dissemination. The relative expression levels of genes that code for proteins involved in the Wnt signaling pathway (CTNNB1, APC, AXIN1 and WNT1) were also analyzed, but no significant correlations were found. In addition, large-cell variant medulloblastomas presented lower relative CTNNB1 expression as compared to the other tumor variants. CONCLUSIONS: A small subset of medulloblastomas carry CTNNB1 mutations with consequent nuclear accumulation of β-catenin. The Wnt signaling pathway plays a role in classic, desmoplastic and extensive nodularity medulloblastoma variants but not in large-cell medulloblastomas.

Published
2013

25. Extraneural metastases in medulloblastoma

Author

V M F Muoio, S O Shinjo, H Matushita, S Rosemberg, M J Teixeira, and S K N Marie

Subjects
medulloblastoma, metastases, extraneural, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Medulloblastoma is the most common childhood malignant tumor of central nervous system, but it may also occur in adults. It presents high invasive growth with spreading of tumor cells into the leptomeningeal space along the neuroaxis early in the course of the disease. Extraneural metastases are rare but frequently lethal, occurring only in 1 to 5% of patients, and are related, in the most of cases, to the presence of ventriculoperitoneal shunt. Here we characterize the clinical profile of five cases of medulloblastoma with systemic spreading of tumor cells, also comparing them to cases already described in the literature.

Published
2011
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26. Memory Metamaterials

Author

Driscoll, T., Kim, Hyun-Tak, Chae, Byung-Gyu, Kim, Bong-Jun, Lee, Yong-Wook, Jokerst, N. Marie, Palit, S., Smith, D. R., Di Ventra, M., and Basov, D. N.

Published
2009
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27. Mitochondria Transcription Factor A: A Putative Target for the Effect of Melatonin on U87MG Malignant Glioma Cell Line

Author

Daiane G. Franco, Isabele F. Moretti, and Suely K. N. Marie

Subjects
melatonin, mitochondria, TFAM, cancer, glioblastoma, Organic chemistry, QD241-441
Abstract

The disruption of mitochondrial activity has been associated with cancer development because it contributes to regulating apoptosis and is the main source of reactive oxygen species (ROS) production. Mitochondrial transcription factor A (TFAM) is a protein that maintains mitochondrial DNA (mtDNA) integrity, and alterations in its expression are associated with mitochondrial damage and cancer development. In addition, studies have shown that mitochondria are a known target of melatonin, the pineal gland hormone that plays an important anti-tumorigenic role. Thus, we hypothesized that melatonin decreases the expression of TFAM (RNA and protein) in the human glioblastoma cell line U87MG, which disrupts mtDNA expression and results in cell death due to increased ROS production and mitochondrial damage. Our results confirm the hypothesis, and also show that melatonin reduced the expression of other mitochondrial transcription factors mRNA (TFB1M and TFB2M) and interfered with mtDNA transcription. Moreover, melatonin delayed cell cycle progression and potentiated the reduction of cell survival due to treatment with the chemotherapeutic agent temozolomide. In conclusion, elucidating the effect of melatonin on TFAM expression should help to understand the signaling pathways involved in glioblastoma progression, and melatonin could be potentially applied in the treatment of this type of brain tumor.

Published
2018
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28. Relato do primeiro paciente brasileiro com a forma infantil da doença de Pompe tratado com alfa-glicosidase recombinante humana Report of the first Brazilian infantile Pompe disease patient to be treated with recombinant human acid alpha-glucosidase

Author

Sandra J. Pereira, Célia R. Berditchevisky, and Suely K. N. Marie

Subjects
Doença de Pompe, doença de depósito de glicogênio tipo II, forma infantil, Myozyme, alfa-glicosidase ácida recombinante humana, tratamento, Pompe disease, infantile glycogen storage disease type II, myozyme, recombinant human acid alpha-glucosidase, treatment, Pediatrics, RJ1-570
Abstract

Objetivo: Relatar o primeiro caso de forma infantil da doença de Pompe tratado no Brasil. Descrição: Trata-se de doença de depósito lisossomal que se caracteriza por defeitos da enzima alfa-glicosidase ácida, com acúmulo intracelular de glicogênio, principalmente nos músculos. São descritas a forma infantil e tardia. Desde 2006, está disponível tratamento com enzima recombinante humana. Descreve-se o primeiro caso de forma infantil da doença tratado no Brasil. Trata-se de menina com 2,5 meses de idade e progressão rápida da doença, com perda dos movimentos dos membros, miocardiopatia hipertrófica e insuficiência respiratória aos 7 meses de idade. Após 10 meses de tratamento, apresentou boa resposta clínica, com remissão da insuficiência respiratória, recuperação parcial dos movimentos dos membros e melhora importante do quadro cardiológico. Comentários: Apesar de pouco freqüente, a forma infantil da doença de Pompe é letal. A disponibilidade de tratamento eficaz aumenta a necessidade de conhecimento e diagnóstico precoce da doença.Objective: To describe the first case of infantile Pompe disease to be treated in Brazil. Description: Pompe disease is a glycogen storage disease related to defects in the acid alpha-glucosidase enzyme, leading to an intracellular accumulation of glycogen, mainly in muscles. Two forms are described: infantile and juvenile. Since 2006, treatment with recombinant human acid alpha-glucosidase has been available. This article describes the first case of infantile Pompe disease treated in Brazil. A girl presented at 2.5 months of age with rapid disease progression, exhibiting severe hypotonia, loss of movements in both upper and lower limbs and hypertrophic cardiomyopathy, progressing to respiratory failure by the age of 7 months. After 10 months of treatment, she exhibited a good clinical response, with remission of the respiratory failure, partial recovery of arm and leg movements and improvement of cardiologic condition. Comments: Despite its low incidence, infantile Pompe disease is lethal. The availability of an effective treatment has created an urgent need to improve knowledge and early diagnosis of this disease.

Published
2008
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29. Fatores de risco associados à calcinose na dermatomiosite juvenil Risk factors associated with calcinosis of juvenile dermatomyositis

Author

Adriana M. E. Sallum, Francine C. M. M. Pivato, Ulysses Doria-Filho, Nádia E. Aikawa, Bernadete L. Liphaus, Suely K. N. Marie, and Clovis A. A. Silva

Subjects
Dermatomiosite juvenil, calcinose, fatores de risco, coração, pulmão, imunossupressor, Juvenile dermatomyositis, calcinosis, risk factors, heart, lungs, immunosuppressors, Pediatrics, RJ1-570
Abstract

OBJETIVO: Identificar fatores de risco associados à calcinose em crianças e adolescentes com dermatomiosite juvenil. MÉTODOS: Prontuários de 54 pacientes com dermatomiosite juvenil foram estudados. Foram avaliados dados demográficos; características clínicas: grau de força muscular (I a V do Medical Research Council), presença de comprometimentos pulmonar (distúrbio ventilatório restritivo com presença ou ausência do anticorpo anti-Jo-1), gastrointestinal (refluxo gastroesofágico) e cardíaco (pericardite e/ou miocardite); exames laboratoriais: elevação de enzimas musculares (creatinoquinase, aspartato aminotransferase, alanina aminotransferase e desidrogenase lática) e terapias utilizadas: corticoterapia isolada ou associada à cloroquina e/ou imunossupressor. Os pacientes foram divididos em dois grupos de acordo com a presença ou ausência de calcinose e foram avaliados através de análise univariada e multivariada. RESULTADOS: Calcinose foi evidenciada em 23 (43%) pacientes, sendo em seis (26%) antes do diagnóstico e em 17 (74%) após. A análise univariada revelou que comprometimentos cardíaco (p = 0,01) e pulmonar (p = 0,02) e necessidade da utilização de um ou mais imunossupressores (metotrexato, ciclosporina A e/ou pulsoterapia com ciclofosfamida endovenosa) no tratamento da dermatomiosite juvenil (p = 0,03) foram associados com uma maior incidência de calcinose. A análise multivariada mostrou que comprometimento cardíaco (OR = 15,56; IC95% 1,59-152,2) e uso de um ou mais imunossupressores (OR = 4,01; IC95% 1,08-14,87) foram as únicas variáveis independentes associadas à presença de calcinose. CONCLUSÕES: O aparecimento da calcinose foi freqüente na dermatomiosite juvenil, habitualmente na evolução da doença. A calcinose foi associada aos casos mais graves, que apresentaram envolvimento cardíaco e necessitaram da utilização de imunossupressores no seu tratamento.OBJECTIVE: To identify risk factors associated with calcinosis in children and adolescents with juvenile dermatomyositis. METHODS: A review was carried out of the medical records of 54 patients with juvenile dermatomyositis. Data were collected on demographic characteristics, clinical features: muscle strength (stages I to V of the Medical Research Council scale), pulmonary involvement (restrictive pulmonary disease with presence or absence of anti-Jo1 antibodies), gastrointestinal problems (gastroesophageal reflux) and/or heart disease (pericarditis and/or myocarditis); laboratory tests: elevated muscle enzyme levels in serum (creatine phosphokinase, aspartate aminotransferase, alanine aminotransferase and/or lactate dehydrogenase); and on the treatments given: corticoid therapy in isolation or associated with hydroxychloroquine and/or immunosuppressants. The patients were divided into two groups, depending on presence or absence of calcinosis and data were evaluated by both univariate and multivariate analyses. RESULTS: Calcinosis was identified in 23 (43%) patients, and in six (26%) patients it had emerged prior to diagnosis while in 17 (74%) it was post diagnosis. The univariate analysis revealed that cardiac (p = 0.01) and pulmonary (p = 0.02) involvement and the need for one or more immunosuppressor (methotrexate, cyclosporine A and/or pulse therapy with intravenous cyclophosphamide) to treat juvenile dermatomyositis (p = 0.03) were all associated with an increased incidence of calcinosis. The multivariate analysis then demonstrated that only cardiac involvement (OR = 15.56; 95%CI 1.59-152.2) and the use of one or more immunosuppressor (OR = 4.01; 95%CI 1.08-14.87) were independently associated with the presence of calcinosis. CONCLUSIONS: Calcinosis was a frequent development among these juvenile dermatomyositis cases, generally emerging as the disease progressed. Calcinosis was associated with the more severe cases that also had cardiac involvement and where immunosuppressors had to be included in the treatment.

Published
2008
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30. Dermatomiosite juvenil e linfoma de Hodgkin: uma rara associação Juvenile dermatomyositis and Hodgkin disease: a rare association

Author

André Cavalcanti, Maria Teresa R. A. Terreri, Adriana M. E. Sallum, Suely K. N. Marie, Flávio Luisi, and Maria Odete E. Hilário

Subjects
dermatomiosite juvenil, neoplasia, linfoma de Hodgkin, adolescência, juvenile dermatomyositis, Hodgkin disease, adolescence, Diseases of the musculoskeletal system, RC925-935
Abstract

A dermatomiosite (DM) em adultos está freqüentemente associada com câncer. Já na faixa etária pediátrica, a dermatomiosite juvenil (DMJ) é predominantemente idiopática, e sua associação com neoplasia é rara e com base apenas em relatos de casos. Embora rara, a presença de neoplasia em pacientes com DMJ deve ser sempre suspeitada quando houver manifestações clínicas atípicas e alterações laboratoriais incomuns. A seguir, descrevemos e discutimos um caso de DMJ e linfoma de Hodgkin em uma adolescente.Dermatomyositis (DM) in adults is frequently associated with cancer. In contrast, during childhood juvenile dermatomyositis (JDM) is predominantly idiopathic and its association with neoplasia is rare and based only in case reports. Although rare, the presence of neoplasia in JDM patients must always be suspected in face of atypical clinical manifestations and uncommon laboratorial findings. We describe and discuss a case of JDM and Hodgkin disease in an adolescent.

Published
2007
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31. Prise en charge de la maladie d’Alzheimer en télémédecine

Author

J.-P. David, I. Fromentin, and N. Marie-Nelly

Subjects
Psychiatry and Mental health, Neurology (clinical), Geriatrics and Gerontology
Abstract

Resume La maladie d’Alzheimer est, en France, une des principales causes de demence, avec un chiffre estime a 1 000 000 de personnes malades. Ces patients le plus souvent âges et dependants ont un acces au soin limite, avec des prises en charge medicales complexes. La telemedecine pourrait faciliter l’acces aux soins de cette population fragilisee et optimiser l’efficience des equipes soignantes. Cette etude descriptive retrospective a analyse les demandes de consultations concernant les troubles du comportement en EHPAD realisees dans l’unite de telemedecine, GERIATRIX du service de geriatrie ambulatoire de l’hopital Emile-Roux (AP–HP). Les consultations etaient realisees par un reseau securise appele ORTIF. Entre juillet 2016 et octobre 2018, 398 consultations ont ete effectuees en telemedecine. Les motifs les plus frequents etaient les plaies chroniques (n = 163, 40,9 %) et les troubles du comportement (n = 142, 35,7 %). Parmi les 142 patients pris en charge pour troubles du comportement, 48,6 % presentaient des troubles a type d’agressivite ou d’agitation et 31,7 % avaient une symptomatologie anxio-depressive. Ces 142 consultations n’ont abouti qu’a 19 hospitalisations (13,4 %). La majorite des patients (76,6 %) sont restes en EHPAD. Les 10 % restants ont beneficie de consultations en service de geriatrie ambulatoire, lorsque le patient necessitait un examen clinique specifique. La telemedecine a deja fait ses preuves dans d’autres domaines et apparait comme un outil efficace dans la prise en charge des personnes âgees dependantes atteintes de maladies d’Alzheimer en EHPAD. L’objectif a moyen terme est de sensibiliser les EHPAD a une prise en charge precoce des troubles du comportement et des autres symptomes geriatriques afin d’eviter les hospitalisations de ces patients.

Published
2019

32. IDH1 mutations in a Brazilian series of Glioblastoma

Author

Miyuki Uno, Sueli Mieko Oba-Shinjo, Roseli da Silva, Flavio Miura, Carlos Afonso Clara, José Reynaldo Walther de Almeida, Suzana M. F Malheiros, André Macedo Bianco, Reynaldo Brandt, Guilherme Carvalhal Ribas, Halim Feres, Carlos Dzik, Sérgio Rosemberg, João Norberto Stavale, Manoel Jacobsen Teixeira, and Suely K. N Marie

Subjects
Medicine (General), R5-920
Published
2011

33. An integrated pipeline for comprehensive analysis of immune cells in human brain tumor clinical samples

Author

Roeltje R, Maas, Klara, Soukup, Florian, Klemm, Mara, Kornete, Robert L, Bowman, Romain, Bedel, Damien N, Marie, Ángel F, Álvarez-Prado, Danny, Labes, Anne, Wilson, Jean-Philippe, Brouland, Roy T, Daniel, Monika E, Hegi, and Johanna A, Joyce

Subjects
Brain Neoplasms, Sequence Analysis, RNA, Gene Expression Profiling, Macrophages, Tumor Microenvironment, Humans
Abstract

Human tissue samples represent an invaluable source of information for the analysis of disease-specific cellular alterations and their variation between different pathologies. In cancer research, advancing a comprehensive understanding of the unique characteristics of individual tumor types and their microenvironment is of considerable importance for clinical translation. However, investigating human brain tumor tissue is challenging due to the often-limited availability of surgical specimens. Here we describe a multimodule integrated pipeline for the processing of freshly resected human brain tumor tissue and matched blood that enables analysis of the tumor microenvironment, with a particular focus on the tumor immune microenvironment (TIME). The protocol maximizes the information yield from limited tissue and includes both the preservation of bulk tissue, which can be performed within 1 h following surgical resection, as well as tissue dissociation for an in-depth characterization of individual TIME cell populations, which typically takes several hours depending on tissue quantity and further downstream processing. We also describe integrated modules for immunofluorescent staining of sectioned tissue, bulk tissue genomic analysis and fluorescence- or magnetic-activated cell sorting of digested tissue for subsequent culture or transcriptomic analysis by RNA sequencing. Applying this pipeline, we have previously described the overall TIME landscape across different human brain malignancies, and were able to delineate disease-specific alterations of tissue-resident versus recruited macrophage populations. This protocol will enable researchers to use this pipeline to address further research questions regarding the tumor microenvironment.

Published
2021

34. Multiphysics CATHARE2 modeling and experimental validation methodology against CABRI transients

Author

N. Marie, Elsa Merle, O. Clamens, J.-M. Labit, CEA Cadarache, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratoire de Physique Subatomique et de Cosmologie (LPSC), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), and Université Grenoble Alpes (UGA)

Subjects
[PHYS.PHYS.PHYS-FLU-DYN]Physics [physics]/Physics [physics]/Fluid Dynamics [physics.flu-dyn], Nuclear and High Energy Physics, Neutron transport, Computer science, 020209 energy, Nuclear engineering, Multiphysics, Neutron poison, 02 engineering and technology, [PHYS.NEXP]Physics [physics]/Nuclear Experiment [nucl-ex], 7. Clean energy, 01 natural sciences, CABRI, 010305 fluids & plasmas, Acceleration, multiphysics, Cabin pressurization, Neutron flux, 0103 physical sciences, 0202 electrical engineering, electronic engineering, information engineering, General Materials Science, Safety, Risk, Reliability and Quality, Waste Management and Disposal, validation, Mechanical Engineering, RIA, Experimental validation, [PHYS.PHYS.PHYS-GEN-PH]Physics [physics]/Physics [physics]/General Physics [physics.gen-ph], Nuclear Energy and Engineering, Transient (oscillation)
Abstract

CABRI is an experimental pulse reactor, funded by the french Institute for Radiological protection and Nuclear Safety (IRSN) and operated by CEA at the Cadarache nuclear center, France. Its aim is to study and thus to better understand RIA (Reactivity-Initiated Accident) effects on nuclear fuels. The restart of the CABRI reactor in 2015 offers the opportunity to validate tools involving multiphysic calculation schemes on reactivity insertions (RI) transients at a system scale. Physics of the in-pile CABRI tests is complex and implies various physical fields (solid and fluid thermics, thermal-hydraulics, mechanics and neutronics) and their coupled effects. The reactivity insertion in CABRI is mastered by the depressurization of a neutron absorber ( 3 He), contained into transient rods. The increase of the neutron flux inside the core induces the neutronic power increase inside the core and a multiphysic effect, called “TOP” effect, inside the in-core transient rods that causes an acceleration of the gas depressurization. The challenge is thus to manage the simulation of these RIA complex transients catching the governing multiphysical phenomena to be identified. In order to achieve this objective, a model for the CABRI transients and a scientific calculation tool have been developed and should be validated. This paper proposes a modeling of governing multiphysic phenomena of RIA transients in CABRI reactor based on a Quantified Phenomena Identification and Ranking Table (QPIRT). These models are introduced in the CATHARE2 tool in a dedicated version named PALANTIR and Best-Estimate simulation results are compared with experimental data obtained on CABRI commission tests: core power and 3 He pressure evolution.

Published
2021

35. Transient heat exchanges under fast Reactivity-Initiated Accident

Author

Elsa Merle, J.-M. Labit, O. Clamens, N. Marie, Département Etude des Réacteurs (DER), CEA-Direction des Energies (ex-Direction de l'Energie Nucléaire) (CEA-DES (ex-DEN)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratoire de Physique Subatomique et de Cosmologie (LPSC), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA), CEA Cadarache, and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)

Subjects
Convection, Nuclear and High Energy Physics, Materials science, 020209 energy, 02 engineering and technology, Heat transfer coefficient, [PHYS.NEXP]Physics [physics]/Nuclear Experiment [nucl-ex], 7. Clean energy, 01 natural sciences, 010305 fluids & plasmas, Physics::Fluid Dynamics, 0103 physical sciences, 0202 electrical engineering, electronic engineering, information engineering, General Materials Science, Safety, Risk, Reliability and Quality, Waste Management and Disposal, Turbulence, Mechanical Engineering, RIA, Mechanics, Thermal conduction, Coolant, Boundary layer, Nuclear Energy and Engineering, Heat flux, analytical Nomenclature, [SPI.MECA.THER]Engineering Sciences [physics]/Mechanics [physics.med-ph]/Thermics [physics.class-ph], Transient (oscillation), Transient heat exchange coefficient
Abstract

International audience; Heat exchanges during fast transient are very complex phenomena. Many studies have been led in this field, trying to quantify the heat exchanges between a heating wall, under fast increasing power, and a coolant. This kind of situation is encountered for instance during RIA (Reactivity-Initiated Accidents) in nuclear reactors, whose characteristics times of wall heat flux excursion can be as low as orders of 1 ms. The CABRI reactor, an experimental pulse reactor funded by the french Institute for Radiological protection and Nuclear Safety (IRSN) and operated by CEA at the Cadarache nuclear center (France), was build in order to study and thus to better understand RIA effects on nuclear fuels. Heat exchanges characterization is definitely one of major points to tackle in the understanding and modeling of such transients, involving single and two phase flows. This paper broaches the question of single phase heat exchanges coefficients during fast transient power excursions in the CABRI reactor. The single phase pure convection is the overlap of two main mechanisms: the advection (wall axial supply in upstream cold water) and the turbulent mixing inside the boundary layer. This latter phenomenon is due to vortices in boundary layers inducing radial mixing through the velocity boundary layer. In most cases involving turbulent flows, the turbulent mixing phenomenon is preponderant. To these mechanisms is added a pure conduction heat exchange mechanism through the thermal boundary layer. Convection and conduction overlap defining a conducto-convective heat transfer coefficient, improperly only called “convection” coefficient. This paper suggests a way to model this coefficient during a CABRI-RIA transient by a non-linear superposition of transient pure conduction and convection mechanisms. Two distinct transient phases are considered; the first one presenting a wall heat flux of exponential shape followed by the second one during which the wall heat flux remains constant. The potency of this analytical model, which is implementable into computational system tools, is demonstrated.

Published
2021

37. Differential expression of ID4 and its association with TP53 mutation, SOX2, SOX4 and OCT-4 expression levels.

Author

Thais Fernanda de Almeida Galatro, Miyuki Uno, Sueli Mieko Oba-Shinjo, Antonio Nogueira Almeida, Manoel J Teixeira, Sérgio Rosemberg, and Suely Kazue N Marie

Subjects
Medicine, Science
Abstract

Inhibitor of DNA Binding 4 (ID4) is a member of the helix-loop-helix ID family of transcription factors, mostly present in the central nervous system during embryonic development, that has been associated with TP53 mutation and activation of SOX2. Along with other transcription factors, ID4 has been implicated in the tumorigenic process of astrocytomas, contributing to cell dedifferentiation, proliferation and chemoresistance. In this study, we aimed to characterize the ID4 expression pattern in human diffusely infiltrative astrocytomas of World Health Organization (WHO) grades II to IV of malignancy (AGII-AGIV); to correlate its expression level to that of SOX2, SOX4, OCT-4 and NANOG, along with TP53 mutational status; and to correlate the results with the clinical end-point of overall survival among glioblastoma patients. Quantitative real time PCR (qRT-PCR) was performed in 130 samples of astrocytomas for relative expression, showing up-regulation of all transcription factors in tumor cases. Positive correlation was found when comparing ID4 relative expression of infiltrative astrocytomas with SOX2 (r = 0.50; p

Published
2013
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38. Extended MSM method to estimate the reactivity of a sub-critical core driven by an accelerator based neutron source

Author

François-René Lecolley, G. Lehaut, G. Vittiglio, Nadia Messaoudi, X. Doligez, N. Marie, A. Krasa, W. Uyttenhove, D. Villamarin, J. Wagemans, T. Chevret, J.L. Lecouey, A. Kochetkov, F. Mellier, V. Bécares, S. Chabod, A. Billebaud, Laboratoire de Physique Subatomique et de Cosmologie (LPSC), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA), Laboratoire de physique corpusculaire de Caen (LPCC), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3), AREVA NP Lyon, Institut de Physique Nucléaire d'Orsay (IPNO), Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université Paris-Sud - Paris 11 (UP11), Centre d'Etude de l'Energie Nucléaire (SCK-CEN), Centro de Investigaciones Energéticas Medioambientales y Tecnológicas [Madrid] (CIEMAT), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Normandie Université (NU)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), and Université Paris-Sud - Paris 11 (UP11)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Physics, ads, [PHYS.PHYS]Physics [physics]/Physics [physics], 010308 nuclear & particles physics, QC1-999, Detector, msm method, [PHYS.NEXP]Physics [physics]/Nuclear Experiment [nucl-ex], 01 natural sciences, Charged particle, Computational physics, Core (optical fiber), reactivity monitoring, 0103 physical sciences, Neutron source, Neutron, Multiplication, 010306 general physics, accelerator based neutron source, Energy (signal processing), Intensity (heat transfer)
Abstract

ISBN 978-1-5272-6447-2; International audience; The Modified Source Multiplication method is used to determine an unknown reactivity level of a reactor from a known one if one has access to the detector counting for both levels when the reactor is fed by a constant neutron source like an Am-Be source. When available, an accelerator driven source, in continuous mode, can be useful as its intensity can be tunable and then adapted to the experimental conditions. However, in that case, the MSM technique must be extended to account for an external source whose intensity, energy and angular distributions can vary from one measurement to another. In this paper, this Modified Multi-Source Multiplication (MMSM) method is applied to measurements done during the FREYA project in the GUINEVERE facility, operated with the GENEPI-3C accelerator providing a mixture of (D,T) and (D,D) neutrons. The monitoring of these sources through the detection of the associated charged particles allows the calculation of the MMSM factors and the estimate of the reactivity values. The results are compared in different configurations with the reactivity obtained with an Am-Be source or in dynamic measurements performed with GENEPI-3C. Their excellent agreement shows the possibility of using such accelerator-based neutron sources for MSM measurements when they are correctly monitored. This is of great interest for deep sub-critical level characterization for which detector count rates per source neutrons might be low.

Published
2020

39. Pengaruh berita sukan terhadap sikap jurulatih dan pemain bola sepak

Author

N. Marie, Vivekananda M. and N. Marie, Vivekananda M.

Abstract

Pelaporan sesuatu mesej mesti menggunakan bahasa yang jelas dan tepat dalam menyampaikan isi kandungan kepada pembaca. Laporan dalam surat khabar juga memainkan peranan penting dalam menyampaikan mesej kepada pembaca. Hampir kesemua surat khabar utama negara mempunyai ruangan sukan bola sepak sebagai daya tarikan kepada pembaca. Laporan sukan bola sepak yang disiarkan boleh mempengaruhi sikap jurulatih dan pemain. Laporan yang baik sudah semestinya mempengaruhi sikap jurulatih dan pemain untuk memberikan persembahan yang baik dan sebaliknya. Laporan yang memberikan motivasi yang baik sudah tentu akan memberikan keyakinan dan semangat kepada jurulatih dan pemain. Berasaskan hal ini, kajian ini adalah mengenai pengaruh laporan berita sukan terhadap sikap jurulatih dan pemain bola sepak. Objektif kajian pertama ialah, mengenal pasti laporan berita sukan bola sepak yang mempengaruhi sikap jurulatih dan pemain. Objektif kedua, menganalisis laporan penulisan berita sukan bola sepak terhadap sikap jurulatih dan pemain berdasarkan Teori Motivasi. Objektif ketiga, menganalisis penggunaan bahasa laporan berita sukan bola sepak terhadap sikap jurulatih dan pemain berdasarkan Teori Kegunaan dan Kepuasan(U&G). Objektif keempat, merumuskan laporan berita sukan bola sepak terhadap sikap jurulatih dan pemain. Kajian ini telah menggunakan Berita Harian sebagai data kajian dan segmen berita sukan bola sepak Liga Malaysia. Kajian meliputi untuk dua tahun iaitu 2015 dan 2016. Sebanyak 143 laporan berita bagi tahun 2015 dan 157 laporan berita bagi tahun tahun 2016 telah diambil sebagai bahan kajian. Kaedah pensampelan sistematik telah digunakan bagi mengambil 20 buah laporan bagi tahun tahun 2015 dan 2016. Bagi tujuan perbincangan telah diambil sebanyak 5 buah petikan berita bagi tahun 2015 dan 2016. Selain itu, telah dijalankan soal selidik terhadap 7 orang jurulatih bola sepak profesional dan 40 orang pemain bola sepak dalam liga Malaysia. Tujuan dijalankan soal selidik adalah untuk m

Published
2020

40. SCALP: a detector for ($n$,$\alpha$) cross-section measurements

Author

G. Lehaut, X. Ledoux, N. Marie, L. Manduci, D. Goupillière, J Lory, M. Henri, Ch. Vandamme, B. Galhaut, M. Bourgeot, F.R. Lecolley, J. Perronnel, Laboratoire de physique corpusculaire de Caen (LPCC), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Ecole des applications militaires de l'énergie atomique (EAMEA), Grand Accélérateur National d'Ions Lourds (GANIL), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Ecole des Applications Militaires de l'Energie Atomique (EAMEA), Ecole des Applications Militaires de l'Energie Atomique, Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3), and Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)

Subjects
Physics, Scintillation, 010308 nuclear & particles physics, Physics::Instrumentation and Detectors, QC1-999, Detector, chemistry.chemical_element, Alpha particle, Kinetic energy, 01 natural sciences, 7. Clean energy, Charged particle, Nuclear physics, chemistry, 0103 physical sciences, Ionization chamber, Neutron, [PHYS.PHYS.PHYS-INS-DET]Physics [physics]/Physics [physics]/Instrumentation and Detectors [physics.ins-det], 010306 general physics, Nuclear Experiment, Helium
Abstract

Neutron induced reactions on oxygen have been studied with strong interest because of the uncertainties generated on the helium production in fuel and on the neutron multiplication factor in nuclear reactors [1], [2]. Still large discrepancies exist and new measurements are welcome in order to acquire new data aiming at the uncertainty reduction [3]. SCALP (Scintillating ionization Chamber for ALPha particle production in neutron induced reaction) is a new scintillating ionization chamber [4] used as an active target to measure the cross section of (n, alpha) reactions on various gaseous targets such as 19F or 16O, from the reaction threshold up to 15 MeV. It consists of an ionization chamber filled with CF4 (for fluorine measurements) or CF4+CO2(for oxygen measurements) allowing the detection of the energy deposed by the light charged particles emitted in the (n, alpha) reaction. In addition, four Photo- Multiplier Tubes detect the scintillation light produced by the interaction of the particles in the gas active volume. Taking advantage of the fast response of the scintillation, the neutron kinetic energy can be inferred by time-of-flight measurements. SCALP is then well adapted to mono-energetic neutron beams or to white neutron beams that will be delivered at the NFS Facility [5]. Because of its good resolution, SCALP discriminates different channel outputs, enabling to disentangle the different reactions [6]. We will present the performances of the SCALP detector in terms of temporal and energetic features. We will also present tests made at the GENESIS plate-form at the LPSC Grenoble [7].

Published
2019

41. Étude coût-efficacité du pamoate d’olanzapine : analyse en miroir sur un an

Author

J, Potaufeu, B, Langrée, D, Drapier, G, Burgot, N, Marie, Centre Hospitalier Public du Cotentin (CHPC), Centre Hospitalier Guillaume Régnier [Rennes], Comportement et noyaux gris centraux = Behavior and Basal Ganglia [Rennes], Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université européenne de Bretagne - European University of Brittany (UEB)-CHU Pontchaillou [Rennes]-Institut des Neurosciences Cliniques de Rennes (INCR)

Subjects
Adult, Male, Endpoint Determination, Cost-Benefit Analysis, Length of Stay, Cohort Studies, Hospitalization, Pharmacoeconomics, Pharmacoéconomie, Olanzapine pamoate, [SDV.SP.MED]Life Sciences [q-bio]/Pharmaceutical sciences/Medication, Olanzapine, Delayed-Action Preparations, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Coût-efficacité, Schizophrenia, Humans, Pamoate d’olanzapine, Female, Cost-effectiveness, Hospital Costs, Schizophrénie, Antipsychotic Agents, Retrospective Studies
Abstract

National audience; Introduction - Olanzapine pamoate has a higher cost of treatment than the oral form and requires administration in a hospital setting (unlike other long-acting antipsychotics), and the cost-effectiveness of this treatment may be questioned. Many scientific societies and national health systems are increasingly interested in the pharmacoeconomic impact of health products. The search for efficacy of a treatment can be done in two ways: medico-economic modeling studies or observational studies i.e. randomized controlled trials or mirror studies. The models are based on theoretical models from published clinical data simulating the course and evolution of patient health conditions, which benefit from a particular therapeutic strategy. Even if the design of observational mirror studies makes it possible to get closer to the clinical reality by observing the patient before and after the initiation of the treatment, the majority of the pharmacoeconomic studies published on olanzapine pamoate are modeling works that do not reflect actual conditions of care. The Guillaume Régnier Hospital Center in Rennes has a large cohort of patients treated with olanzapine pamoate: 121 instauration treatments are recorded from April 1, 2010 to Mars 1, 2015. The objective of this study is to evaluate the cost-effectiveness of olanzapine pamoate in actual clinical practice. Methods - This is a one-year cost-effectiveness retrospective observational mirror-image study of a cohort of 52 patients with schizophrenia who were treated for at least three months with olanzapine pamoate. The primary efficacy endpoint is the differential in the number of full-time hospitalizations before and after the introduction of olanzapine pamoate versus the hospital cost differential. The secondary criteria are the difference of the number of the days spent in hospital and the number of outpatient consultations between the year preceding the injection and the year following it. The results were calculated on the general cohort and within 2 subgroups: patients treated for more than one year and those receiving less than one year of treatment with olanzapine pamoate. Results - Fifty-two patients were included (median age=35 years, sex ratio H/F=2.7) and only 38.5% discontinued treatment. For patients who maintained long-acting treatment, they received a dosage of 25mg oral olanzapine (min=7.5mg, max=60mg), 5mg more medially than the group having stopped the olanzapine pamoate (20mg; min=10mg, max=40mg). The majority of these patients were receiving off-label authorized marketing doses of oral olanzapine, whereas 22% of them had off-label dosages of olanzapine pamoate. The main causes of discontinuation were symptom persistence, loss of vision and the occurrence of adverse effects (including weight gain and sedation). Olanzapine pamoate significantly reduced the number of hospitalizations compared to the previous management strategy (1 less hospitalization, P

Published
2019

42. 4CPS-173 8 years’ evolution of antipsychotics prescriptions in a mental health public institution

Author

R. Bellay, B. Langree, C Barbazan, and N. Marie

Subjects
Olanzapine, Pediatrics, medicine.medical_specialty, Risperidone, business.industry, Loxapine, medicine.disease, 030226 pharmacology & pharmacy, 03 medical and health sciences, 0302 clinical medicine, Defined daily dose, Tolerability, medicine, Paliperidone, 030212 general & internal medicine, Bipolar disorder, business, Clozapine, medicine.drug
Abstract

Background Our hospital is a public mental health institution of 806 inpatient beds and 962 medical and social care places. Antipsychotics (APs) are used mainly in schizophrenia and bipolar disorder, and represent one of the most prescribed pharmacological classes in our hospital. Purpose The aim of this study was to assess the compared evolution of APs prescriptions to one another over the period 2010–2017. Material and methods An extraction of the consumption of all APs between 2010 and 2017 was performed. The defined daily dose (DDD) established by the World Health Organisation was used for the analysis. These were expressed in number of DDD/1000 days of hospitalisation (DH) to consider the evolution of the hospital’s activity during the study period. Results A total of 22 molecules were studied (six second-generation AP-SGA- and 16 first-generation AP-FGA). The most consumed molecules were loxapine, olanzapine, cyamemazine and risperidone. Since 2010, the consumption of FGAs has decreased by 23.5% in favour of SGAs (45.4% increase). Some APCs are almost no longer prescribed (pipotiazine, pimozide) and some SGAs are increasingly used (long-acting olanzapine, long-acting paliperidone). The top prescribed SGAs are olanzapine (437 DDD/1000DH, 17.3% increase), risperidone (320 DDD/1000DH, 8% decrease) and clozapine (218 DDD/1000DH, 23% increase). Regarding FGAs, despite a slight decrease in consumption, zuclopentixol, haloperidol and flupentixol are still frequently prescribed (approximately 140 DDD/1000DH). Finally, we observed a 16% increase in depot forms and a 5% decrease in immediate-release forms. Conclusion As consumption in our hospital shows, loxapine and cyamemazine are mainly used in patient’s sedation. The increased SGAs use reflects international recommendations for the use of SGAs as first-line treatment based on the drug’s superior tolerability and a greater efficacy on negative symptoms. Surprisingly, olanzapine is the molecule with the highest DDD/1000DH: this may be related to psychiatrists’ practices in our hospital and the use of significantly higher doses than DDD. This study allowed us to assess the evolution of APs consumption in our hospital, which confirms the predominant use of SGA and the use of extended-release forms. However, we can question the relevance of DDDs in psychiatry given the variability of APs doses used according to the molecules and psychiatrists’ patterns. References and/or acknowledgements No conflict of interest

Published
2019

43. Impact of medication reconciliation in rehospitalization of elderly heart failure patients

Author

A. Broussier, T. Derguini, G. Motamed, M.C. Sagnier, L. Labon, V. Brunie, N. Liu, I. Fromentin, Jean-Philippe David, A. Lout, E. Thomas, and N. Marie-Nelly

Subjects
education.field_of_study, medicine.medical_specialty, Ejection fraction, business.industry, Incidence (epidemiology), Population, medicine.disease, Clinical pharmacy, Medication Reconciliation, Heart failure, Elderly population, Emergency medicine, medicine, Cardiology and Cardiovascular Medicine, education, business, Cohort study
Abstract

Introduction The incidence and prevalence of heart failure (HF) increase with age. After an hospitalization for acute heart failure (AHF), the risk of readmission is high, especially in elderly population. Medication reconciliation secures the management of patient during their hospitalization, particularly at the entry and discharge, source of iatrogeny. The aim of this study was to analyze the impact of medication reconciliation in rehospitalization of elderly HF patients. Methodology We conducted a prospective, mono-centric, exposed-unexposed, cohort study within an acute cardiogeriatrics department. In the exposed group, patients with AHF received medication reconciliation, in partnership with clinical pharmacist, within 72 hours of admission, combined, as far as possible, with medication reconciliation within 48 hours before discharge. Results Between February 2019 and February 2020, 76 patients have benefited from medication reconciliation. 60 patients (22 males, median age 87 years) were analyzed, 28 received entry and discharge medication reconciliation. 32% had a left ventricular ejection fraction Table 1 ). Conclusion In a population of elderly HF patients, the rate of 90-days all-cause readmissions was significantly lower when patients have received an entry and discharge medication reconciliation. Reassuring management of elderly HF patients, it will be necessary to perpetuate these multidisciplinary activities if the results are confirmed in the final analysis.

Published
2021

44. Intérêt du dosage de la clozapine en routine par méthode immunoenzymatique (Cobas 6000) dans le suivi thérapeutique pharmacologique des patients

Author

R. Thomas, A. Coriton, N. Marie, B. Langrée, and D. Drapier

Abstract

Le suivi therapeutique pharmacologique des patients traites par antipsychotique est un enjeu majeur de la medecine psychiatrique actuelle et conditionne leur prise en charge clinique [1] . Notre etude a concerne le dosage de la clozapine, molecule de premiere intention dans la prise en charge des etats psychotiques pharmacoresistants. Ce dosage habituellement realise par chromatographie liquide couplee a la spectrometrie de masse (LCMS) presente un delai de rendu usuel du resultat d’environ 1 semaine [2] . Une societe americaine propose de nouveaux reactifs permettant un dosage par methode immunoenzymatique sur des automates de routine [3] . Notre laboratoire a teste les performances de ce nouveau kit sur le COBAS 6000 notamment en terme de repetivite, reproductibilite et correlation avec la methode de reference selon la norme ISO 15189. Notre objectif etait de pouvoir garantir un resultat plus rapide, fiable permettant de fournir une aide decisionnelle au clinicien en evitant des adaptations therapeutiques nombreuses et couteuses [4] . Les donnees de repetabilite, reproductibilite fournissent de tres bons resultats par rapport aux valeurs attendues pour chacun des niveaux de controles utilises. Les etudes de correlation avec la technique par LCMS sont coherentes et tres acceptables compte tenu des differences de methodologie ( Annexe ). De plus, le delai de rendu moyen adapte a notre volume d’activite est evalue a 3 jours pour nos cliniciens.

Published
2019

45. Targeted Assessment of

Author

Dipika R, Mohan, Antonio Marcondes, Lerario, Tobias, Else, Bhramar, Mukherjee, Madson Q, Almeida, Michelle, Vinco, Juilee, Rege, Beatriz M P, Mariani, Maria Claudia N, Zerbini, Berenice B, Mendonca, Ana Claudia, Latronico, Suely K N, Marie, William E, Rainey, Thomas J, Giordano, Maria Candida B V, Fragoso, and Gary D, Hammer

Subjects
Male, Cell Cycle Proteins, DNA Methylation, Prognosis, behavioral disciplines and activities, Adrenal Cortex Neoplasms, Article, Phenotype, Genetic Loci, Recurrence, Cell Line, Tumor, Adrenocortical Carcinoma, Biomarkers, Tumor, Data Mining, Humans, CpG Islands, Female, Gene Silencing, Neoplasm Grading
Abstract

PURPOSE: Adrenocortical carcinoma (ACC) is a rare, aggressive malignancy with few therapies; however, patients with locoregional disease have variable outcomes. The Cancer Genome Atlas project on ACC (ACC-TCGA) identified that cancers of patients with homogeneously rapidly recurrent or fatal disease bear a unique CpG island hypermethylation phenotype, “CIMP-high.” We sought to identify a biomarker that faithfully captures this subgroup. EXPERIMENTAL DESIGN: We analyzed ACC-TCGA data to characterize differentially regulated biological processes, and identify a biomarker that is methylated and silenced exclusively in CIMP-high ACC. In an independent cohort of 114 adrenocortical tumors (80 treatment-naive primary ACC, 22 adrenocortical adenomas, and 12 non-naive/non-primary ACC), we evaluated biomarker methylation by a restriction digest/qPCR-based approach, validated by targeted bisulfite sequencing. We evaluated expression of this biomarker and additional prognostic markers by qPCR. RESULTS: We show that CIMP-high ACC is characterized by upregulation of cell cycle and DNA damage response programs, and identify that hypermethylation and silencing of G0S2 distinguishes this subgroup. We confirmed G0S2 hypermethylation and silencing is exclusive to 40% of ACC, and independently predicts shorter disease-free and overall survival (median 14 and 17 months, respectively). Finally, G0S2 methylation combined with validated molecular markers (BUB1B-PINK1) stratifies ACC into three groups, with uniformly favorable, intermediate, and uniformly dismal outcomes. CONCLUSIONS: G0S2 hypermethylation is a hallmark of rapidly recurrent or fatal ACC, amenable to targeted assessment using routine molecular diagnostics. Assessing G0S2 methylation is straightforward, feasible for clinical decision-making, and will enable the direction of efficacious adjuvant therapies for patients with aggressive ACC.

Published
2018

46. Nutrition Financing in Senegal

Author

Offosse N., Marie-Jeanne

Subjects
CASH TRANSFERS, NUTRITION PROMOTION, MATERNAL NUTRITION, NUTRITION FINANCE, HEALTH EXPENDITURE, CONDITIONAL CASH TRANSFER, MALNUTRITION, NUTRITION EXPENDITURE, CHILD NUTRITION, CHILD HEALTH
Abstract

Senegal is known for having one of the most effective and far-reaching nutrition service delivery systems in Africa. Government commitment to improving the nutritional status of the population has increased over time and has been marked, among other things, by the creation in 2001 of the CLM and its Bureau Exécutif National (National Executive Bureau) (BEN); an increase in annual budget allocations to nutrition (from $0.3 million in 2002 to $5.7 million in 2015); and intensificationof community-based nutrition interventions. These commitments are reflected in the improvementof nutrition indicators, notably a 46 percent reduction in under-five stunting from 1992 to 2014.Unfortunately, these improvements have not led to greater visibility of nutrition sensitive interventions in relevant sectors such as agriculture, livestock, education, social protection and health. This shortfall, combined with a recent series of exogenous shocks, has led to recurrent fragmentation of nutrition approaches, paradigms and interventions, resulting in the absence ofa general framework that provides guidance on both nutrition-specific and nutrition-sensitive investments.Meanwhile, progress in reducing stunting has slowed,and low birthweight, iron-deficiency anemia, adolescent undernutrition, and maternal undernutrition have received little attention. These shortcomings threaten the achievements of recent decades. Recognizing this challenge, the government of Senegal joined the Mouvement pour le Renforcement de la Nutrition (Scaling Up Nutrition) SUN Movement in 2011 and adopted the United Nations Approach to Renewed Efforts Against Child Hunger and Undernutrition (REACH) in 2014. These initiatives aim to strengthen institutional capacity and facilitate a multisectoral process to help governments plan, prioritize and more efficiently manage nutrition actions involving multiple stakeholders. With respect to national policy, the government of Senegal has adopted the Politique Nationale de Développement de la Nutrition (National Policy for the Development of Nutrition)(PNDN)2 covering the period 2015 to 2025, which will be operationalized through a multisectoral nutrition strategy, outlined in the Plan Stratégique Multisectoriel de la Nutrition (Multisectoral Nutrition Strategic Plan) (PSNM). These policies aim to expand coverage and improve the quality of nutrition services in sectors whose functional prerogatives affect the prevention and management of malnutrition.

Published
2018

47. Prise en charge thérapeutique des auteurs d’agressions sexuelles

Author

F. Lanoe, A. Jehannin, N. Marie, M. Abondo, B. Le Daré, Camille Tassel, and F. Philippe

Subjects
Pharmacology, Psychotherapist, Medical treatment, business.industry, medicine.medical_treatment, media_common.quotation_subject, Pharmaceutical Science, Serotonin reuptake, Discretion, Treatment management, Cognitive behavioral therapy, Medicine, business, media_common
Abstract

In France, the Court can issue a medical treatment order only for criminally responsible persons. The nature of the treatment to be administered is at the discretion of the physician in charge of the sexual offender's care. Treatment management of sexual offenders relies essentially on psychotherapy, and preferentially cognitive behavioral therapy. For most severe sexual offenders, drug treatments, including hormonal treatment and selective serotonin reuptake inhibitors, are used to complement psychotherapy. This literature review aims at synthesizing practice changes in the treatment management of sexual offenders.

Published
2015

48. Prevalence of Age-Related Macular Degeneration in Europe: The Past and the Future

Author

Colijn, J.M. (Johanna), Buitendijk, G.H.S. (Gabrielle), Prokofyeva, E. (Elena), Alves, D. (Dalila), Cachulo, M.L. (Maria L.), Khawaja, A.P. (Anthony), Cougnard-Grégoire, A. (Audrey), Merle, B.M.J. (Bénédicte M.J.), Korb, C. (Christina), Erke, M.G. (Maja Gran), Bron, A. (Alain), Anastasopoulos, E. (Eleftherios), Meester-Smoor, M.A. (Magda), Segato, T. (Tatiana), Piermarocchi, S. (Stefano), Jong, P.T.V.M. (Paulus) de, Vingerling, J.R. (Hans), Topouzis, F. (Fotis), Creuzot-Garcher, C. (Catherine), Bertelsen, G. (Geir), Pfeiffer, A.F.H. (Andreas), Fletcher, A.E. (Astrid E.), Foster, P.J. (Paul), Silva, R. (Rufino), Korobelnik, J.-F. (Jean-François), Delcourt, C. (Cécile), Klaver, C.C.W. (Caroline), Ajana, S. (Soufiane), Arango-Gonzalez, B. (Blanca), Arndt, V. (Verena), Bhatia, V. (Vaibhav), Bhattacharya, S.S. (Shomi S.), Biarnés, M. (Marc), Borrell, A. (Anna), Bühren, S. (Sebastian), Calado, S.M. (Sofia M.), Colijn, J.M. (Johanna M.), Dammeier, S. (Sascha), Jong, E.K. (Eiko) de, De la Cerda, B. (Berta), den Hollander, A.I. (Anneke I.), Diaz-Corrales, F.J. (Francisco J.), Diether, S. (Sigrid), Emri, E. (Eszter), Endermann, T. (Tanja), Ferraro, L.L. (Lucia L.), Garcia, M. (Míriam), Heesterbeek, T.J. (Thomas J.), Honisch, S. (Sabina), Hoyng, C.B. (Carel B.), Kersten, E. (Eveline), Kilger, E. (Ellen), Klaver, C.C.W. (Caroline C.W.), Langen, H. (Hanno), Lengyel, I. (Imre), Luthert, P. (Phil), Maugeais, C. (Cyrille), Meester-Smoor, M. (Magda), Monés, J. (Jordi), Nogoceke, E. (Everson), Peto, T. (Tunde), Pool, F.M. (Frances M.), Rodríguez, E. (Eduardo), Ueffing, M. (Marius), Ulrich Bartz-Schmidt, K.U. (Karl U.), van Leeuwen, E.M. (Elisabeth M.), Verzijden, T. (Timo), Zumbansen, M. (Markus), Acar, N. (Niyazi), Anastosopoulos, E. (Eleftherios), Azuara-Blanco, A. (Augusto), Bergen, A.A.B. (Arthur), Binquet, C. (Christine), Bird, A.C. (Alan), Bretillon, L. (Lionel), Buitendijk, G. (Gabrielle), Cachulo, M.L. (Maria Luz), Chakravarthy, U. (Usha), Chan, M. (Michelle), Chang, P. (Petrus), Colijn, J. (Johanna), Cumberland, P. (Phillippa), Cunha-Vaz, J. (José), Daien, V. (Vincent), Deak, G. (Gabor), Delyfer, M.-N. (Marie-Noëlle), Hollander, A.I. (Anneke), Dietzel, M. (Martha), Fauser, S. (Sascha), Finger, R. (Robert), Fletcher, A. (Astrid), Foster, P.J. (Paul J.), Founti, P. (Panayiota), Göbel, A. (Arno), Gorgels, T.G.M.F. (Theo), Grauslund, J. (Jakob), Grus, F. (Franz), Hammond, C.J. (Christopher), Helmer, C. (Catherine), Hense, H.-W. (Hans-Werner), Hermann, M. (Manuel), Hoehn, R. (René), Hogg, R. (Ruth), Holz, F.G. (Frank), Hoyng, C.B. (Carel), Jansonius, N.M. (Nomdo), Janssen, S.F. (Sarah), Khawaja, A. (Anthony), Lamparter, J. (Julia), Le Goff, M. (Mélanie), Leal, S. (Sergio), Lechanteur, Y.T.E. (Yara T. E.), Lehtimäki, T. (Terho), Lotery, A.J. (Andrew), Leung, I. (Irene), Mauschitz, M. (Matthias), Merle, B. (Bénédicte), Meyer zu Westrup, V. (Verena), Midena, E. (Edoardo), Miotto, S. (Stefania), Mirshahi, A. (Alireza), Mohan-Saïd, S. (Sadek), Mueller, M. (Michael), Muldrew, A. (Alyson), Nunes, S. (Sandrina), Oexle, K. (Konrad), Peto, T. (Tünde), Rahi, J. (Jugnoo), Raitakari, O. (Olli), Ribeiro, L. (Luisa), Rougier, M.-B. (Marie-Bénédicte), Sahel, J.-A. (José-Alain), Salonikiou, A. (Aggeliki), Sanchez, C. (Clarisa), Schmitz-Valckenberg, S. (Steffen), Schweitzer, C.M.C. (C. M C), Shehata, J. (Jasmin), Silvestri, G. (Giuliana), Simader, C. (Christian), Souied, E.H. (Eric), Springelkamp, H. (Henriët), Tapp, R. (Robyn), Verhoeven, V. (Virginie), Von Hanno, T. (Therese), Vujosevic, S. (Stela), Williams, K. (Katie), Wolfram, C. (Christian), Yip, J. (Jennifer), Zerbib, J. (Jennyfer), Zwiener, I. (Isabella), Colijn, J.M. (Johanna), Buitendijk, G.H.S. (Gabrielle), Prokofyeva, E. (Elena), Alves, D. (Dalila), Cachulo, M.L. (Maria L.), Khawaja, A.P. (Anthony), Cougnard-Grégoire, A. (Audrey), Merle, B.M.J. (Bénédicte M.J.), Korb, C. (Christina), Erke, M.G. (Maja Gran), Bron, A. (Alain), Anastasopoulos, E. (Eleftherios), Meester-Smoor, M.A. (Magda), Segato, T. (Tatiana), Piermarocchi, S. (Stefano), Jong, P.T.V.M. (Paulus) de, Vingerling, J.R. (Hans), Topouzis, F. (Fotis), Creuzot-Garcher, C. (Catherine), Bertelsen, G. (Geir), Pfeiffer, A.F.H. (Andreas), Fletcher, A.E. (Astrid E.), Foster, P.J. (Paul), Silva, R. (Rufino), Korobelnik, J.-F. (Jean-François), Delcourt, C. (Cécile), Klaver, C.C.W. (Caroline), Ajana, S. (Soufiane), Arango-Gonzalez, B. (Blanca), Arndt, V. (Verena), Bhatia, V. (Vaibhav), Bhattacharya, S.S. (Shomi S.), Biarnés, M. (Marc), Borrell, A. (Anna), Bühren, S. (Sebastian), Calado, S.M. (Sofia M.), Colijn, J.M. (Johanna M.), Dammeier, S. (Sascha), Jong, E.K. (Eiko) de, De la Cerda, B. (Berta), den Hollander, A.I. (Anneke I.), Diaz-Corrales, F.J. (Francisco J.), Diether, S. (Sigrid), Emri, E. (Eszter), Endermann, T. (Tanja), Ferraro, L.L. (Lucia L.), Garcia, M. (Míriam), Heesterbeek, T.J. (Thomas J.), Honisch, S. (Sabina), Hoyng, C.B. (Carel B.), Kersten, E. (Eveline), Kilger, E. (Ellen), Klaver, C.C.W. (Caroline C.W.), Langen, H. (Hanno), Lengyel, I. (Imre), Luthert, P. (Phil), Maugeais, C. (Cyrille), Meester-Smoor, M. (Magda), Monés, J. (Jordi), Nogoceke, E. (Everson), Peto, T. (Tunde), Pool, F.M. (Frances M.), Rodríguez, E. (Eduardo), Ueffing, M. (Marius), Ulrich Bartz-Schmidt, K.U. (Karl U.), van Leeuwen, E.M. (Elisabeth M.), Verzijden, T. (Timo), Zumbansen, M. (Markus), Acar, N. (Niyazi), Anastosopoulos, E. (Eleftherios), Azuara-Blanco, A. (Augusto), Bergen, A.A.B. (Arthur), Binquet, C. (Christine), Bird, A.C. (Alan), Bretillon, L. (Lionel), Buitendijk, G. (Gabrielle), Cachulo, M.L. (Maria Luz), Chakravarthy, U. (Usha), Chan, M. (Michelle), Chang, P. (Petrus), Colijn, J. (Johanna), Cumberland, P. (Phillippa), Cunha-Vaz, J. (José), Daien, V. (Vincent), Deak, G. (Gabor), Delyfer, M.-N. (Marie-Noëlle), Hollander, A.I. (Anneke), Dietzel, M. (Martha), Fauser, S. (Sascha), Finger, R. (Robert), Fletcher, A. (Astrid), Foster, P.J. (Paul J.), Founti, P. (Panayiota), Göbel, A. (Arno), Gorgels, T.G.M.F. (Theo), Grauslund, J. (Jakob), Grus, F. (Franz), Hammond, C.J. (Christopher), Helmer, C. (Catherine), Hense, H.-W. (Hans-Werner), Hermann, M. (Manuel), Hoehn, R. (René), Hogg, R. (Ruth), Holz, F.G. (Frank), Hoyng, C.B. (Carel), Jansonius, N.M. (Nomdo), Janssen, S.F. (Sarah), Khawaja, A. (Anthony), Lamparter, J. (Julia), Le Goff, M. (Mélanie), Leal, S. (Sergio), Lechanteur, Y.T.E. (Yara T. E.), Lehtimäki, T. (Terho), Lotery, A.J. (Andrew), Leung, I. (Irene), Mauschitz, M. (Matthias), Merle, B. (Bénédicte), Meyer zu Westrup, V. (Verena), Midena, E. (Edoardo), Miotto, S. (Stefania), Mirshahi, A. (Alireza), Mohan-Saïd, S. (Sadek), Mueller, M. (Michael), Muldrew, A. (Alyson), Nunes, S. (Sandrina), Oexle, K. (Konrad), Peto, T. (Tünde), Rahi, J. (Jugnoo), Raitakari, O. (Olli), Ribeiro, L. (Luisa), Rougier, M.-B. (Marie-Bénédicte), Sahel, J.-A. (José-Alain), Salonikiou, A. (Aggeliki), Sanchez, C. (Clarisa), Schmitz-Valckenberg, S. (Steffen), Schweitzer, C.M.C. (C. M C), Shehata, J. (Jasmin), Silvestri, G. (Giuliana), Simader, C. (Christian), Souied, E.H. (Eric), Springelkamp, H. (Henriët), Tapp, R. (Robyn), Verhoeven, V. (Virginie), Von Hanno, T. (Therese), Vujosevic, S. (Stela), Williams, K. (Katie), Wolfram, C. (Christian), Yip, J. (Jennifer), Zerbib, J. (Jennyfer), and Zwiener, I. (Isabella)

Abstract

Purpose Age-related macular degeneration (AMD) is a frequent, complex disorder in elderly of European ancestry. Risk profiles and treatment options have changed considerably over the years, which may have affected disease prevalence and outcome. We determined the prevalence of early and late AMD in Europe from 1990 to 2013 using the European Eye Epidemiology (E3) consortium, and made projections for the future. Design Meta-analysis of prevalence data. Participants A total of 42 080 individuals 40 years of age and older participating in 14 population-based cohorts from 10 countries in Europe. Methods AMD was diagnosed based on fundus photographs using the Rotterdam Classification. Prevalence of early and late AMD was calculated using random-effects meta-analysis stratified for age, birth cohort, gender, geographic region, and time period of the study. Best-corrected visual acuity (BCVA) was compared between late AMD subtypes; geographic atrophy (GA) and choroidal neovascularization (CNV). Main Outcome Measures Prevalence of early and late AMD, BCVA, and number of AMD cases. Results Prevalence of early AMD increased from 3.5% (95% confidence interval [CI] 2.1%–5.0%) in those aged 55–59 years to 17.6% (95% C

Published
2017
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49. Genome-wide physical activity interactions in adiposity:a meta-analysis of 200,452 adults

Author

Graff, M. (Mariaelisa), Scott, R. A. (Robert A.), Justice, A. E. (Anne E.), Young, K. L. (Kristin L.), Feitosa, M. F. (Mary F.), Barata, L. (Llilda), Winkler, T. W. (Thomas W.), Chu, A. Y. (Audrey Y.), Mahajan, A. (Anubha), Hadley, D. (David), Xue, L. (Luting), Workalemahu, T. (Tsegaselassie), Heard-Costa, N. L. (Nancy L.), den Hoed, M. (Marcel), Ahluwalia, T. S. (Tarunveer S.), Qi, Q. (Qibin), Ngwa, J. S. (Julius S.), Renstrom, F. (Frida), Quaye, L. (Lydia), Eicher, J. D. (John D.), Hayes, J. E. (James E.), Cornelis, M. (Marilyn), Kutalik, Z. (Zoltan), Lim, E. (Elise), Luan, J. (Jian'an), Huffman, J. E. (Jennifer E.), Zhang, W. (Weihua), Zhao, W. (Wei), Griffin, P. J. (Paula J.), Haller, T. (Toomas), Ahmad, S. (Shafqat), Marques-Vidal, P. M. (Pedro M.), Bien, S. (Stephanie), Yengo, L. (Loic), Teumer, A. (Alexander), Smith, A. V. (Albert Vernon), Kumari, M. (Meena), Harder, M. N. (Marie Neergaard), Justesen, J. M. (Johanne Marie), Kleber, M. E. (Marcus E.), Hollensted, M. (Mette), Lohman, K. (Kurt), Rivera, N. V. (Natalia V.), Whitfield, J. B. (John B.), Zhao, J. H. (Jing Hua), Stringham, H. M. (Heather M.), Lyytikainen, L.-P. (Leo-Pekka), Huppertz, C. (Charlotte), Willemsen, G. (Gonneke), Peyrot, W. J. (Wouter J.), Wu, Y. (Ying), Kristiansson, K. (Kati), Demirkan, A. (Ayse), Fornage, M. (Myriam), Hassinen, M. (Maija), Bielak, L. F. (Lawrence F.), Cadby, G. (Gemma), Tanaka, T. (Toshiko), Magl, R. (Reedlk), Van der Most, P. J. (Peter J.), Jackson, A. U. (Anne U.), Bragg-Gresham, J. L. (Jennifer L.), Vitart, V. (Veronique), Marten, J. (Jonathan), Navarro, P. (Pau), Bellis, C. (Claire), Pasko, D. (Dorota), Johansson, A. (Asa), Snitker, S. (Soren), Cheng, Y.-C. (Yu-Ching), Eriksson, J. (Joel), Lim, U. (Unhee), Aadahl, M. (Mette), Adair, L. S. (Linda S.), Amin, N. (Najaf), Balkau, B. (Beverley), Auvinen, J. (Juha), Beilby, J. (John), Bergman, R. N. (Richard N.), Bergmann, S. (Sven), Bertoni, A. G. (Alain G.), Blangero, J. (John), Bonnefond, A. (Amelle), Bonnycastle, L. L. (Lori L.), Borja, J. B. (Judith B.), Brage, S. (Soren), Busonero, F. (Fabio), Buyske, S. (Steve), Campbell, H. (Harry), Chines, P. S. (Peter S.), Collins, F. S. (Francis S.), Corre, T. (Tanguy), Smith, G. D. (George Davey), Delgado, G. E. (Graciela E.), Dueker, N. (Nicole), Doerr, M. (Marcus), Ebeling, T. (Tapani), Eiriksdottir, G. (Gudny), Esko, T. (Tonu), Faul, J. D. (Jessica D.), Fu, M. (Mao), Faerch, K. (Kristine), Gieger, C. (Christian), Glaeser, S. (Sven), Gong, J. (Jian), Gordon-Larsen, P. (Penny), Grallert, H. (Harald), Grammer, T. B. (Tanja B.), Grarup, N. (Niels), van Grootheest, G. (Gerard), Harald, K. (Kennet), Hastie, N. D. (Nicholas D.), Havulinna, A. S. (Aki S.), Hernandez, D. (Dena), Hindorff, L. (Lucia), Hocking, L. J. (Lynne J.), Holmens, O. L. (Oddgeir L.), Holzapfel, C. (Christina), Hottenga, J. J. (Jouke Jan), Huang, J. (Jie), Huang, T. (Tao), Hui, J. (Jennie), Huth, C. (Cornelia), Hutri-Kahonen, N. (Nina), James, A. L. (Alan L.), Jansson, J.-O. (John-Olov), Jhun, M. A. (Min A.), Juonala, M. (Markus), Kinnunen, L. (Leena), Koistinen, H. A. (Heikki A.), Kolcic, I. (Ivana), Komulainen, P. (Pirjo), Kuusisto, J. (Johanna), Kvaloy, K. (Kirsti), Kahonen, M. (Mika), Lakka, T. A. (Timo A.), Launer, L. J. (Lenore J.), Lehne, B. (Benjamin), Lindgren, C. M. (Cecilia M.), Lorentzon, M. (Mattias), Luben, R. (Robert), Marre, M. (Michel), Milaneschi, Y. (Yuri), Monda, K. L. (Keri L.), Montgomery, G. W. (Grant W.), De Moor, M. H. (Marleen H. M.), Mulas, A. (Antonella), Mueller-Nurasyid, M. (Martina), Musk, A. W. (A. W.), Mannikko, R. (Reija), Mannisto, S. (Satu), Narisu, N. (Narisu), Nauck, M. (Matthias), Nettleton, J. A. (Jennifer A.), Nolte, I. M. (Ilja M.), Oldehinkel, A. J. (Albertine J.), Olden, M. (Matthias), Ong, K. K. (Ken K.), Padmanabhan, S. (Sandosh), Paternoster, L. (Lavinia), Perez, J. (Jeremiah), Perola, M. (Markus), Peters, A. (Annette), Peters, U. (Ulrike), Peyser, P. A. (Patricia A.), Prokopenko, I. (Inga), Puolijoki, H. (Hannu), Raitakari, O. T. (Olli T.), Rankinen, T. (Tuomo), Rasmussen-Torvik, L. J. (Laura J.), Rawal, R. (Rajesh), Ridker, P. M. (Paul M.), Rose, L. M. (Lynda M.), Rudan, I. (Igor), Sarti, C. (Cinzia), Sarzynski, M. A. (Mark A.), Savonen, K. (Kai), Scott, W. R. (William R.), Sanna, S. (Serena), Shuldiner, A. R. (Alan R.), Sidney, S. (Steve), Silbernagel, G. (Guenther), Smith, B. H. (Blair H.), Smith, J. A. (Jennifer A.), Snieder, H. (Harold), Stancakova, A. (Alena), Sternfeld, B. (Barbara), Swift, A. J. (Amy J.), Tammelin, T. (Tuija), Tan, S.-T. (Sian-Tsung), Thorand, B. (Barbara), Thuillier, D. (Dorothee), Vandenput, L. (Liesbeth), Vestergaard, H. (Henrik), van Vliet-Ostaptchouk, J. V. (Jana V.), Vohl, M.-C. (Marie-Claude), Voelker, U. (Uwe), Waeber, G. (Gerard), Walker, M. (Mark), Wild, S. (Sarah), Wong, A. (Andrew), Wright, A. F. (Alan F.), Zillikens, M. C. (M. Carola), Zubair, N. (Niha), Haiman, C. A. (Christopher A.), Lemarchand, L. (Loic), Gyllensten, U. (Ulf), Ohlsson, C. (Claes), Hofman, A. (Albert), Rivadeneira, F. (Fernando), Uitterlinden, A. G. (Andre G.), Perusse, L. (Louis), Wilson, J. F. (James F.), Hayward, C. (Caroline), Polasek, O. (Ozren), Cucca, F. (Francesco), Hveem, K. (Kristian), Hartman, C. A. (Catharina A.), Toenjes, A. (Anke), Bandinelli, S. (Stefania), Palmer, L. J. (Lyle J.), Kardia, S. L. (Sharon L. R.), Rauramaa, R. (Rainer), Sorensen, T. I. (Thorkild I. A.), Tuomilehto, J. (Jaakko), Salomaa, V. (Veikko), Penninx, B. W. (Brenda W. J. H.), de Geus, E. J. (Eco J. C.), Boomsma, D. I. (Dorret I.), Lehtimaki, T. (Terho), Mangino, M. (Massimo), Laakso, M. (Markku), Bouchard, C. (Claude), Martin, N. G. (Nicholas G.), Kuh, D. (Diana), Liu, Y. (Yongmei), Linneberg, A. (Allan), Maerz, W. (Winfried), Strauch, K. (Konstantin), Kivimaki, M. (Mika), Harris, T. B. (Tamara B.), Gudnason, V. (Vilmundur), Voelzke, H. (Henry), Qi, L. (Lu), Jarvelin, M.-R. (Marjo-Riitta), Chambers, J. C. (John C.), Kooner, J. S. (Jaspal S.), Froguel, P. (Philippe), Kooperberg, C. (Charles), Vollenweider, P. (Peter), Hallmans, G. (Goran), Hansen, T. (Torben), Pedersen, O. (Oluf), Metspalu, A. (Andres), Wareham, N. J. (Nicholas J.), Langenberg, C. (Claudia), Weir, D. R. (David R.), Porteous, D. J. (David J.), Boerwinkle, E. (Eric), Chasman, D. I. (Daniel I.), Abecasis, G. R. (Goncalo R.), Barroso, I. (Ines), McCarthy, M. I. (Mark I.), Frayling, T. M. (Timothy M.), O'Connell, J. R. (Jeffrey R.), van Duijn, C. M. (Cornelia M.), Boehnke, M. (Michael), Heid, I. M. (Iris M.), Mohlke, K. L. (Karen L.), Strachan, D. P. (David P.), Fox, C. S. (Caroline S.), Liu, C.-T. (Ching-Ti), Hirschhorn, J. N. (Joel N.), Klein, R. J. (Robert J.), Johnson, A. D. (Andrew D.), Borecki, I. B. (Ingrid B.), Franks, P. W. (Paul W.), North, K. E. (Kari E.), Cupples, L. A. (L. Adrienne), Loos, R. J. (Ruth J. F.), Kilpelainen, T. O. (Tuomas O.), Graff, M. (Mariaelisa), Scott, R. A. (Robert A.), Justice, A. E. (Anne E.), Young, K. L. (Kristin L.), Feitosa, M. F. (Mary F.), Barata, L. (Llilda), Winkler, T. W. (Thomas W.), Chu, A. Y. (Audrey Y.), Mahajan, A. (Anubha), Hadley, D. (David), Xue, L. (Luting), Workalemahu, T. (Tsegaselassie), Heard-Costa, N. L. (Nancy L.), den Hoed, M. (Marcel), Ahluwalia, T. S. (Tarunveer S.), Qi, Q. (Qibin), Ngwa, J. S. (Julius S.), Renstrom, F. (Frida), Quaye, L. (Lydia), Eicher, J. D. (John D.), Hayes, J. E. (James E.), Cornelis, M. (Marilyn), Kutalik, Z. (Zoltan), Lim, E. (Elise), Luan, J. (Jian'an), Huffman, J. E. (Jennifer E.), Zhang, W. (Weihua), Zhao, W. (Wei), Griffin, P. J. (Paula J.), Haller, T. (Toomas), Ahmad, S. (Shafqat), Marques-Vidal, P. M. (Pedro M.), Bien, S. (Stephanie), Yengo, L. (Loic), Teumer, A. (Alexander), Smith, A. V. (Albert Vernon), Kumari, M. (Meena), Harder, M. N. (Marie Neergaard), Justesen, J. M. (Johanne Marie), Kleber, M. E. (Marcus E.), Hollensted, M. (Mette), Lohman, K. (Kurt), Rivera, N. V. (Natalia V.), Whitfield, J. B. (John B.), Zhao, J. H. (Jing Hua), Stringham, H. M. (Heather M.), Lyytikainen, L.-P. (Leo-Pekka), Huppertz, C. (Charlotte), Willemsen, G. (Gonneke), Peyrot, W. J. (Wouter J.), Wu, Y. (Ying), Kristiansson, K. (Kati), Demirkan, A. (Ayse), Fornage, M. (Myriam), Hassinen, M. (Maija), Bielak, L. F. (Lawrence F.), Cadby, G. (Gemma), Tanaka, T. (Toshiko), Magl, R. (Reedlk), Van der Most, P. J. (Peter J.), Jackson, A. U. (Anne U.), Bragg-Gresham, J. L. (Jennifer L.), Vitart, V. (Veronique), Marten, J. (Jonathan), Navarro, P. (Pau), Bellis, C. (Claire), Pasko, D. (Dorota), Johansson, A. (Asa), Snitker, S. (Soren), Cheng, Y.-C. (Yu-Ching), Eriksson, J. (Joel), Lim, U. (Unhee), Aadahl, M. (Mette), Adair, L. S. (Linda S.), Amin, N. (Najaf), Balkau, B. (Beverley), Auvinen, J. (Juha), Beilby, J. (John), Bergman, R. N. (Richard N.), Bergmann, S. (Sven), Bertoni, A. G. (Alain G.), Blangero, J. (John), Bonnefond, A. (Amelle), Bonnycastle, L. L. (Lori L.), Borja, J. B. (Judith B.), Brage, S. (Soren), Busonero, F. (Fabio), Buyske, S. (Steve), Campbell, H. (Harry), Chines, P. S. (Peter S.), Collins, F. S. (Francis S.), Corre, T. (Tanguy), Smith, G. D. (George Davey), Delgado, G. E. (Graciela E.), Dueker, N. (Nicole), Doerr, M. (Marcus), Ebeling, T. (Tapani), Eiriksdottir, G. (Gudny), Esko, T. (Tonu), Faul, J. D. (Jessica D.), Fu, M. (Mao), Faerch, K. (Kristine), Gieger, C. (Christian), Glaeser, S. (Sven), Gong, J. (Jian), Gordon-Larsen, P. (Penny), Grallert, H. (Harald), Grammer, T. B. (Tanja B.), Grarup, N. (Niels), van Grootheest, G. (Gerard), Harald, K. (Kennet), Hastie, N. D. (Nicholas D.), Havulinna, A. S. (Aki S.), Hernandez, D. (Dena), Hindorff, L. (Lucia), Hocking, L. J. (Lynne J.), Holmens, O. L. (Oddgeir L.), Holzapfel, C. (Christina), Hottenga, J. J. (Jouke Jan), Huang, J. (Jie), Huang, T. (Tao), Hui, J. (Jennie), Huth, C. (Cornelia), Hutri-Kahonen, N. (Nina), James, A. L. (Alan L.), Jansson, J.-O. (John-Olov), Jhun, M. A. (Min A.), Juonala, M. (Markus), Kinnunen, L. (Leena), Koistinen, H. A. (Heikki A.), Kolcic, I. (Ivana), Komulainen, P. (Pirjo), Kuusisto, J. (Johanna), Kvaloy, K. (Kirsti), Kahonen, M. (Mika), Lakka, T. A. (Timo A.), Launer, L. J. (Lenore J.), Lehne, B. (Benjamin), Lindgren, C. M. (Cecilia M.), Lorentzon, M. (Mattias), Luben, R. (Robert), Marre, M. (Michel), Milaneschi, Y. (Yuri), Monda, K. L. (Keri L.), Montgomery, G. W. (Grant W.), De Moor, M. H. (Marleen H. M.), Mulas, A. (Antonella), Mueller-Nurasyid, M. (Martina), Musk, A. W. (A. W.), Mannikko, R. (Reija), Mannisto, S. (Satu), Narisu, N. (Narisu), Nauck, M. (Matthias), Nettleton, J. A. (Jennifer A.), Nolte, I. M. (Ilja M.), Oldehinkel, A. J. (Albertine J.), Olden, M. (Matthias), Ong, K. K. (Ken K.), Padmanabhan, S. (Sandosh), Paternoster, L. (Lavinia), Perez, J. (Jeremiah), Perola, M. (Markus), Peters, A. (Annette), Peters, U. (Ulrike), Peyser, P. A. (Patricia A.), Prokopenko, I. (Inga), Puolijoki, H. (Hannu), Raitakari, O. T. (Olli T.), Rankinen, T. (Tuomo), Rasmussen-Torvik, L. J. (Laura J.), Rawal, R. (Rajesh), Ridker, P. M. (Paul M.), Rose, L. M. (Lynda M.), Rudan, I. (Igor), Sarti, C. (Cinzia), Sarzynski, M. A. (Mark A.), Savonen, K. (Kai), Scott, W. R. (William R.), Sanna, S. (Serena), Shuldiner, A. R. (Alan R.), Sidney, S. (Steve), Silbernagel, G. (Guenther), Smith, B. H. (Blair H.), Smith, J. A. (Jennifer A.), Snieder, H. (Harold), Stancakova, A. (Alena), Sternfeld, B. (Barbara), Swift, A. J. (Amy J.), Tammelin, T. (Tuija), Tan, S.-T. (Sian-Tsung), Thorand, B. (Barbara), Thuillier, D. (Dorothee), Vandenput, L. (Liesbeth), Vestergaard, H. (Henrik), van Vliet-Ostaptchouk, J. V. (Jana V.), Vohl, M.-C. (Marie-Claude), Voelker, U. (Uwe), Waeber, G. (Gerard), Walker, M. (Mark), Wild, S. (Sarah), Wong, A. (Andrew), Wright, A. F. (Alan F.), Zillikens, M. C. (M. Carola), Zubair, N. (Niha), Haiman, C. A. (Christopher A.), Lemarchand, L. (Loic), Gyllensten, U. (Ulf), Ohlsson, C. (Claes), Hofman, A. (Albert), Rivadeneira, F. (Fernando), Uitterlinden, A. G. (Andre G.), Perusse, L. (Louis), Wilson, J. F. (James F.), Hayward, C. (Caroline), Polasek, O. (Ozren), Cucca, F. (Francesco), Hveem, K. (Kristian), Hartman, C. A. (Catharina A.), Toenjes, A. (Anke), Bandinelli, S. (Stefania), Palmer, L. J. (Lyle J.), Kardia, S. L. (Sharon L. R.), Rauramaa, R. (Rainer), Sorensen, T. I. (Thorkild I. A.), Tuomilehto, J. (Jaakko), Salomaa, V. (Veikko), Penninx, B. W. (Brenda W. J. H.), de Geus, E. J. (Eco J. C.), Boomsma, D. I. (Dorret I.), Lehtimaki, T. (Terho), Mangino, M. (Massimo), Laakso, M. (Markku), Bouchard, C. (Claude), Martin, N. G. (Nicholas G.), Kuh, D. (Diana), Liu, Y. (Yongmei), Linneberg, A. (Allan), Maerz, W. (Winfried), Strauch, K. (Konstantin), Kivimaki, M. (Mika), Harris, T. B. (Tamara B.), Gudnason, V. (Vilmundur), Voelzke, H. (Henry), Qi, L. (Lu), Jarvelin, M.-R. (Marjo-Riitta), Chambers, J. C. (John C.), Kooner, J. S. (Jaspal S.), Froguel, P. (Philippe), Kooperberg, C. (Charles), Vollenweider, P. (Peter), Hallmans, G. (Goran), Hansen, T. (Torben), Pedersen, O. (Oluf), Metspalu, A. (Andres), Wareham, N. J. (Nicholas J.), Langenberg, C. (Claudia), Weir, D. R. (David R.), Porteous, D. J. (David J.), Boerwinkle, E. (Eric), Chasman, D. I. (Daniel I.), Abecasis, G. R. (Goncalo R.), Barroso, I. (Ines), McCarthy, M. I. (Mark I.), Frayling, T. M. (Timothy M.), O'Connell, J. R. (Jeffrey R.), van Duijn, C. M. (Cornelia M.), Boehnke, M. (Michael), Heid, I. M. (Iris M.), Mohlke, K. L. (Karen L.), Strachan, D. P. (David P.), Fox, C. S. (Caroline S.), Liu, C.-T. (Ching-Ti), Hirschhorn, J. N. (Joel N.), Klein, R. J. (Robert J.), Johnson, A. D. (Andrew D.), Borecki, I. B. (Ingrid B.), Franks, P. W. (Paul W.), North, K. E. (Kari E.), Cupples, L. A. (L. Adrienne), Loos, R. J. (Ruth J. F.), and Kilpelainen, T. O. (Tuomas O.)

Abstract

Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.

Published
2017

50. Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits

Author

Justice, A. E. (Anne E.), Winkler, T. W. (Thomas W.), Feitosa, M. F. (Mary F.), Graff, M. (Misa), Fisher, V. A. (Virginia A.), Young, K. (Kristin), Barata, L. (Llilda), Deng, X. (Xuan), Czajkowski, J. (Jacek), Hadley, D. (David), Ngwa, J. S. (Julius S.), Ahluwalia, T. S. (Tarunveer S.), Chu, A. Y. (Audrey Y.), Heard-Costa, N. L. (Nancy L.), Lim, E. (Elise), Perez, J. (Jeremiah), Eicher, J. D. (John D.), Kutalik, Z. (Zoltan), Xue, L. (Luting), Mahajan, A. (Anubha), Renstrom, F. (Frida), Wu, J. (Joseph), Qi, Q. (Qibin), Ahmad, S. (Shafqat), Alfred, T. (Tamuno), Amin, N. (Najaf), Bielak, L. F. (Lawrence F.), Bonnefond, A. (Amelie), Bragg, J. (Jennifer), Cadby, G. (Gemma), Chittani, M. (Martina), Coggeshall, S. (Scott), Corre, T. (Tanguy), Direk, N. (Nese), Eriksson, J. (Joel), Fischer, K. (Krista), Gorski, M. (Mathias), Harder, M. N. (Marie Neergaard), Horikoshi, M. (Momoko), Huang, T. (Tao), Huffman, J. E. (Jennifer E.), Jackson, A. U. (Anne U.), Justesen, J. M. (Johanne Marie), Kanoni, S. (Stavroula), Kinnunen, L. (Leena), Kleber, M. E. (Marcus E.), Komulainen, P. (Pirjo), Kumari, M. (Meena), Lim, U. (Unhee), Luan, J. (Jian'an), Lyytikäinen, L.-P. (Leo-Pekka), Mangino, M. (Massimo), Manichaikul, A. (Ani), Marten, J. (Jonathan), Middelberg, R. P. (Rita P. S.), Mueller-Nurasyid, M. (Martina), Navarro, P. (Pau), Perusse, L. (Louis), Pervjakova, N. (Natalia), Sarti, C. (Cinzia), Smith, A. V. (Albert Vernon), Smith, J. A. (Jennifer A.), Stancakova, A. (Alena), Strawbridge, R. J. (Rona J.), Stringham, H. M. (Heather M.), Sung, Y. J. (Yun Ju), Tanaka, T. (Toshiko), Teumer, A. (Alexander), Trompet, S. (Stella), van der Laan, S. W. (Sander W.), van der Most, P. J. (Peter J.), Van Vliet-Ostaptchouk, J. V. (Jana V.), Vedantam, S. L. (Sailaja L.), Verweij, N. (Niek), Vink, J. M. (Jacqueline M.), Vitart, V. (Veronique), Wu, Y. (Ying), Yengo, L. (Loic), Zhang, W. (Weihua), Zhao, J. H. (Jing Hua), Zimmermann, M. E. (Martina E.), Zubair, N. (Niha), Abecasis, G. R. (Goncalo R.), Adair, L. S. (Linda S.), Afaq, S. (Saima), Afzal, U. (Uzma), Bakker, S. J. (Stephan J. L.), Bartz, T. M. (Traci M.), Beilby, J. (John), Bergman, R. N. (Richard N.), Bergmann, S. (Sven), Biffar, R. (Reiner), Blangero, J. (John), Boerwinkle, E. (Eric), Bonnycastle, L. L. (Lori L.), Bottinger, E. (Erwin), Braga, D. (Daniele), Buckley, B. M. (Brendan M.), Buyske, S. (Steve), Campbell, H. (Harry), Chambers, J. C. (John C.), Collins, F. S. (Francis S.), Curran, J. E. (Joanne E.), de Borst, G. J. (Gert J.), de Craen, A. J. (Anton J. M.), de Geus, E. J. (Eco J. C.), Dedoussis, G. (George), Delgado, G. E. (Graciela E.), den Ruijter, H. M. (Hester M.), Eiriksdottir, G. (Gudny), Eriksson, A. L. (Anna L.), Esko, T. (Tonu), Faul, J. D. (Jessica D.), Ford, I. (Ian), Forrester, T. (Terrence), Gertow, K. (Karl), Gigante, B. (Bruna), Glorioso, N. (Nicola), Gong, J. (Jian), Grallert, H. (Harald), Grammer, T. B. (Tanja B.), Grarup, N. (Niels), Haitjema, S. (Saskia), Hallmans, G. (Goran), Hamsten, A. (Anders), Hansen, T. (Torben), Harris, T. B. (Tamara B.), Hartman, C. A. (Catharina A.), Hassinen, M. (Maija), Hastie, N. D. (Nicholas D.), Heath, A. C. (Andrew C.), Hernandez, D. (Dena), Hindorff, L. (Lucia), Hocking, L. J. (Lynne J.), Hollensted, M. (Mette), Holmen, O. L. (Oddgeir L.), Homuth, G. (Georg), Hottenga, J. J. (Jouke Jan), Huang, J. (Jie), Hung, J. (Joseph), Hutri-Kähönen, N. (Nina), Ingelsson, E. (Erik), James, A. L. (Alan L.), Jansson, J.-O. (John-Olov), Järvelin, M.-R. (Marjo-Riitta), Jhun, M. A. (Min A.), Jorgensen, M. E. (Marit E.), Juonala, M. (Markus), Kähönen, M. (Mika), Karlsson, M. (Magnus), Koistinen, H. A. (Heikki A.), Kolcic, I. (Ivana), Kolovou, G. (Genovefa), Kooperberg, C. (Charles), Kramer, B. K. (Bernhard K.), Kuusisto, J. (Johanna), Kvaloy, K. (Kirsti), Lakka, T. A. (Timo A.), Langenberg, C. (Claudia), Launer, L. J. (Lenore J.), Leander, K. (Karin), Lee, N. R. (Nanette R.), Lind, L. (Lars), Lindgren, C. M. (Cecilia M.), Linneberg, A. (Allan), Lobbens, S. (Stephane), Loh, M. (Marie), Lorentzon, M. (Mattias), Luben, R. (Robert), Lubke, G. (Gitta), Ludolph-Donislawski, A. (Anja), Lupoli, S. (Sara), Madden, P. A. (Pamela A. F.), Männikkö, R. (Reija), Marques-Vidal, P. (Pedro), Martin, N. G. (Nicholas G.), McKenzie, C. A. (Colin A.), McKnight, B. (Barbara), Mellstrom, D. (Dan), Menni, C. (Cristina), Montgomery, G. W. (Grant W.), Musk, A. W. (A. W. (Bill)), Narisu, N. (Narisu), Nauck, M. (Matthias), Nolte, I. M. (Ilja M.), Oldehinkel, A. J. (Albertine J.), Olden, M. (Matthias), Ong, K. K. (Ken K.), Padmanabhan, S. (Sandosh), Peyser, P. A. (Patricia A.), Pisinger, C. (Charlotta), Porteous, D. J. (David J.), Raitakari, O. T. (Olli T.), Rankinen, T. (Tuomo), Rao, D. C. (D. C.), Rasmussen-Torvik, L. J. (Laura J.), Rawal, R. (Rajesh), Rice, T. (Treva), Ridker, P. M. (Paul M.), Rose, L. M. (Lynda M.), Bien, S. A. (Stephanie A.), Rudan, I. (Igor), Sanna, S. (Serena), Sarzynski, M. A. (Mark A.), Sattar, N. (Naveed), Savonen, K. (Kai), Schlessinger, D. (David), Scholtens, S. (Salome), Schurmann, C. (Claudia), Scott, R. A. (Robert A.), Sennblad, B. (Bengt), Siemelink, M. A. (Marten A.), Silbernagel, G. (Gunther), Slagboom, P. E. (P. Eline), Snieder, H. (Harold), Staessen, J. A. (Jan A.), Stott, D. J. (David J.), Swertz, M. A. (Morris A.), Swift, A. J. (Amy J.), Taylor, K. D. (Kent D.), Tayo, B. O. (Bamidele O.), Thorand, B. (Barbara), Thuillier, D. (Dorothee), Tuomilehto, J. (Jaakko), Uitterlinden, A. G. (Andre G.), Vandenput, L. (Liesbeth), Vohl, M.-C. (Marie-Claude), Volzke, H. (Henry), Vonk, J. M. (Judith M.), Waeber, G. (Gerard), Waldenberger, M. (Melanie), Westendorp, R. G. (R. G. J.), Wild, S. (Sarah), Willemsen, G. (Gonneke), Wolffenbuttel, B. H. (Bruce H. R.), Wong, A. (Andrew), Wright, A. F. (Alan F.), Zhao, W. (Wei), Zillikens, M. C. (M. Carola), Baldassarre, D. (Damiano), Balkau, B. (Beverley), Bandinelli, S. (Stefania), Boger, C. A. (Carsten A.), Boomsma, D. I. (Dorret I.), Bouchard, C. (Claude), Bruinenberg, M. (Marcel), Chasman, D. I. (Daniel I.), Chen, Y. I. (Yii-Der Ida), Chines, P. S. (Peter S.), Cooper, R. S. (Richard S.), Cucca, F. (Francesco), Cusi, D. (Daniele), de Faire, U. (Ulf), Ferrucci, L. (Luigi), Franks, P. W. (Paul W.), Froguel, P. (Philippe), Gordon-Larsen, P. (Penny), Grabe, H.-J. (Hans-Jorgen), Gudnason, V. (Vilmundur), Haiman, C. A. (Christopher A.), Hayward, C. (Caroline), Hveem, K. (Kristian), Johnson, A. D. (Andrew D.), Jukema, W. (Wouter), Kardia, S. L. (Sharon L. R.), Kivimäki, M. (Mika), Kooner, J. S. (Jaspal S.), Kuh, D. (Diana), Laakso, M. (Markku), Lehtimäki, T. (Terho), Le Marchand, L. (Loic), Marz, W. (Winfried), McCarthy, M. I. (Mark I.), Metspalu, A. (Andres), Morris, A. P. (Andrew P.), Ohlsson, C. (Claes), Palmer, L. J. (Lyle J.), Pasterkamp, G. (Gerard), Pedersen, O. (Oluf), Peters, A. (Annette), Peters, U. (Ulrike), Polasek, O. (Ozren), Psaty, B. M. (Bruce M.), Qi, L. (Lu), Rauramaa, R. (Rainer), Smith, B. H. (Blair H.), Sorensen, T. I. (Thorkild I. A.), Strauch, K. (Konstantin), Tiemeier, H. (Henning), Tremoli, E. (Elena), Van der Harst, P. (Pim), Vestergaard, H. (Henrik), Vollenweider, P. (Peter), Wareham, N. J. (Nicholas J.), Weir, D. R. (David R.), Whitfield, J. B. (John B.), Wilson, J. F. (James F.), Tyrrell, J. (Jessica), Frayling, T. M. (Timothy M.), Barroso, I. (Ines), Boehnke, M. (Michael), Deloukas, P. (Panagiotis), Fox, C. S. (Caroline S.), Hirschhorn, J. N. (Joel N.), Hunter, D. J. (David J.), Spector, T. D. (Tim D.), Strachan, D. P. (David P.), van Duijn, C. M. (Cornelia M.), Heid, I. M. (Iris M.), Mohlke, K. L. (Karen L.), Marchini, J. (Jonathan), Loos, R. J. (Ruth J. F.), Kilpeläinen, T. O. (Tuomas O.), Liu, C.-T. (Ching-Ti), Borecki, I. B. (Ingrid B.), North, K. E. (Kari E.), Cupples, L. A. (L. Adrienne), Justice, A. E. (Anne E.), Winkler, T. W. (Thomas W.), Feitosa, M. F. (Mary F.), Graff, M. (Misa), Fisher, V. A. (Virginia A.), Young, K. (Kristin), Barata, L. (Llilda), Deng, X. (Xuan), Czajkowski, J. (Jacek), Hadley, D. (David), Ngwa, J. S. (Julius S.), Ahluwalia, T. S. (Tarunveer S.), Chu, A. Y. (Audrey Y.), Heard-Costa, N. L. (Nancy L.), Lim, E. (Elise), Perez, J. (Jeremiah), Eicher, J. D. (John D.), Kutalik, Z. (Zoltan), Xue, L. (Luting), Mahajan, A. (Anubha), Renstrom, F. (Frida), Wu, J. (Joseph), Qi, Q. (Qibin), Ahmad, S. (Shafqat), Alfred, T. (Tamuno), Amin, N. (Najaf), Bielak, L. F. (Lawrence F.), Bonnefond, A. (Amelie), Bragg, J. (Jennifer), Cadby, G. (Gemma), Chittani, M. (Martina), Coggeshall, S. (Scott), Corre, T. (Tanguy), Direk, N. (Nese), Eriksson, J. (Joel), Fischer, K. (Krista), Gorski, M. (Mathias), Harder, M. N. (Marie Neergaard), Horikoshi, M. (Momoko), Huang, T. (Tao), Huffman, J. E. (Jennifer E.), Jackson, A. U. (Anne U.), Justesen, J. M. (Johanne Marie), Kanoni, S. (Stavroula), Kinnunen, L. (Leena), Kleber, M. E. (Marcus E.), Komulainen, P. (Pirjo), Kumari, M. (Meena), Lim, U. (Unhee), Luan, J. (Jian'an), Lyytikäinen, L.-P. (Leo-Pekka), Mangino, M. (Massimo), Manichaikul, A. (Ani), Marten, J. (Jonathan), Middelberg, R. P. (Rita P. S.), Mueller-Nurasyid, M. (Martina), Navarro, P. (Pau), Perusse, L. (Louis), Pervjakova, N. (Natalia), Sarti, C. (Cinzia), Smith, A. V. (Albert Vernon), Smith, J. A. (Jennifer A.), Stancakova, A. (Alena), Strawbridge, R. J. (Rona J.), Stringham, H. M. (Heather M.), Sung, Y. J. (Yun Ju), Tanaka, T. (Toshiko), Teumer, A. (Alexander), Trompet, S. (Stella), van der Laan, S. W. (Sander W.), van der Most, P. J. (Peter J.), Van Vliet-Ostaptchouk, J. V. (Jana V.), Vedantam, S. L. (Sailaja L.), Verweij, N. (Niek), Vink, J. M. (Jacqueline M.), Vitart, V. (Veronique), Wu, Y. (Ying), Yengo, L. (Loic), Zhang, W. (Weihua), Zhao, J. H. (Jing Hua), Zimmermann, M. E. (Martina E.), Zubair, N. (Niha), Abecasis, G. R. (Goncalo R.), Adair, L. S. (Linda S.), Afaq, S. (Saima), Afzal, U. (Uzma), Bakker, S. J. (Stephan J. L.), Bartz, T. M. (Traci M.), Beilby, J. (John), Bergman, R. N. (Richard N.), Bergmann, S. (Sven), Biffar, R. (Reiner), Blangero, J. (John), Boerwinkle, E. (Eric), Bonnycastle, L. L. (Lori L.), Bottinger, E. (Erwin), Braga, D. (Daniele), Buckley, B. M. (Brendan M.), Buyske, S. (Steve), Campbell, H. (Harry), Chambers, J. C. (John C.), Collins, F. S. (Francis S.), Curran, J. E. (Joanne E.), de Borst, G. J. (Gert J.), de Craen, A. J. (Anton J. M.), de Geus, E. J. (Eco J. C.), Dedoussis, G. (George), Delgado, G. E. (Graciela E.), den Ruijter, H. M. (Hester M.), Eiriksdottir, G. (Gudny), Eriksson, A. L. (Anna L.), Esko, T. (Tonu), Faul, J. D. (Jessica D.), Ford, I. (Ian), Forrester, T. (Terrence), Gertow, K. (Karl), Gigante, B. (Bruna), Glorioso, N. (Nicola), Gong, J. (Jian), Grallert, H. (Harald), Grammer, T. B. (Tanja B.), Grarup, N. (Niels), Haitjema, S. (Saskia), Hallmans, G. (Goran), Hamsten, A. (Anders), Hansen, T. (Torben), Harris, T. B. (Tamara B.), Hartman, C. A. (Catharina A.), Hassinen, M. (Maija), Hastie, N. D. (Nicholas D.), Heath, A. C. (Andrew C.), Hernandez, D. (Dena), Hindorff, L. (Lucia), Hocking, L. J. (Lynne J.), Hollensted, M. (Mette), Holmen, O. L. (Oddgeir L.), Homuth, G. (Georg), Hottenga, J. J. (Jouke Jan), Huang, J. (Jie), Hung, J. (Joseph), Hutri-Kähönen, N. (Nina), Ingelsson, E. (Erik), James, A. L. (Alan L.), Jansson, J.-O. (John-Olov), Järvelin, M.-R. (Marjo-Riitta), Jhun, M. A. (Min A.), Jorgensen, M. E. (Marit E.), Juonala, M. (Markus), Kähönen, M. (Mika), Karlsson, M. (Magnus), Koistinen, H. A. (Heikki A.), Kolcic, I. (Ivana), Kolovou, G. (Genovefa), Kooperberg, C. (Charles), Kramer, B. K. (Bernhard K.), Kuusisto, J. (Johanna), Kvaloy, K. (Kirsti), Lakka, T. A. (Timo A.), Langenberg, C. (Claudia), Launer, L. J. (Lenore J.), Leander, K. (Karin), Lee, N. R. (Nanette R.), Lind, L. (Lars), Lindgren, C. M. (Cecilia M.), Linneberg, A. (Allan), Lobbens, S. (Stephane), Loh, M. (Marie), Lorentzon, M. (Mattias), Luben, R. (Robert), Lubke, G. (Gitta), Ludolph-Donislawski, A. (Anja), Lupoli, S. (Sara), Madden, P. A. (Pamela A. F.), Männikkö, R. (Reija), Marques-Vidal, P. (Pedro), Martin, N. G. (Nicholas G.), McKenzie, C. A. (Colin A.), McKnight, B. (Barbara), Mellstrom, D. (Dan), Menni, C. (Cristina), Montgomery, G. W. (Grant W.), Musk, A. W. (A. W. (Bill)), Narisu, N. (Narisu), Nauck, M. (Matthias), Nolte, I. M. (Ilja M.), Oldehinkel, A. J. (Albertine J.), Olden, M. (Matthias), Ong, K. K. (Ken K.), Padmanabhan, S. (Sandosh), Peyser, P. A. (Patricia A.), Pisinger, C. (Charlotta), Porteous, D. J. (David J.), Raitakari, O. T. (Olli T.), Rankinen, T. (Tuomo), Rao, D. C. (D. C.), Rasmussen-Torvik, L. J. (Laura J.), Rawal, R. (Rajesh), Rice, T. (Treva), Ridker, P. M. (Paul M.), Rose, L. M. (Lynda M.), Bien, S. A. (Stephanie A.), Rudan, I. (Igor), Sanna, S. (Serena), Sarzynski, M. A. (Mark A.), Sattar, N. (Naveed), Savonen, K. (Kai), Schlessinger, D. (David), Scholtens, S. (Salome), Schurmann, C. (Claudia), Scott, R. A. (Robert A.), Sennblad, B. (Bengt), Siemelink, M. A. (Marten A.), Silbernagel, G. (Gunther), Slagboom, P. E. (P. Eline), Snieder, H. (Harold), Staessen, J. A. (Jan A.), Stott, D. J. (David J.), Swertz, M. A. (Morris A.), Swift, A. J. (Amy J.), Taylor, K. D. (Kent D.), Tayo, B. O. (Bamidele O.), Thorand, B. (Barbara), Thuillier, D. (Dorothee), Tuomilehto, J. (Jaakko), Uitterlinden, A. G. (Andre G.), Vandenput, L. (Liesbeth), Vohl, M.-C. (Marie-Claude), Volzke, H. (Henry), Vonk, J. M. (Judith M.), Waeber, G. (Gerard), Waldenberger, M. (Melanie), Westendorp, R. G. (R. G. J.), Wild, S. (Sarah), Willemsen, G. (Gonneke), Wolffenbuttel, B. H. (Bruce H. R.), Wong, A. (Andrew), Wright, A. F. (Alan F.), Zhao, W. (Wei), Zillikens, M. C. (M. Carola), Baldassarre, D. (Damiano), Balkau, B. (Beverley), Bandinelli, S. (Stefania), Boger, C. A. (Carsten A.), Boomsma, D. I. (Dorret I.), Bouchard, C. (Claude), Bruinenberg, M. (Marcel), Chasman, D. I. (Daniel I.), Chen, Y. I. (Yii-Der Ida), Chines, P. S. (Peter S.), Cooper, R. S. (Richard S.), Cucca, F. (Francesco), Cusi, D. (Daniele), de Faire, U. (Ulf), Ferrucci, L. (Luigi), Franks, P. W. (Paul W.), Froguel, P. (Philippe), Gordon-Larsen, P. (Penny), Grabe, H.-J. (Hans-Jorgen), Gudnason, V. (Vilmundur), Haiman, C. A. (Christopher A.), Hayward, C. (Caroline), Hveem, K. (Kristian), Johnson, A. D. (Andrew D.), Jukema, W. (Wouter), Kardia, S. L. (Sharon L. R.), Kivimäki, M. (Mika), Kooner, J. S. (Jaspal S.), Kuh, D. (Diana), Laakso, M. (Markku), Lehtimäki, T. (Terho), Le Marchand, L. (Loic), Marz, W. (Winfried), McCarthy, M. I. (Mark I.), Metspalu, A. (Andres), Morris, A. P. (Andrew P.), Ohlsson, C. (Claes), Palmer, L. J. (Lyle J.), Pasterkamp, G. (Gerard), Pedersen, O. (Oluf), Peters, A. (Annette), Peters, U. (Ulrike), Polasek, O. (Ozren), Psaty, B. M. (Bruce M.), Qi, L. (Lu), Rauramaa, R. (Rainer), Smith, B. H. (Blair H.), Sorensen, T. I. (Thorkild I. A.), Strauch, K. (Konstantin), Tiemeier, H. (Henning), Tremoli, E. (Elena), Van der Harst, P. (Pim), Vestergaard, H. (Henrik), Vollenweider, P. (Peter), Wareham, N. J. (Nicholas J.), Weir, D. R. (David R.), Whitfield, J. B. (John B.), Wilson, J. F. (James F.), Tyrrell, J. (Jessica), Frayling, T. M. (Timothy M.), Barroso, I. (Ines), Boehnke, M. (Michael), Deloukas, P. (Panagiotis), Fox, C. S. (Caroline S.), Hirschhorn, J. N. (Joel N.), Hunter, D. J. (David J.), Spector, T. D. (Tim D.), Strachan, D. P. (David P.), van Duijn, C. M. (Cornelia M.), Heid, I. M. (Iris M.), Mohlke, K. L. (Karen L.), Marchini, J. (Jonathan), Loos, R. J. (Ruth J. F.), Kilpeläinen, T. O. (Tuomas O.), Liu, C.-T. (Ching-Ti), Borecki, I. B. (Ingrid B.), North, K. E. (Kari E.), and Cupples, L. A. (L. Adrienne)

Abstract

Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution.

Published
2017

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