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1. Genomic and transcriptomic features of androgen receptor signaling inhibitor resistance in metastatic castration-resistant prostate cancer.

Author

Zhu, Xiaolin, Farsh, Tatyanah, Vis, Daniël, Yu, Ivan, Li, Haolong, Liu, Tianyi, Sjöström, Martin, Shrestha, Raunak, Kneppers, Jeroen, Severson, Tesa, Zhang, Meng, Lundberg, Arian, Moreno Rodriguez, Thaidy, Weinstein, Alana, Foye, Adam, Mehra, Niven, Aggarwal, Rahul, Bergman, Andries, Small, Eric, Lack, Nathan, Zwart, Wilbert, Quigley, David, van der Heijden, Michiel, and Feng, Felix

Subjects
Oncology, Prostate cancer, Male, Humans, Prostatic Neoplasms, Castration-Resistant, Receptors, Androgen, Drug Resistance, Neoplasm, Cell Line, Tumor, Signal Transduction, Transcriptome, Neoplasm Metastasis, Receptors, Somatostatin, Gene Expression Regulation, Neoplastic, Androgen Receptor Antagonists, Neoplasm Proteins
Abstract

BACKGROUNDAndrogen receptor signaling inhibitors (ARSIs) have improved outcomes for patients with metastatic castration-resistant prostate cancer (mCRPC), but their clinical benefit is limited by treatment resistance.METHODSTo investigate the mechanisms of ARSI resistance, we analyzed the whole-genome (n = 45) and transcriptome (n = 31) sequencing data generated from paired metastatic biopsies obtained before initiation of first-line ARSI therapy for mCRPC and after radiographic disease progression. We investigated the effects of genetic and pharmacologic modulation of SSTR1 in 22Rv1 cells, a representative mCRPC cell line.RESULTSWe confirmed the predominant role of tumor genetic alterations converging on augmenting androgen receptor (AR) signaling and the increased transcriptional heterogeneity and lineage plasticity during the emergence of ARSI resistance. We further identified amplifications involving a putative enhancer downstream of the AR and transcriptional downregulation of SSTR1, encoding somatostatin receptor 1, in ARSI-resistant tumors. We found that patients with SSTR1-low mCRPC tumors derived less benefit from subsequent ARSI therapy in a retrospective cohort. We showed that SSTR1 was antiproliferative in 22Rv1 cells and that the FDA-approved drug pasireotide suppressed 22Rv1 cell proliferation.CONCLUSIONOur findings expand the knowledge of ARSI resistance and point out actionable next steps, exemplified by potentially targeting SSTR1, to improve patient outcomes.FUNDINGNational Cancer Institute (NCI), NIH; Prostate Cancer Foundation; Conquer Cancer, American Society of Clinical Oncology Foundation; UCSF Benioff Initiative for Prostate Cancer Research; Netherlands Cancer Institute.

Published
2024

2. Integrated analyses highlight interactions between the three-dimensional genome and DNA, RNA and epigenomic alterations in metastatic prostate cancer.

Author

Zhao, Shuang, Bootsma, Matthew, Zhou, Stanley, Shrestha, Raunak, Moreno-Rodriguez, Thaidy, Lundberg, Arian, Pan, Chu, Arlidge, Christopher, Hawley, James, Foye, Adam, Weinstein, Alana, Sjöström, Martin, Zhang, Meng, Li, Haolong, Chesner, Lisa, Rydzewski, Nicholas, Helzer, Kyle, Shi, Yue, Lynch, Molly, Dehm, Scott, Lang, Joshua, Alumkal, Joshi, He, Hansen, Wyatt, Alexander, Aggarwal, Rahul, Zwart, Wilbert, Small, Eric, Quigley, David, Lupien, Mathieu, and Feng, Felix

Subjects
Humans, Male, DNA Methylation, 5-Methylcytosine, Gene Expression Regulation, Neoplastic, Epigenomics, Neoplasm Metastasis, Genome, Human, Prostatic Neoplasms, Epigenesis, Genetic, Receptors, Androgen, Chromatin, Prostatic Neoplasms, Castration-Resistant, Oncogene Proteins, Fusion, DNA, Whole Genome Sequencing, RNA, Prognosis
Abstract

The impact of variations in the three-dimensional structure of the genome has been recognized, but solid cancer tissue studies are limited. Here, we performed integrated deep Hi-C sequencing with matched whole-genome sequencing, whole-genome bisulfite sequencing, 5-hydroxymethylcytosine (5hmC) sequencing and RNA sequencing across a cohort of 80 biopsy samples from patients with metastatic castration-resistant prostate cancer. Dramatic differences were present in gene expression, 5-methylcytosine/5hmC methylation and in structural variation versus mutation rate between A and B (open and closed) chromatin compartments. A subset of tumors exhibited depleted regional chromatin contacts at the AR locus, linked to extrachromosomal circular DNA (ecDNA) and worse response to AR signaling inhibitors. We also identified topological subtypes associated with stark differences in methylation structure, gene expression and prognosis. Our data suggested that DNA interactions may predispose to structural variant formation, exemplified by the recurrent TMPRSS2-ERG fusion. This comprehensive integrated sequencing effort represents a unique clinical tumor resource.

Published
2024

3. Extensive androgen receptor enhancer heterogeneity in primary prostate cancers underlies transcriptional diversity and metastatic potential.

Author

Kneppers, Jeroen, Severson, Tesa, Siefert, Joseph, Schol, Pieter, Joosten, Stacey, Yu, Ivan, Huang, Chia-Chi, Morova, Tunç, Altıntaş, Umut, Giambartolomei, Claudia, Seo, Ji-Heui, Baca, Sylvan, Carneiro, Isa, Emberly, Eldon, Pasaniuc, Bogdan, Jerónimo, Carmen, Henrique, Rui, Freedman, Matthew, Wessels, Lodewyk, Lack, Nathan, Bergman, Andries, and Zwart, Wilbert

Subjects
Male, Humans, Receptors, Androgen, Regulatory Sequences, Nucleic Acid, Prostatic Neoplasms, Prostate, Chromatin
Abstract

Androgen receptor (AR) drives prostate cancer (PCa) development and progression. AR chromatin binding profiles are highly plastic and form recurrent programmatic changes that differentiate disease stages, subtypes and patient outcomes. While prior studies focused on concordance between patient subgroups, inter-tumor heterogeneity of AR enhancer selectivity remains unexplored. Here we report high levels of AR chromatin binding heterogeneity in human primary prostate tumors, that overlap with heterogeneity observed in healthy prostate epithelium. Such heterogeneity has functional consequences, as somatic mutations converge on commonly-shared AR sites in primary over metastatic tissues. In contrast, less-frequently shared AR sites associate strongly with AR-driven gene expression, while such heterogeneous AR enhancer usage also distinguishes patients outcome. These findings indicate that epigenetic heterogeneity in primary disease is directly informative for risk of biochemical relapse. Cumulatively, our results illustrate a high level of AR enhancer heterogeneity in primary PCa driving differential expression and clinical impact.

Published
2022

4. The 5-Hydroxymethylcytosine Landscape of Prostate Cancer

Author

Sjöström, Martin, Zhao, Shuang G, Levy, Samuel, Zhang, Meng, Ning, Yuhong, Shrestha, Raunak, Lundberg, Arian, Herberts, Cameron, Foye, Adam, Aggarwal, Rahul, Hua, Junjie T, Li, Haolong, Bergamaschi, Anna, Maurice-Dror, Corinne, Maheshwari, Ashutosh, Chen, Sujun, Ng, Sarah WS, Ye, Wenbin, Petricca, Jessica, Fraser, Michael, Chesner, Lisa, Perry, Marc D, Moreno-Rodriguez, Thaidy, Chen, William S, Alumkal, Joshi J, Chou, Jonathan, Morgans, Alicia K, Beer, Tomasz M, Thomas, George V, Gleave, Martin, Lloyd, Paul, Phillips, Tierney, McCarthy, Erin, Haffner, Michael C, Zoubeidi, Amina, Annala, Matti, Reiter, Robert E, Rettig, Matthew B, Witte, Owen N, Fong, Lawrence, Bose, Rohit, Huang, Franklin W, Luo, Jianhua, Bjartell, Anders, Lang, Joshua M, Mahajan, Nupam P, Lara, Primo N, Evans, Christopher P, Tran, Phuoc T, Posadas, Edwin M, He, Chuan, Cui, Xiao-Long, Huang, Jiaoti, Zwart, Wilbert, Gilbert, Luke A, Maher, Christopher A, Boutros, Paul C, N., Kim, Ashworth, Alan, Small, Eric J, He, Housheng H, Wyatt, Alexander W, Quigley, David A, and Feng, Felix Y

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Clinical Sciences, Oncology and Carcinogenesis, Urologic Diseases, Cancer, Prostate Cancer, Human Genome, Aging, Cancer Genomics, 4.1 Discovery and preclinical testing of markers and technologies, 2.1 Biological and endogenous factors, 4.2 Evaluation of markers and technologies, Good Health and Well Being, Male, Humans, 5-Methylcytosine, Prostatic Neoplasms, Prostate, Biopsy, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

Analysis of DNA methylation is a valuable tool to understand disease progression and is increasingly being used to create diagnostic and prognostic clinical biomarkers. While conversion of cytosine to 5-methylcytosine (5mC) commonly results in transcriptional repression, further conversion to 5-hydroxymethylcytosine (5hmC) is associated with transcriptional activation. Here we perform the first study integrating whole-genome 5hmC with DNA, 5mC, and transcriptome sequencing in clinical samples of benign, localized, and advanced prostate cancer. 5hmC is shown to mark activation of cancer drivers and downstream targets. Furthermore, 5hmC sequencing revealed profoundly altered cell states throughout the disease course, characterized by increased proliferation, oncogenic signaling, dedifferentiation, and lineage plasticity to neuroendocrine and gastrointestinal lineages. Finally, 5hmC sequencing of cell-free DNA from patients with metastatic disease proved useful as a prognostic biomarker able to identify an aggressive subtype of prostate cancer using the genes TOP2A and EZH2, previously only detectable by transcriptomic analysis of solid tumor biopsies. Overall, these findings reveal that 5hmC marks epigenomic activation in prostate cancer and identify hallmarks of prostate cancer progression with potential as biomarkers of aggressive disease.SignificanceIn prostate cancer, 5-hydroxymethylcytosine delineates oncogene activation and stage-specific cell states and can be analyzed in liquid biopsies to detect cancer phenotypes. See related article by Wu and Attard, p. 3880.

Published
2022

5. Drug-Induced Epigenomic Plasticity Reprograms Circadian Rhythm Regulation to Drive Prostate Cancer toward Androgen Independence.

Author

Linder, Simon, Hoogstraat, Marlous, Stelloo, Suzan, Eickhoff, Nils, Schuurman, Karianne, de Barros, Hilda, Alkemade, Maartje, Bekers, Elise M, Severson, Tesa M, Sanders, Joyce, Huang, Chia-Chi Flora, Morova, Tunc, Altintas, Umut Berkay, Hoekman, Liesbeth, Kim, Yongsoo, Baca, Sylvan C, Sjöström, Martin, Zaalberg, Anniek, Hintzen, Dorine C, de Jong, Jeroen, Kluin, Roelof JC, de Rink, Iris, Giambartolomei, Claudia, Seo, Ji-Heui, Pasaniuc, Bogdan, Altelaar, Maarten, Medema, René H, Feng, Felix Y, Zoubeidi, Amina, Freedman, Matthew L, Wessels, Lodewyk FA, Butler, Lisa M, Lack, Nathan A, van der Poel, Henk, Bergman, Andries M, and Zwart, Wilbert

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Prostate Cancer, Aging, Urologic Diseases, Biotechnology, Cancer, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, 2.1 Biological and endogenous factors, Aetiology, ARNTL Transcription Factors, Androgens, Cell Line, Tumor, Circadian Rhythm, Drug Resistance, Neoplasm, Epigenomics, Humans, Male, Nitriles, Prostatic Neoplasms, Castration-Resistant, Receptors, Androgen, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

In prostate cancer, androgen receptor (AR)-targeting agents are very effective in various disease stages. However, therapy resistance inevitably occurs, and little is known about how tumor cells adapt to bypass AR suppression. Here, we performed integrative multiomics analyses on tissues isolated before and after 3 months of AR-targeting enzalutamide monotherapy from patients with high-risk prostate cancer enrolled in a neoadjuvant clinical trial. Transcriptomic analyses demonstrated that AR inhibition drove tumors toward a neuroendocrine-like disease state. Additionally, epigenomic profiling revealed massive enzalutamide-induced reprogramming of pioneer factor FOXA1 from inactive chromatin sites toward active cis-regulatory elements that dictate prosurvival signals. Notably, treatment-induced FOXA1 sites were enriched for the circadian clock component ARNTL. Posttreatment ARNTL levels were associated with patients' clinical outcomes, and ARNTL knockout strongly decreased prostate cancer cell growth. Our data highlight a remarkable cistromic plasticity of FOXA1 following AR-targeted therapy and revealed an acquired dependency on the circadian regulator ARNTL, a novel candidate therapeutic target.SignificanceUnderstanding how prostate cancers adapt to AR-targeted interventions is critical for identifying novel drug targets to improve the clinical management of treatment-resistant disease. Our study revealed an enzalutamide-induced epigenomic plasticity toward prosurvival signaling and uncovered the circadian regulator ARNTL as an acquired vulnerability after AR inhibition, presenting a novel lead for therapeutic development. See related commentary by Zhang et al., p. 2017. This article is highlighted in the In This Issue feature, p. 2007.

Published
2022

6. Genetic determinants of chromatin reveal prostate cancer risk mediated by context-dependent gene regulation

Author

Baca, Sylvan C, Singler, Cassandra, Zacharia, Soumya, Seo, Ji-Heui, Morova, Tunc, Hach, Faraz, Ding, Yi, Schwarz, Tommer, Huang, Chia-Chi Flora, Anderson, Jacob, Fay, André P, Kalita, Cynthia, Groha, Stefan, Pomerantz, Mark M, Wang, Victoria, Linder, Simon, Sweeney, Christopher J, Zwart, Wilbert, Lack, Nathan A, Pasaniuc, Bogdan, Takeda, David Y, Gusev, Alexander, and Freedman, Matthew L

Subjects
Biological Sciences, Genetics, Prevention, Aging, Human Genome, Cancer, Biotechnology, Prostate Cancer, Urologic Diseases, Aetiology, 2.1 Biological and endogenous factors, Chromatin, Gene Expression Regulation, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Polymorphism, Single Nucleotide, Prostatic Neoplasms, Quantitative Trait Loci, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Many genetic variants affect disease risk by altering context-dependent gene regulation. Such variants are difficult to study mechanistically using current methods that link genetic variation to steady-state gene expression levels, such as expression quantitative trait loci (eQTLs). To address this challenge, we developed the cistrome-wide association study (CWAS), a framework for identifying genotypic and allele-specific effects on chromatin that are also associated with disease. In prostate cancer, CWAS identified regulatory elements and androgen receptor-binding sites that explained the association at 52 of 98 known prostate cancer risk loci and discovered 17 additional risk loci. CWAS implicated key developmental transcription factors in prostate cancer risk that are overlooked by eQTL-based approaches due to context-dependent gene regulation. We experimentally validated associations and demonstrated the extensibility of CWAS to additional epigenomic datasets and phenotypes, including response to prostate cancer treatment. CWAS is a powerful and biologically interpretable paradigm for studying variants that influence traits by affecting transcriptional regulation.

Published
2022

7. An androgen receptor switch underlies lineage infidelity in treatment-resistant prostate cancer

Author

Davies, Alastair, Nouruzi, Shaghayegh, Ganguli, Dwaipayan, Namekawa, Takeshi, Thaper, Daksh, Linder, Simon, Karaoğlanoğlu, Fatih, Omur, Meltem E, Kim, Soojin, Kobelev, Maxim, Kumar, Sahil, Sivak, Olena, Bostock, Chiara, Bishop, Jennifer, Hoogstraat, Marlous, Talal, Amina, Stelloo, Suzan, van der Poel, Henk, Bergman, Andries M, Ahmed, Musaddeque, Fazli, Ladan, Huang, Haojie, Tilley, Wayne, Goodrich, David, Feng, Felix Y, Gleave, Martin, He, Housheng Hansen, Hach, Faraz, Zwart, Wilbert, Beltran, Himisha, Selth, Luke, and Zoubeidi, Amina

Subjects
Prostate Cancer, Genetics, Cancer, Stem Cell Research, Urologic Diseases, Aetiology, 1.1 Normal biological development and functioning, Underpinning research, 2.1 Biological and endogenous factors, Cell Line, Tumor, Enhancer of Zeste Homolog 2 Protein, Gene Expression Regulation, Neoplastic, Gene Regulatory Networks, Humans, Male, Prostatic Neoplasms, Receptors, Androgen, Signal Transduction, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Cancers adapt to increasingly potent targeted therapies by reprogramming their phenotype. Here we investigated such a phenomenon in prostate cancer, in which tumours can escape epithelial lineage confinement and transition to a high-plasticity state as an adaptive response to potent androgen receptor (AR) antagonism. We found that AR activity can be maintained as tumours adopt alternative lineage identities, with changes in chromatin architecture guiding AR transcriptional rerouting. The epigenetic regulator enhancer of zeste homologue 2 (EZH2) co-occupies the reprogrammed AR cistrome to transcriptionally modulate stem cell and neuronal gene networks-granting privileges associated with both fates. This function of EZH2 was associated with T350 phosphorylation and establishment of a non-canonical polycomb subcomplex. Our study provides mechanistic insights into the plasticity of the lineage-infidelity state governed by AR reprogramming that enabled us to redirect cell fate by modulating EZH2 and AR, highlighting the clinical potential of reversing resistance phenotypes.

Published
2021

8. Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors

Author

Bakker, Mark K, van der Spek, Rick AA, van Rheenen, Wouter, Morel, Sandrine, Bourcier, Romain, Hostettler, Isabel C, Alg, Varinder S, van Eijk, Kristel R, Koido, Masaru, Akiyama, Masato, Terao, Chikashi, Matsuda, Koichi, Walters, Robin G, Lin, Kuang, Li, Liming, Millwood, Iona Y, Chen, Zhengming, Rouleau, Guy A, Zhou, Sirui, Rannikmäe, Kristiina, Sudlow, Cathie LM, Houlden, Henry, van den Berg, Leonard H, Dina, Christian, Naggara, Olivier, Gentric, Jean-Christophe, Shotar, Eimad, Eugène, François, Desal, Hubert, Winsvold, Bendik S, Børte, Sigrid, Johnsen, Marianne Bakke, Brumpton, Ben M, Sandvei, Marie Søfteland, Willer, Cristen J, Hveem, Kristian, Zwart, John-Anker, Verschuren, WM Monique, Friedrich, Christoph M, Hirsch, Sven, Schilling, Sabine, Dauvillier, Jérôme, Martin, Olivier, Jones, Gregory T, Bown, Matthew J, Ko, Nerissa U, Kim, Helen, Coleman, Jonathan RI, Breen, Gerome, Zaroff, Jonathan G, Klijn, Catharina JM, Malik, Rainer, Dichgans, Martin, Sargurupremraj, Muralidharan, Tatlisumak, Turgut, Amouyel, Philippe, Debette, Stéphanie, Rinkel, Gabriel JE, Worrall, Bradford B, Pera, Joanna, Slowik, Agnieszka, Gaál-Paavola, Emília I, Niemelä, Mika, Jääskeläinen, Juha E, von Und Zu Fraunberg, Mikael, Lindgren, Antti, Broderick, Joseph P, Werring, David J, Woo, Daniel, Redon, Richard, Bijlenga, Philippe, Kamatani, Yoichiro, Veldink, Jan H, and Ruigrok, Ynte M

Subjects
Genetics, Brain Disorders, Human Genome, Clinical Research, Prevention, Stroke, Neurosciences, Aetiology, 2.1 Biological and endogenous factors, Cardiovascular, Asian People, Blood Pressure, Case-Control Studies, Endothelial Cells, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Hypertension, Intracranial Aneurysm, Polymorphism, Single Nucleotide, Risk Factors, Smoking, Subarachnoid Hemorrhage, White People, HUNT All-In Stroke, China Kadoorie Biobank Collaborative Group, BioBank Japan Project Consortium, ICAN Study Group, CADISP Group, Genetics and Observational Subarachnoid Haemorrhage (GOSH) Study investigators, International Stroke Genetics Consortium, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Rupture of an intracranial aneurysm leads to subarachnoid hemorrhage, a severe type of stroke. To discover new risk loci and the genetic architecture of intracranial aneurysms, we performed a cross-ancestry, genome-wide association study in 10,754 cases and 306,882 controls of European and East Asian ancestry. We discovered 17 risk loci, 11 of which are new. We reveal a polygenic architecture and explain over half of the disease heritability. We show a high genetic correlation between ruptured and unruptured intracranial aneurysms. We also find a suggestive role for endothelial cells by using gene mapping and heritability enrichment. Drug-target enrichment shows pleiotropy between intracranial aneurysms and antiepileptic and sex hormone drugs, providing insights into intracranial aneurysm pathophysiology. Finally, genetic risks for smoking and high blood pressure, the two main clinical risk factors, play important roles in intracranial aneurysm risk, and drive most of the genetic correlation between intracranial aneurysms and other cerebrovascular traits.

Published
2020

9. Tailored design of protein nanoparticle scaffolds for multivalent presentation of viral glycoprotein antigens.

Author

Ueda, George, Antanasijevic, Aleksandar, Fallas, Jorge A, Sheffler, William, Copps, Jeffrey, Ellis, Daniel, Hutchinson, Geoffrey B, Moyer, Adam, Yasmeen, Anila, Tsybovsky, Yaroslav, Park, Young-Jun, Bick, Matthew J, Sankaran, Banumathi, Gillespie, Rebecca A, Brouwer, Philip Jm, Zwart, Peter H, Veesler, David, Kanekiyo, Masaru, Graham, Barney S, Sanders, Rogier W, Moore, John P, Klasse, Per Johan, Ward, Andrew B, King, Neil P, and Baker, David

Subjects
Humans, Glycoproteins, Influenza Vaccines, Antigens, Viral, Cryoelectron Microscopy, Vaccination, Nanoparticles, Immunity, Humoral, B lymphocytes, BL21, E. coli, HEK293F, Lemo21, computational biology, human, immunology, inflammation, systems biology, virus, Antigens, Viral, Immunity, Humoral, Biochemistry and Cell Biology
Abstract

Multivalent presentation of viral glycoproteins can substantially increase the elicitation of antigen-specific antibodies. To enable a new generation of anti-viral vaccines, we designed self-assembling protein nanoparticles with geometries tailored to present the ectodomains of influenza, HIV, and RSV viral glycoprotein trimers. We first de novo designed trimers tailored for antigen fusion, featuring N-terminal helices positioned to match the C termini of the viral glycoproteins. Trimers that experimentally adopted their designed configurations were incorporated as components of tetrahedral, octahedral, and icosahedral nanoparticles, which were characterized by cryo-electron microscopy and assessed for their ability to present viral glycoproteins. Electron microscopy and antibody binding experiments demonstrated that the designed nanoparticles presented antigenically intact prefusion HIV-1 Env, influenza hemagglutinin, and RSV F trimers in the predicted geometries. This work demonstrates that antigen-displaying protein nanoparticles can be designed from scratch, and provides a systematic way to investigate the influence of antigen presentation geometry on the immune response to vaccination.

Published
2020

10. Prostate cancer reactivates developmental epigenomic programs during metastatic progression

Author

Pomerantz, Mark M, Qiu, Xintao, Zhu, Yanyun, Takeda, David Y, Pan, Wenting, Baca, Sylvan C, Gusev, Alexander, Korthauer, Keegan D, Severson, Tesa M, Ha, Gavin, Viswanathan, Srinivas R, Seo, Ji-Heui, Nguyen, Holly M, Zhang, Baohui, Pasaniuc, Bogdan, Giambartolomei, Claudia, Alaiwi, Sarah A, Bell, Connor A, O’Connor, Edward P, Chabot, Matthew S, Stillman, David R, Lis, Rosina, Font-Tello, Alba, Li, Lewyn, Cejas, Paloma, Bergman, Andries M, Sanders, Joyce, van der Poel, Henk G, Gayther, Simon A, Lawrenson, Kate, Fonseca, Marcos AS, Reddy, Jessica, Corona, Rosario I, Martovetsky, Gleb, Egan, Brian, Choueiri, Toni, Ellis, Leigh, Garraway, Isla P, Lee, Gwo-Shu Mary, Corey, Eva, Long, Henry W, Zwart, Wilbert, and Freedman, Matthew L

Subjects
Agricultural, Veterinary and Food Sciences, Biological Sciences, Bioinformatics and Computational Biology, Genetics, Agricultural Biotechnology, Aging, Human Genome, Urologic Diseases, Cancer, Prostate Cancer, 2.1 Biological and endogenous factors, Aetiology, Cell Line, Cell Line, Tumor, Disease Progression, Epigenomics, Gene Expression Regulation, Neoplastic, HEK293 Cells, Hepatocyte Nuclear Factor 3-alpha, Humans, Male, Prostate, Prostatic Neoplasms, Receptors, Androgen, Regulatory Sequences, Nucleic Acid, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Epigenetic processes govern prostate cancer (PCa) biology, as evidenced by the dependency of PCa cells on the androgen receptor (AR), a prostate master transcription factor. We generated 268 epigenomic datasets spanning two state transitions-from normal prostate epithelium to localized PCa to metastases-in specimens derived from human tissue. We discovered that reprogrammed AR sites in metastatic PCa are not created de novo; rather, they are prepopulated by the transcription factors FOXA1 and HOXB13 in normal prostate epithelium. Reprogrammed regulatory elements commissioned in metastatic disease hijack latent developmental programs, accessing sites that are implicated in prostate organogenesis. Analysis of reactivated regulatory elements enabled the identification and functional validation of previously unknown metastasis-specific enhancers at HOXB13, FOXA1 and NKX3-1. Finally, we observed that prostate lineage-specific regulatory elements were strongly associated with PCa risk heritability and somatic mutation density. Examining prostate biology through an epigenomic lens is fundamental for understanding the mechanisms underlying tumor progression.

Published
2020

11. The DNA methylation landscape of advanced prostate cancer

Author

Zhao, Shuang G, Chen, William S, Li, Haolong, Foye, Adam, Zhang, Meng, Sjöström, Martin, Aggarwal, Rahul, Playdle, Denise, Liao, Arnold, Alumkal, Joshi J, Das, Rajdeep, Chou, Jonathan, Hua, Junjie T, Barnard, Travis J, Bailey, Adina M, Chow, Eric D, Perry, Marc D, Dang, Ha X, Yang, Rendong, Moussavi-Baygi, Ruhollah, Zhang, Li, Alshalalfa, Mohammed, Laura Chang, S, Houlahan, Kathleen E, Shiah, Yu-Jia, Beer, Tomasz M, Thomas, George, Chi, Kim N, Gleave, Martin, Zoubeidi, Amina, Reiter, Robert E, Rettig, Matthew B, Witte, Owen, Yvonne Kim, M, Fong, Lawrence, Spratt, Daniel E, Morgan, Todd M, Bose, Rohit, Huang, Franklin W, Li, Hui, Chesner, Lisa, Shenoy, Tanushree, Goodarzi, Hani, Asangani, Irfan A, Sandhu, Shahneen, Lang, Joshua M, Mahajan, Nupam P, Lara, Primo N, Evans, Christopher P, Febbo, Phillip, Batzoglou, Serafim, Knudsen, Karen E, He, Housheng H, Huang, Jiaoti, Zwart, Wilbert, Costello, Joseph F, Luo, Jianhua, Tomlins, Scott A, Wyatt, Alexander W, Dehm, Scott M, Ashworth, Alan, Gilbert, Luke A, Boutros, Paul C, Farh, Kyle, Chinnaiyan, Arul M, Maher, Christopher A, Small, Eric J, Quigley, David A, and Feng, Felix Y

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Cancer, Prostate Cancer, Human Genome, Urologic Diseases, Cancer Genomics, Biotechnology, 2.1 Biological and endogenous factors, Aged, Aged, 80 and over, Carcinogenesis, DNA Methylation, Epigenomics, Gene Expression Regulation, Neoplastic, Genome, Humans, Male, Middle Aged, Mutation, Prospective Studies, Prostatic Neoplasms, Sequence Analysis, DNA, Exome Sequencing, Whole Genome Sequencing, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Although DNA methylation is a key regulator of gene expression, the comprehensive methylation landscape of metastatic cancer has never been defined. Through whole-genome bisulfite sequencing paired with deep whole-genome and transcriptome sequencing of 100 castration-resistant prostate metastases, we discovered alterations affecting driver genes that were detectable only with integrated whole-genome approaches. Notably, we observed that 22% of tumors exhibited a novel epigenomic subtype associated with hypermethylation and somatic mutations in TET2, DNMT3B, IDH1 and BRAF. We also identified intergenic regions where methylation is associated with RNA expression of the oncogenic driver genes AR, MYC and ERG. Finally, we showed that differential methylation during progression preferentially occurs at somatic mutational hotspots and putative regulatory regions. This study is a large integrated study of whole-genome, whole-methylome and whole-transcriptome sequencing in metastatic cancer that provides a comprehensive overview of the important regulatory role of methylation in metastatic castration-resistant prostate cancer.

Published
2020

12. Minimally disruptive optical control of protein tyrosine phosphatase 1B.

Author

Hongdusit, Akarawin, Zwart, Petrus, Sankaran, Banumathi, and Fox, Jerome

Subjects
Allosteric Regulation, Animals, Biosensing Techniques, COS Cells, Chlorocebus aethiops, Crystallography, X-Ray, Fluorescence Resonance Energy Transfer, HEK293 Cells, Humans, Optogenetics, Phosphorylation, Phototropins, Protein Tyrosine Phosphatase, Non-Receptor Type 1, Receptor, Insulin, Recombinant Proteins
Abstract

Protein tyrosine phosphatases regulate a myriad of essential subcellular signaling events, yet they remain difficult to study in their native biophysical context. Here we develop a minimally disruptive optical approach to control protein tyrosine phosphatase 1B (PTP1B)-an important regulator of receptor tyrosine kinases and a therapeutic target for the treatment of diabetes, obesity, and cancer-and we use that approach to probe the intracellular function of this enzyme. Our conservative architecture for photocontrol, which consists of a protein-based light switch fused to an allosteric regulatory element, preserves the native structure, activity, and subcellular localization of PTP1B, affords changes in activity that match those elicited by post-translational modifications inside the cell, and permits experimental analyses of the molecular basis of optical modulation. Findings indicate, most strikingly, that small changes in the activity of PTP1B can cause large shifts in the phosphorylation states of its regulatory targets.

Published
2020

13. Noncoding mutations target cis-regulatory elements of the FOXA1 plexus in prostate cancer.

Author

Zhou, Stanley, Hawley, James R, Soares, Fraser, Grillo, Giacomo, Teng, Mona, Madani Tonekaboni, Seyed Ali, Hua, Junjie Tony, Kron, Ken J, Mazrooei, Parisa, Ahmed, Musaddeque, Arlidge, Christopher, Yun, Hwa Young, Livingstone, Julie, Huang, Vincent, Yamaguchi, Takafumi N, Espiritu, Shadrielle MG, Zhu, Yanyun, Severson, Tesa M, Murison, Alex, Cameron, Sarina, Zwart, Wilbert, van der Kwast, Theodorus, Pugh, Trevor J, Fraser, Michael, Boutros, Paul C, Bristow, Robert G, He, Housheng Hansen, and Lupien, Mathieu

Subjects
Cell Line, Tumor, Humans, Prostatic Neoplasms, Transcription Factors, Cell Proliferation, Gene Expression Regulation, Neoplastic, Binding Sites, Regulatory Sequences, Nucleic Acid, Mutation, Male, Hepatocyte Nuclear Factor 3-alpha, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Regulatory Sequences, Nucleic Acid
Abstract

Prostate cancer is the second most commonly diagnosed malignancy among men worldwide. Recurrently mutated in primary and metastatic prostate tumors, FOXA1 encodes a pioneer transcription factor involved in disease onset and progression through both androgen receptor-dependent and androgen receptor-independent mechanisms. Despite its oncogenic properties however, the regulation of FOXA1 expression remains unknown. Here, we identify a set of six cis-regulatory elements in the FOXA1 regulatory plexus harboring somatic single-nucleotide variants in primary prostate tumors. We find that deletion and repression of these cis-regulatory elements significantly decreases FOXA1 expression and prostate cancer cell growth. Six of the ten single-nucleotide variants mapping to FOXA1 regulatory plexus significantly alter the transactivation potential of cis-regulatory elements by modulating the binding of transcription factors. Collectively, our results identify cis-regulatory elements within the FOXA1 plexus mutated in primary prostate tumors as potential targets for therapeutic intervention.

Published
2020

14. The genomic landscape of metastatic castration-resistant prostate cancers reveals multiple distinct genotypes with potential clinical impact.

Author

van Dessel, Lisanne F, van Riet, Job, Smits, Minke, Zhu, Yanyun, Hamberg, Paul, van der Heijden, Michiel S, Bergman, Andries M, van Oort, Inge M, de Wit, Ronald, Voest, Emile E, Steeghs, Neeltje, Yamaguchi, Takafumi N, Livingstone, Julie, Boutros, Paul C, Martens, John WM, Sleijfer, Stefan, Cuppen, Edwin, Zwart, Wilbert, van de Werken, Harmen JG, Mehra, Niven, and Lolkema, Martijn P

Subjects
Lymph Nodes, Humans, Bone Neoplasms, Liver Neoplasms, Soft Tissue Neoplasms, Prostatic Neoplasms, Neoplasm Metastasis, Cyclin-Dependent Kinases, Oncogene Proteins, Fusion, BRCA2 Protein, Receptors, Androgen, Genotype, Male, Microsatellite Instability, Enhancer Elements, Genetic, DNA Copy Number Variations, Recombinational DNA Repair, Prostatic Neoplasms, Castration-Resistant, Whole Genome Sequencing, Chromatin Immunoprecipitation Sequencing, Oncogene Proteins, Fusion, Receptors, Androgen, Enhancer Elements, Genetic, Castration-Resistant, Biotechnology, Genetics, Cancer, Prostate Cancer, Urologic Diseases, Human Genome
Abstract

Metastatic castration-resistant prostate cancer (mCRPC) has a highly complex genomic landscape. With the recent development of novel treatments, accurate stratification strategies are needed. Here we present the whole-genome sequencing (WGS) analysis of fresh-frozen metastatic biopsies from 197 mCRPC patients. Using unsupervised clustering based on genomic features, we define eight distinct genomic clusters. We observe potentially clinically relevant genotypes, including microsatellite instability (MSI), homologous recombination deficiency (HRD) enriched with genomic deletions and BRCA2 aberrations, a tandem duplication genotype associated with CDK12-/- and a chromothripsis-enriched subgroup. Our data suggests that stratification on WGS characteristics may improve identification of MSI, CDK12-/- and HRD patients. From WGS and ChIP-seq data, we show the potential relevance of recurrent alterations in non-coding regions identified with WGS and highlight the central role of AR signaling in tumor progression. These data underline the potential value of using WGS to accurately stratify mCRPC patients into clinically actionable subgroups.

Published
2019

15. The NASA Twins Study: A multidimensional analysis of a year-long human spaceflight

Author

Garrett-Bakelman, Francine E, Darshi, Manjula, Green, Stefan J, Gur, Ruben C, Lin, Ling, Macias, Brandon R, McKenna, Miles J, Meydan, Cem, Mishra, Tejaswini, Nasrini, Jad, Piening, Brian D, Rizzardi, Lindsay F, Sharma, Kumar, Siamwala, Jamila H, Taylor, Lynn, Vitaterna, Martha Hotz, Afkarian, Maryam, Afshinnekoo, Ebrahim, Ahadi, Sara, Ambati, Aditya, Arya, Maneesh, Bezdan, Daniela, Callahan, Colin M, Chen, Songjie, Choi, Augustine MK, Chlipala, George E, Contrepois, Kévin, Covington, Marisa, Crucian, Brian E, De Vivo, Immaculata, Dinges, David F, Ebert, Douglas J, Feinberg, Jason I, Gandara, Jorge A, George, Kerry A, Goutsias, John, Grills, George S, Hargens, Alan R, Heer, Martina, Hillary, Ryan P, Hoofnagle, Andrew N, Hook, Vivian YH, Jenkinson, Garrett, Jiang, Peng, Keshavarzian, Ali, Laurie, Steven S, Lee-McMullen, Brittany, Lumpkins, Sarah B, MacKay, Matthew, Maienschein-Cline, Mark G, Melnick, Ari M, Moore, Tyler M, Nakahira, Kiichi, Patel, Hemal H, Pietrzyk, Robert, Rao, Varsha, Saito, Rintaro, Salins, Denis N, Schilling, Jan M, Sears, Dorothy D, Sheridan, Caroline K, Stenger, Michael B, Tryggvadottir, Rakel, Urban, Alexander E, Vaisar, Tomas, Van Espen, Benjamin, Zhang, Jing, Ziegler, Michael G, Zwart, Sara R, Charles, John B, Kundrot, Craig E, Scott, Graham BI, Bailey, Susan M, Basner, Mathias, Feinberg, Andrew P, Lee, Stuart MC, Mason, Christopher E, Mignot, Emmanuel, Rana, Brinda K, Smith, Scott M, Snyder, Michael P, and Turek, Fred W

Subjects
Mental Health, Genetics, Adaptation, Physiological, Adaptive Immunity, Astronauts, Body Weight, Carotid Arteries, Carotid Intima-Media Thickness, DNA Damage, DNA Methylation, Gastrointestinal Microbiome, Genomic Instability, Humans, Male, Space Flight, Telomere Homeostasis, Time Factors, United States, United States National Aeronautics and Space Administration, General Science & Technology
Abstract

To understand the health impact of long-duration spaceflight, one identical twin astronaut was monitored before, during, and after a 1-year mission onboard the International Space Station; his twin served as a genetically matched ground control. Longitudinal assessments identified spaceflight-specific changes, including decreased body mass, telomere elongation, genome instability, carotid artery distension and increased intima-media thickness, altered ocular structure, transcriptional and metabolic changes, DNA methylation changes in immune and oxidative stress-related pathways, gastrointestinal microbiota alterations, and some cognitive decline postflight. Although average telomere length, global gene expression, and microbiome changes returned to near preflight levels within 6 months after return to Earth, increased numbers of short telomeres were observed and expression of some genes was still disrupted. These multiomic, molecular, physiological, and behavioral datasets provide a valuable roadmap of the putative health risks for future human spaceflight.

Published
2019

16. Abietane-Type Diterpenoids Inhibit Protein Tyrosine Phosphatases by Stabilizing an Inactive Enzyme Conformation

Author

Hjortness, Michael K, Riccardi, Laura, Hongdusit, Akarawin, Ruppe, Sophia, Zhao, Mengxia, Kim, Edward Y, Zwart, Peter H, Sankaran, Banumathi, Arthanari, Haribabu, Sousa, Marcelo C, De Vivo, Marco, and Fox, Jerome M

Subjects
Biochemistry and Cell Biology, Medicinal and Biomolecular Chemistry, Chemical Sciences, Biological Sciences, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Generic health relevance, Abietanes, Humans, Models, Molecular, Molecular Dynamics Simulation, Nuclear Magnetic Resonance, Biomolecular, Protein Domains, Protein Folding, Protein Kinase Inhibitors, Protein Tyrosine Phosphatase, Non-Receptor Type 1, Medical Biochemistry and Metabolomics, Biochemistry & Molecular Biology, Biochemistry and cell biology, Medical biochemistry and metabolomics, Medicinal and biomolecular chemistry
Abstract

Protein tyrosine phosphatases (PTPs) contribute to a striking variety of human diseases, yet they remain vexingly difficult to inhibit with uncharged, cell-permeable molecules; no inhibitors of PTPs have been approved for clinical use. This study uses a broad set of biophysical analyses to evaluate the use of abietane-type diterpenoids, a biologically active class of phytometabolites with largely nonpolar structures, for the development of pharmaceutically relevant PTP inhibitors. Results of nuclear magnetic resonance analyses, mutational studies, and molecular dynamics simulations indicate that abietic acid can inhibit protein tyrosine phosphatase 1B, a negative regulator of insulin signaling and an elusive drug target, by binding to its active site in a non-substrate-like manner that stabilizes the catalytically essential WPD loop in an inactive conformation; detailed kinetic studies, in turn, show that minor changes in the structures of abietane-type diterpenoids (e.g., the addition of hydrogens) can improve potency (i.e., lower IC50) by 7-fold. These findings elucidate a previously uncharacterized mechanism of diterpenoid-mediated inhibition and suggest, more broadly, that abietane-type diterpenoids are a promising source of structurally diverse-and, intriguingly, microbially synthesizable-molecules on which to base the design of new PTP-inhibiting therapeutics.

Published
2018

17. Water‐Restructuring Mutations Can Reverse the Thermodynamic Signature of Ligand Binding to Human Carbonic Anhydrase

Author

Fox, Jerome M, Kang, Kyungtae, Sastry, Madhavi, Sherman, Woody, Sankaran, Banumathi, Zwart, Peter H, and Whitesides, George M

Subjects
Medicinal and Biomolecular Chemistry, Chemical Sciences, Binding Sites, Carbonic Anhydrase II, Humans, Hydrophobic and Hydrophilic Interactions, Ligands, Models, Molecular, Molecular Conformation, Mutation, Thermodynamics, Water, enthalpy-entropy compensation, hydrophobic effects, mutational analysis, protein-ligand interactions, Organic Chemistry, Chemical sciences
Abstract

This study uses mutants of human carbonic anhydrase (HCAII) to examine how changes in the organization of water within a binding pocket can alter the thermodynamics of protein-ligand association. Results from calorimetric, crystallographic, and theoretical analyses suggest that most mutations strengthen networks of water-mediated hydrogen bonds and reduce binding affinity by increasing the enthalpic cost and, to a lesser extent, the entropic benefit of rearranging those networks during binding. The organization of water within a binding pocket can thus determine whether the hydrophobic interactions in which it engages are enthalpy-driven or entropy-driven. Our findings highlight a possible asymmetry in protein-ligand association by suggesting that, within the confines of the binding pocket of HCAII, binding events associated with enthalpically favorable rearrangements of water are stronger than those associated with entropically favorable ones.

Published
2017

18. An Antiestrogenic Activity Score for tamoxifen and its metabolites is associated with breast cancer outcome

Author

de Vries Schultink, AHM, Alexi, X, van Werkhoven, E, Madlensky, L, Natarajan, L, Flatt, SW, Zwart, W, Linn, SC, Parker, BA, Wu, AHB, Pierce, JP, Huitema, ADR, and Beijnen, JH

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Breast Cancer, Antineoplastic Agents, Hormonal, Breast Neoplasms, Dose-Response Relationship, Drug, Estrogen Antagonists, Female, Humans, Inhibitory Concentration 50, Kaplan-Meier Estimate, Prognosis, Proportional Hazards Models, Tamoxifen, Treatment Outcome, Metabolites, Algorithm, Recurrence-free survival, Clinical Sciences, Oncology & Carcinogenesis, Clinical sciences, Oncology and carcinogenesis
Abstract

PurposeEndoxifen concentrations have been associated with breast cancer recurrence in tamoxifen-treated patients. However, tamoxifen itself and other metabolites also show antiestrogenic anti-tumor activity. Therefore, the aim of this study was to develop a comprehensive Antiestrogenic Activity Score (AAS), which accounts for concentration and antiestrogenic activity of tamoxifen and three metabolites. An association between the AAS and recurrence-free survival was investigated and compared to a previously published threshold for endoxifen concentrations of 5.97 ng/mL.Patients and methodsThe antiestrogenic activities of tamoxifen, (Z)-endoxifen, (Z)-4-hydroxytamoxifen, and N-desmethyltamoxifen were determined in a cell proliferation assay. The AAS was determined by calculating the sum of each metabolite concentration multiplied by an IC50 ratio, relative to tamoxifen. The AAS was calculated for 1370 patients with estrogen receptor alpha (ERα)-positive breast cancer. An association between AAS and recurrence was investigated using Cox regression and compared with the 5.97 ng/mL endoxifen threshold using concordance indices.ResultsAn AAS threshold of 1798 was associated with recurrence-free survival, hazard ratio (HR) 0.67 (95% confidence interval (CI) 0.47-0.96), bias corrected after bootstrap HR 0.69 (95% CI 0.48-0.99). The concordance indices for AAS and endoxifen did not significantly differ; however, using the AAS threshold instead of endoxifen led to different dose recommendations for 5.2% of the patients.ConclusionsEndoxifen concentrations can serve as a proxy for the antiestrogenic effect of tamoxifen and metabolites. However, for the aggregate effect of tamoxifen and three metabolites, defined by an integrative algorithm, a trend towards improving treatment is seen and moreover, is significantly associated with breast cancer recurrence.

Published
2017

19. Shared genetic risk between migraine and coronary artery disease: A genome-wide analysis of common variants.

Author

Winsvold, Bendik S, Bettella, Francesco, Witoelar, Aree, Anttila, Verneri, Gormley, Padhraig, Kurth, Tobias, Terwindt, Gisela M, Freilinger, Tobias M, Frei, Oleksander, Shadrin, Alexey, Wang, Yunpeng, Dale, Anders M, van den Maagdenberg, Arn MJM, Chasman, Daniel I, Nyholt, Dale R, Palotie, Aarno, Andreassen, Ole A, Zwart, John-Anker, and International Headache Genetics Consortium

Subjects
International Headache Genetics Consortium, Humans, Genetic Predisposition to Disease, Phenotype, Polymorphism, Single Nucleotide, Female, Male, Migraine Disorders, Coronary Artery Disease, Genome-Wide Association Study, General Science & Technology
Abstract

Migraine is a recurrent pain condition traditionally viewed as a neurovascular disorder, but little is known of its vascular basis. In epidemiological studies migraine is associated with an increased risk of cardiovascular disease, including coronary artery disease (CAD), suggesting shared pathogenic mechanisms. This study aimed to determine the genetic overlap between migraine and CAD, and to identify shared genetic risk loci, utilizing a conditional false discovery rate approach and data from two large-scale genome-wide association studies (GWAS) of CAD (C4D, 15,420 cases, 15,062 controls; CARDIoGRAM, 22,233 cases, 64,762 controls) and one of migraine (22,120 cases, 91,284 controls). We found significant enrichment of genetic variants associated with CAD as a function of their association with migraine, which was replicated across two independent CAD GWAS studies. One shared risk locus in the PHACTR1 gene (conjunctional false discovery rate for index SNP rs9349379 < 3.90 x 10-5), which was also identified in previous studies, explained much of the enrichment. Two further loci (in KCNK5 and AS3MT) showed evidence for shared risk (conjunctional false discovery rate < 0.05). The index SNPs at two of the three loci had opposite effect directions in migraine and CAD. Our results confirm previous reports that migraine and CAD share genetic risk loci in excess of what would be expected by chance, and highlight one shared risk locus in PHACTR1. Understanding the biological mechanisms underpinning this shared risk is likely to improve our understanding of both disorders.

Published
2017

20. Genetic Markers of Human Evolution Are Enriched in Schizophrenia

Author

Srinivasan, Saurabh, Bettella, Francesco, Mattingsdal, Morten, Wang, Yunpeng, Witoelar, Aree, Schork, Andrew J, Thompson, Wesley K, Zuber, Verena, Consortium, The International Headache Genetics Consortium The Schizophrenia Working Group of the Psychiatric Genomics, Winsvold, Bendik S, Zwart, John-Anker, Collier, David A, Desikan, Rahul S, Melle, Ingrid, Werge, Thomas, Dale, Anders M, Djurovic, Srdjan, and Andreassen, Ole A

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Biological Psychology, Psychology, Pharmacology and Pharmaceutical Sciences, Prevention, Clinical Research, Mental Health, Biotechnology, Schizophrenia, Brain Disorders, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Mental health, Biological Evolution, Brain, Genetic Markers, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Evolution, GWAS, Human, Neanderthal, Polygenic, Schizophrenia Working Group of the Psychiatric Genomics Consortium, The International Headache Genetics Consortium, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Biological sciences, Biomedical and clinical sciences
Abstract

BackgroundWhy schizophrenia has accompanied humans throughout our history despite its negative effect on fitness remains an evolutionary enigma. It is proposed that schizophrenia is a by-product of the complex evolution of the human brain and a compromise for humans' language, creative thinking, and cognitive abilities.MethodsWe analyzed recent large genome-wide association studies of schizophrenia and a range of other human phenotypes (anthropometric measures, cardiovascular disease risk factors, immune-mediated diseases) using a statistical framework that draws on polygenic architecture and ancillary information on genetic variants. We used information from the evolutionary proxy measure called the Neanderthal selective sweep (NSS) score.ResultsGene loci associated with schizophrenia are significantly (p = 7.30 × 10(-9)) more prevalent in genomic regions that are likely to have undergone recent positive selection in humans (i.e., with a low NSS score). Variants in brain-related genes with a low NSS score confer significantly higher susceptibility than variants in other brain-related genes. The enrichment is strongest for schizophrenia, but we cannot rule out enrichment for other phenotypes. The false discovery rate conditional on the evolutionary proxy points to 27 candidate schizophrenia susceptibility loci, 12 of which are associated with schizophrenia and other psychiatric disorders or linked to brain development.ConclusionsOur results suggest that there is a polygenic overlap between schizophrenia and NSS score, a marker of human evolution, which is in line with the hypothesis that the persistence of schizophrenia is related to the evolutionary process of becoming human.

Published
2016

21. Genome wide association study identifies variants in NBEA associated with migraine in bipolar disorder

Author

Jacobsen, Kaya K, Nievergelt, Caroline M, Zayats, Tetyana, Greenwood, Tiffany A, Anttila, Verneri, Akiskal, Hagop S, Consortium, BiGS, Consortium, IHG, include:, BiGS Consortium Co-Authors, Kelsoe, John R, McKinney, Rebecca, Shilling, Paul D, Smith, Erin N, Schork, Nicholas J, Bloss, Cinnamon S, Nurnberger, John I, Edenberg, Howard J, Foroud, Tatiana, Koller, Daniel L, Gershon, Elliot S, Badner, Judith A, Liu, Chunyu, Scheftner, William A, Lawson, William B, Nwulia, Evaristus A, Hipolito, Maria, Potash, James, Coryell, William, Rice, John, Byerley, William, McMahon, Francis J, Berrettini, Wade H, Zandi, Peter P, Mahon, Pamela B, McInnis, Melvin G, Zöllner, Sebastian, Zhang, Peng, Craig, David W, Szelinger, Szabolics, Barrett, Thomas B, Schulze, Thomas G, include:, IHG Consortium Co-Authors, Wedenoja, Juho, Kaunisto, Mari A, Heikkilä, Kauko, Kaprio, Jaakko, Wessman, Maija, Kallela, Mikko, Färkkilä, Markus, Artto, Ville, Aromaa, Arpo, Eriksson, Johan G, Winsvold, Bendik S, Zwart, John-Anker, Gormley, Padhraig, Palotie, Aarno, Kurth, Tobias, Rose, Lynda M, Buring, Julie E, Ridker, Paul M, Chasman, Daniel I, Bettella, Francesco, Steinberg, Stacy, Stefansson, Hreinn, Stefansson, Kari, McMahon, George, Davey-Smith, George, Malik, Rainer, Freilinger, Tobias, Wichmann, Heinz Erich, Dichgans, Martin, Muller-Myhsok, Bertram, Meitinger, Thomas, de Vries, Boukje, Terwindt, Gisela, Stam, Anine H, Frants, Rune R, Pelzer, Nadine, Weller, Claudia M, Zielman, Ronald, Ferrari, Michel D, van den Maagdenberg, Arn MJM, Medland, Sarah E, Montgomery, Grant W, Martin, Nicholas G, Nyholt, Dale R, Todt, Unda, Borck, Guntram, Kubisch, Christian, Quaye, Lydia, Williams, Frances MK, Cherkas, Lynn, Koiranen, Markku, Hartikainen, Anna-Liisa, Pouta, Anneli, Jarvelin, Marjo-Riitta, Ikram, M Arfan, and van den Ende, Joyce

Subjects
Biomedical and Clinical Sciences, Headaches, Bipolar Disorder, Human Genome, Genetics, Mental Health, Pain Research, Migraines, Serious Mental Illness, Chronic Pain, Mental Illness, Neurosciences, Brain Disorders, 2.1 Biological and endogenous factors, Neurological, Adult, Carrier Proteins, Comorbidity, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Migraine Disorders, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Bipolar disorder, Migraine, NBEA, Neurobeachin, BiGS Consortium, IHG Consortium, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Biomedical and clinical sciences, Health sciences, Psychology
Abstract

BackgroundMigraine is a common comorbidity among individuals with bipolar disorder, but the underlying mechanisms for this co-occurrence are poorly understood. The aim of this study was to investigate the genetic background of bipolar patients with and without migraine.MethodsWe performed a genome-wide association analysis contrasting 460 bipolar migraneurs with 914 bipolar patients without migraine from the Bipolar Genome Study (BiGS).ResultsWe identified one genome-wide significant association between migraine in bipolar disorder patients and rs1160720, an intronic single nucleotide polymorphism (SNP) in the NBEA gene (P=2.97 × 10(-8), OR: 1.82, 95% CI: 1.47-2.25), although this was not replicated in a smaller sample of 289 migraine cases.LimitationsOur study is based on self-reported migraine.ConclusionsNBEA encodes neurobeachin, a scaffolding protein primarily expressed in the brain and involved in trafficking of vesicles containing neurotransmitter receptors. This locus has not previously been implicated in migraine per se. We found no evidence of association in data from the GWAS migraine meta-analysis consortium (n=118,710 participants) suggesting that the association might be specific to migraine co-morbid with bipolar disorder.

Published
2015

22. Genetic Risk Score for Intracranial Aneurysms: Prediction of Subarachnoid Hemorrhage and Role in Clinical Heterogeneity

Author

Mark K. Bakker, Jos P. Kanning, Gad Abraham, Amy E. Martinsen, Bendik S. Winsvold, John-Anker Zwart, Romain Bourcier, Tomonobu Sawada, Masaru Koido, Yoichiro Kamatani, Sandrine Morel, Philippe Amouyel, Stéphanie Debette, Philippe Bijlenga, Takiy Berrandou, Santhi K. Ganesh, Nabila Bouatia-Naji, Gregory Jones, Matthew Bown, Gabriel J.E. Rinkel, Jan H. Veldink, Ynte M. Ruigrok, Anne Hege Aamodt, Anne Heidi Skogholt, Ben M Brumpton, Cristen J Willer, Else C Sandset, Espen S Kristoffersen, Hanne Ellekjær, Ingrid Heuch, Jonas B Nielsen, Knut Hagen, Kristian Hveem, Lars G Fritsche, Laurent F Thomas, Linda M Pedersen, Maiken E Gabrielsen, Oddgeir L Holmen, Sigrid Børte, Wei Zhou, Shérine Abboud, Massimo Pandolfo, Vincent Thijs, Didier Leys, Marie Bodenant, Fabien Louillet, Emmanuel Touzé, Jean-Louis Mas, Yves Samson, Sara Leder, Anne Léger, Sandrine Deltour, Sophie Crozier, Isabelle Méresse, Sandrine Canaple, Olivier Godefroy, Maurice Giroud, Yannick Béjot, Pierre Decavel, Elizabeth Medeiros, Paola Montiel, Thierry Moulin, Fabrice Vuillier, Jean Dallongeville, Antti J Metso, Tiina Metso, Turgut Tatlisumak, Caspar Grond-Ginsbach, Christoph Lichy, Manja Kloss, Inge Werner, Marie-Luise Arnold, Michael Dos Santos, Armin Grau, Martin Dichgans, Constanze Thomas-Feles, Ralf Weber, Tobias Brandt, Alessandro Pezzini, Valeria De Giuli, Filomena Caria, Loris Poli, Alessandro Padovani, Anna Bersano, Silvia Lanfranconi, Simone Beretta, Carlo Ferrarese, Giacomo Giacolone, Stefano Paolucci, Philippe Lyrer, Stefan Engelter, Felix Fluri, Florian Hatz, Dominique Gisler, Leo Bonati, Henrik Gensicke, Margareth Amort, Hugh Markus, Jennifer Majersik, Bradford Worrall, Andrew Southerland, John Cole, Steven Kittner, Evangelos Evangelou, Helen R Warren, He Gao, Georgios Ntritsos, Niki Dimou, Tonu Esko, Reedik Mägi, Lili Milani, Peter Almgren, Thibaud Boutin, Jun Ding, Franco Giulianini, Elizabeth G Holliday, Anne U Jackson, Ruifang Li-Gao, Wei-Yu Lin, Jian’an Luan, Massimo Mangino, Christopher Oldmeadow, Bram Peter Prins, Yong Qian, Muralidharan Sargurupremraj, Nabi Shah, Praveen Surendran, Sébastien Thériault, Niek Verweij, Sara M Willems, Jing-Hua Zhao, John Connell, Renée de Mutsert, Alex SF Doney, Martin Farrall, Cristina Menni, Andrew D Morris, Raymond Noordam, Guillaume Paré, Neil R Poulter, Denis C Shields, Alice Stanton, Simon Thom, Gonçalo Abecasis, Najaf Amin, Dan E Arking, Kristin L Ayers, Caterina M Barbieri, Chiara Batini, Joshua C Bis, Tineka Blake, Murielle Bochud, Michael Boehnke, Eric Boerwinkle, Dorret I Boomsma, Erwin P Bottinger, Peter S Braund, Marco Brumat, Archie Campbell, Harry Campbell, Aravinda Chakravarti, John C Chambers, Ganesh Chauhan, Marina Ciullo, Massimiliano Cocca, Francis Collins, Heather J Cordell, Gail Davies, Martin H de Borst, Eco J de Geus, Ian J Deary, Joris Deelen, Fabiola Del Greco M, Cumhur Yusuf Demirkale, Marcus Dörr, Georg B Ehret, Roberto Elosua, Stefan Enroth, A Mesut Erzurumluoglu, Teresa Ferreira, Mattias Frånberg, Oscar H Franco, Ilaria Gandin, Paolo Gasparini, Vilmantas Giedraitis, Christian Gieger, Giorgia Girotto, Anuj Goel, Alan J Gow, Vilmundur Gudnason, Xiuqing Guo, Ulf Gyllensten, Anders Hamsten, Tamara B Harris, Sarah E Harris, Catharina A Hartman, Aki S Havulinna, Andrew A Hicks, Edith Hofer, Albert Hofman, Jouke-Jan Hottenga, Jennifer E Huffman, Shih-Jen Hwang, Erik Ingelsson, Alan James, Rick Jansen, Marjo-Riitta Jarvelin, Roby Joehanes, Åsa Johansson, Andrew D Johnson, Peter K Joshi, Pekka Jousilahti, J Wouter Jukema, Antti Jula, Mika Kähönen, Sekar Kathiresan, Bernard D Keavney, Kay-Tee Khaw, Paul Knekt, Joanne Knight, Ivana Kolcic, Jaspal S Kooner, Seppo Koskinen, Kati Kristiansson, Zoltan Kutalik, Maris Laan, Marty Larson, Lenore J Launer, Benjamin Lehne, Terho Lehtimäki, David CM Liewald, Li Lin, Lars Lind, Cecilia M Lindgren, YongMei Liu, Ruth JF Loos, Lorna M Lopez, Yingchang Lu, Leo-Pekka Lyytikäinen, Anubha Mahajan, Chrysovalanto Mamasoula, Jaume Marrugat, Jonathan Marten, Yuri Milaneschi, Anna Morgan, Andrew P Morris, Alanna C Morrison, Peter J Munson, Mike A Nalls, Priyanka Nandakumar, Christopher P Nelson, Teemu Niiranen, Ilja M Nolte, Teresa Nutile, Albertine J Oldehinkel, Ben A Oostra, Paul F O’Reilly, Elin Org, Sandosh Padmanabhan, Walter Palmas, Aarno Palotie, Alison Pattie, Brenda WJH Penninx, Markus Perola, Annette Peters, Ozren Polasek, Peter P Pramstaller, Quang Tri Nguyen, Olli T Raitakari, Rainer Rettig, Kenneth Rice, Paul M Ridker, Janina S Ried, Harriëtte Riese, Samuli Ripatti, Antonietta Robino, Lynda M Rose, Jerome I Rotter, Igor Rudan, Daniela Ruggiero, Yasaman Saba, Cinzia F Sala, Veikko Salomaa, Nilesh J Samani, Antti-Pekka Sarin, Reinhold Schmidt, Helena Schmidt, Nick Shrine, David Siscovick, Albert V Smith, Harold Snieder, Siim Sõber, Rossella Sorice, John M Starr, David J Stott, David P Strachan, Rona J Strawbridge, Johan Sundström, Morris A Swertz, Kent D Taylor, Alexander Teumer, Martin D Tobin, Maciej Tomaszewski, Daniela Toniolo, Michela Traglia, Stella Trompet, Jaakko Tuomilehto, Christophe Tzourio, André G Uitterlinden, Ahmad Vaez, Peter J van der Most, Cornelia M van Duijn, Germaine C Verwoert, Veronique Vitart, Uwe Völker, Peter Vollenweider, Dragana Vuckovic, Hugh Watkins, Sarah H Wild, Gonneke Willemsen, James F Wilson, Alan F Wright, Jie Yao, Tatijana Zemunik, Weihua Zhang, John R Attia, Adam S Butterworth, Daniel I Chasman, David Conen, Francesco Cucca, John Danesh, Caroline Hayward, Joanna MM Howson, Markku Laakso, Edward G Lakatta, Claudia Langenberg, Olle Melander, Dennis O Mook-Kanamori, Colin NA Palmer, Lorenz Risch, Robert A Scott, Rodney J Scott, Peter Sever, Tim D Spector, Pim van der Harst, Nicholas J Wareham, Eleftheria Zeggini, Daniel Levy, Patricia B Munroe, Christopher Newton-Cheh, Morris J Brown, Andres Metspalu, Bruce M. Psaty, Louise V Wain, Paul Elliott, Mark J Caulfield, Padhraig Gormley, Verneri Anttila, Priit Palta, Tune H Pers, Kai-How Farh, Ester Cuenca-Leon, Mikko Muona, Nicholas A Furlotte, Tobias Kurth, Andres Ingason, George McMahon, Lannie Ligthart, Gisela M Terwindt, Mikko Kallela, Tobias M Freilinger, Caroline Ran, Scott G Gordon, Anine H Stam, Stacy Steinberg, Guntram Borck, Markku Koiranen, Lydia Quaye, Hieab H H Adams, Juho Wedenoja, David A Hinds, Julie E Buring, Markus Schürks, Maria Gudlaug Hrafnsdottir, Hreinn Stefansson, Susan M Ring, Brenda W J H Penninx, Markus Färkkilä, Ville Artto, Mari Kaunisto, Salli Vepsäläinen, Rainer Malik, Andrew C Heath, Pamela A F Madden, Nicholas G Martin, Grant W Montgomery, Mitja I Kurki, Mart Kals, Kalle Pärn, Eija Hämäläinen, Hailiang Huang, Andrea E Byrnes, Lude Franke, Jie Huang, Evie Stergiakouli, Phil H Lee, Cynthia Sandor, Caleb Webber, Zameel Cader, Bertram Muller-Myhsok, Stefan Schreiber, Thomas Meitinger, Johan G Eriksson, Kauko Heikkilä, Elizabeth Loehrer, Andre G Uitterlinden, Lynn Cherkas, Audun Stubhaug, Christopher S Nielsen, Minna Männikkö, Evelin Mihailov, Hartmut Göbel, Ann-Louise Esserlind, Anne Francke Christensen, Thomas Folkmann Hansen, Thomas Werge, Jaakko Kaprio, Arpo J Aromaa, Olli Raitakari, M Arfan Ikram, Tim Spector, Marjo-Riitta Järvelin, Christian Kubisch, Michel D Ferrari, Andrea C Belin, Maija Wessman, Arn M J M van den Maagdenberg, George Davey Smith, Kari Stefansson, Nicholas Eriksson, Mark J Daly, Benjamin M Neale, Jes Olesen, Dale R Nyholt, Masato Akiyama, Varinder S. Alg, Joseph P. Broderick, Ben M. Brumpton, Jérôme Dauvillier, Hubert Desal, Christian Dina, Christoph M. Friedrich, Emília I. Gaál-Paavola, Jean-Christophe Gentric, Sven Hirsch, Isabel C. Hostettler, Henry Houlden, Juha E. Jääskeläinen, Marianne Bakke Johnsen, Liming Li, Kuang Lin, Antti Lindgren, Olivier Martin, Koichi Matsuda, Iona Y. Millwood, Olivier Naggara, Mika Niemelä, Joanna Pera, Richard Redon, Guy A. Rouleau, Marie Søfteland Sandvei, Sabine Schilling, Eimad Shotar, Agnieszka Slowik, Chikashi Terao, W. M. Monique Verschuren, Robin G. Walters, David J. Werring, Cristen J. Willer, Daniel Woo, Bradford B. Worrall, Sirui Zhou, Biological Psychology, Amsterdam Reproduction & Development, APH - Mental Health, APH - Methodology, AMS - Sports, AMS - Ageing & Vitality, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Systems Ecology, Sociology and Social Gerontology, Bakker, Mark K., Kanning, Jos P., Abraham, Gad, Martinsen, Amy E., Winsvold, Bendik S., Zwart, John-Anker, Bourcier, Romain, Sawada, Tomonobu, Koido, Masaru, Kamatani, Yoichiro, Morel, Sandrine, Amouyel, Philippe, Debette, Stéphanie, Bijlenga, Philippe, Berrandou, Takiy, Ganesh, Santhi K., Bouatia-Naji, Nabila, Jones, Gregory, Bown, Matthew, Rinkel, Gabriel J. E., Veldink, Jan H., Ruigrok, Ynte M., Girotto, G., All-In Stroke, Hunt, Group, Cadisp, Consortium for Blood Pressure, International, Headache Genetics Consortium, International, Stroke Genetics Consortium (ISGC) Intracranial Aneurysm Working Group, International, Utrecht University [Utrecht], Baker Heart and Diabetes Institute (AUSTRALIA), University of Melbourne, University of Oslo (UiO), Norwegian University of Science and Technology (NTNU), Oslo University Hospital [Oslo], Centre hospitalier universitaire de Nantes (CHU Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), The University of Tokyo (UTokyo), RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Hôpital Universitaire de Genève = University Hospitals of Geneva (HUG), Université de Genève = University of Geneva (UNIGE), Excellence Laboratory LabEx DISTALZ, Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University of Michigan Medical School [Ann Arbor], University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, University of Otago [Dunedin, Nouvelle-Zélande], University of Leicester, Laboratoire de Neurosciences Fonctionnelles et Pathologies - UR UPJV 4559 (LNFP), Université de Picardie Jules Verne (UPJV), CHU Amiens-Picardie, HUNT All-In Stroke, CADISP group, International Consortium for Blood Pressure, International Headache Genetics Consortium, International Stroke Genetics Consortium (ISGC) Intracranial Aneurysm Working Group: Anne Hege Aamodt, Anne Heidi Skogholt, Ben M Brumpton, Cristen J Willer, Else C Sandset, Espen S Kristoffersen, Hanne Ellekjær, Ingrid Heuch, Jonas B Nielsen, Knut Hagen, Kristian Hveem, Lars G Fritsche, Laurent F Thomas, Linda M Pedersen, Maiken E Gabrielsen, Oddgeir L Holmen, Sigrid Børte, Wei Zhou, Shérine Abboud, Massimo Pandolfo, Vincent Thijs, Didier Leys, Marie Bodenant, Fabien Louillet, Emmanuel Touzé, Jean-Louis Mas, Yves Samson, Sara Leder, Anne Léger, Sandrine Deltour, Sophie Crozier, Isabelle Méresse, Sandrine Canaple, Olivier Godefroy, Maurice Giroud, Yannick Béjot, Pierre Decavel, Elizabeth Medeiros, Paola Montiel, Thierry Moulin, Fabrice Vuillier, Jean Dallongeville, Antti J Metso, Tiina Metso, Turgut Tatlisumak, Caspar Grond-Ginsbach, Christoph Lichy, Manja Kloss, Inge Werner, Marie-Luise Arnold, Michael Dos Santos, Armin Grau, Martin Dichgans, Constanze Thomas-Feles, Ralf Weber, Tobias Brandt, Alessandro Pezzini, Valeria De Giuli, Filomena Caria, Loris Poli, Alessandro Padovani, Anna Bersano, Silvia Lanfranconi, Simone Beretta, Carlo Ferrarese, Giacomo Giacolone, Stefano Paolucci, Philippe Lyrer, Stefan Engelter, Felix Fluri, Florian Hatz, Dominique Gisler, Leo Bonati, Henrik Gensicke, Margareth Amort, Hugh Markus, Jennifer Majersik, Bradford Worrall, Andrew Southerland, John Cole, Steven Kittner, Evangelos Evangelou, Helen R Warren, He Gao, Georgios Ntritsos, Niki Dimou, Tonu Esko, Reedik Mägi, Lili Milani, Peter Almgren, Thibaud Boutin, Jun Ding, Franco Giulianini, Elizabeth G Holliday, Anne U Jackson, Ruifang Li-Gao, Wei-Yu Lin, Jian'an Luan, Massimo Mangino, Christopher Oldmeadow, Bram Peter Prins, Yong Qian, Muralidharan Sargurupremraj, Nabi Shah, Praveen Surendran, Sébastien Thériault, Niek Verweij, Sara M Willems, Jing-Hua Zhao, John Connell, Renée de Mutsert, Alex Sf Doney, Martin Farrall, Cristina Menni, Andrew D Morris, Raymond Noordam, Guillaume Paré, Neil R Poulter, Denis C Shields, Alice Stanton, Simon Thom, Gonçalo Abecasis, Najaf Amin, Dan E Arking, Kristin L Ayers, Caterina M Barbieri, Chiara Batini, Joshua C Bis, Tineka Blake, Murielle Bochud, Michael Boehnke, Eric Boerwinkle, Dorret I Boomsma, Erwin P Bottinger, Peter S Braund, Marco Brumat, Archie Campbell, Harry Campbell, Aravinda Chakravarti, John C Chambers, Ganesh Chauhan, Marina Ciullo, Massimiliano Cocca, Francis Collins, Heather J Cordell, Gail Davies, Martin H de Borst, Eco J de Geus, Ian J Deary, Joris Deelen, Fabiola Del Greco M, Cumhur Yusuf Demirkale, Marcus Dörr, Georg B Ehret, Roberto Elosua, Stefan Enroth, A Mesut Erzurumluoglu, Teresa Ferreira, Mattias Frånberg, Oscar H Franco, Ilaria Gandin, Paolo Gasparini, Vilmantas Giedraitis, Christian Gieger, Giorgia Girotto, Anuj Goel, Alan J Gow, Vilmundur Gudnason, Xiuqing Guo, Ulf Gyllensten, Anders Hamsten, Tamara B Harris, Sarah E Harris, Catharina A Hartman, Aki S Havulinna, Andrew A Hicks, Edith Hofer, Albert Hofman, Jouke-Jan Hottenga, Jennifer E Huffman, Shih-Jen Hwang, Erik Ingelsson, Alan James, Rick Jansen, Marjo-Riitta Jarvelin, Roby Joehanes, Åsa Johansson, Andrew D Johnson, Peter K Joshi, Pekka Jousilahti, J Wouter Jukema, Antti Jula, Mika Kähönen, Sekar Kathiresan, Bernard D Keavney, Kay-Tee Khaw, Paul Knekt, Joanne Knight, Ivana Kolcic, Jaspal S Kooner, Seppo Koskinen, Kati Kristiansson, Zoltan Kutalik, Maris Laan, Marty Larson, Lenore J Launer, Benjamin Lehne, Terho Lehtimäki, David Cm Liewald, Li Lin, Lars Lind, Cecilia M Lindgren, YongMei Liu, Ruth Jf Loos, Lorna M Lopez, Yingchang Lu, Leo-Pekka Lyytikäinen, Anubha Mahajan, Chrysovalanto Mamasoula, Jaume Marrugat, Jonathan Marten, Yuri Milaneschi, Anna Morgan, Andrew P Morris, Alanna C Morrison, Peter J Munson, Mike A Nalls, Priyanka Nandakumar, Christopher P Nelson, Teemu Niiranen, Ilja M Nolte, Teresa Nutile, Albertine J Oldehinkel, Ben A Oostra, Paul F O'Reilly, Elin Org, Sandosh Padmanabhan, Walter Palmas, Aarno Palotie, Alison Pattie, Brenda Wjh Penninx, Markus Perola, Annette Peters, Ozren Polasek, Peter P Pramstaller, Quang Tri Nguyen, Olli T Raitakari, Rainer Rettig, Kenneth Rice, Paul M Ridker, Janina S Ried, Harriëtte Riese, Samuli Ripatti, Antonietta Robino, Lynda M Rose, Jerome I Rotter, Igor Rudan, Daniela Ruggiero, Yasaman Saba, Cinzia F Sala, Veikko Salomaa, Nilesh J Samani, Antti-Pekka Sarin, Reinhold Schmidt, Helena Schmidt, Nick Shrine, David Siscovick, Albert V Smith, Harold Snieder, Siim Sõber, Rossella Sorice, John M Starr, David J Stott, David P Strachan, Rona J Strawbridge, Johan Sundström, Morris A Swertz, Kent D Taylor, Alexander Teumer, Martin D Tobin, Maciej Tomaszewski, Daniela Toniolo, Michela Traglia, Stella Trompet, Jaakko Tuomilehto, Christophe Tzourio, André G Uitterlinden, Ahmad Vaez, Peter J van der Most, Cornelia M van Duijn, Germaine C Verwoert, Veronique Vitart, Uwe Völker, Peter Vollenweider, Dragana Vuckovic, Hugh Watkins, Sarah H Wild, Gonneke Willemsen, James F Wilson, Alan F Wright, Jie Yao, Tatijana Zemunik, Weihua Zhang, John R Attia, Adam S Butterworth, Daniel I Chasman, David Conen, Francesco Cucca, John Danesh, Caroline Hayward, Joanna Mm Howson, Markku Laakso, Edward G Lakatta, Claudia Langenberg, Olle Melander, Dennis O Mook-Kanamori, Colin Na Palmer, Lorenz Risch, Robert A Scott, Rodney J Scott, Peter Sever, Tim D Spector, Pim van der Harst, Nicholas J Wareham, Eleftheria Zeggini, Daniel Levy, Patricia B Munroe, Christopher Newton-Cheh, Morris J Brown, Andres Metspalu, Bruce M Psaty, Louise V Wain, Paul Elliott, Mark J Caulfield, Padhraig Gormley, Verneri Anttila, Priit Palta, Tonu Esko, Tune H Pers, Kai-How Farh, Ester Cuenca-Leon, Mikko Muona, Nicholas A Furlotte, Tobias Kurth, Andres Ingason, George McMahon, Lannie Ligthart, Gisela M Terwindt, Mikko Kallela, Tobias M Freilinger, Caroline Ran, Scott G Gordon, Anine H Stam, Stacy Steinberg, Guntram Borck, Markku Koiranen, Lydia Quaye, Hieab H H Adams, Terho Lehtimäki, Antti-Pekka Sarin, Juho Wedenoja, David A Hinds, Julie E Buring, Markus Schürks, Paul M Ridker, Maria Gudlaug Hrafnsdottir, Hreinn Stefansson, Susan M Ring, Jouke-Jan Hottenga, Brenda W J H Penninx, Markus Färkkilä, Ville Artto, Mari Kaunisto, Salli Vepsäläinen, Rainer Malik, Andrew C Heath, Pamela A F Madden, Nicholas G Martin, Grant W Montgomery, Mitja I Kurki, Mart Kals, Reedik Mägi, Kalle Pärn, Eija Hämäläinen, Hailiang Huang, Andrea E Byrnes, Lude Franke, Jie Huang, Evie Stergiakouli, Phil H Lee, Cynthia Sandor, Caleb Webber, Zameel Cader, Bertram Muller-Myhsok, Stefan Schreiber, Thomas Meitinger, Johan G Eriksson, Veikko Salomaa, Kauko Heikkilä, Elizabeth Loehrer, Andre G Uitterlinden, Albert Hofman, Cornelia M van Duijn, Lynn Cherkas, Linda M Pedersen, Audun Stubhaug, Christopher S Nielsen, Minna Männikkö, Evelin Mihailov, Lili Milani, Hartmut Göbel, Ann-Louise Esserlind, Anne Francke Christensen, Thomas Folkmann Hansen, Thomas Werge, Jaakko Kaprio, Arpo J Aromaa, Olli Raitakari, M Arfan Ikram, Tim Spector, Marjo-Riitta Järvelin, Andres Metspalu, Christian Kubisch, David P Strachan, Michel D Ferrari, Andrea C Belin, Martin Dichgans, Maija Wessman, Arn M J M van den Maagdenberg, Dorret I Boomsma, George Davey Smith, Kari Stefansson, Nicholas Eriksson, Mark J Daly, Benjamin M Neale, Jes Olesen, Daniel I Chasman, Dale R Nyholt, Aarno Palotie, Masato Akiyama, Varinder S Alg, Sigrid Børte, Joseph P Broderick, Ben M Brumpton, Jérôme Dauvillier, Hubert Desal, Christian Dina, Christoph M Friedrich, Emília I Gaál-Paavola, Jean-Christophe Gentric, Sven Hirsch, Isabel C Hostettler, Henry Houlden, Kristian Hveem, Juha E Jääskeläinen, Marianne Bakke Johnsen, Liming Li, Kuang Lin, Antti Lindgren, Olivier Martin, Koichi Matsuda, Iona Y Millwood, Olivier Naggara, Mika Niemelä, Joanna Pera, Richard Redon, Guy A Rouleau, Marie Søfteland Sandvei, Sabine Schilling, Eimad Shotar, Agnieszka Slowik, Chikashi Terao, W M Monique Verschuren, Robin G Walters, David J Werring, Cristen J Willer, Daniel Woo, Bradford B Worrall, Sirui Zhou, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, and Admin, Oskar

Subjects
Advanced and Specialized Nursing, Incidence, risk assessment, Smoking/epidemiology, intracranial aneurysm, genetic heterogeneity, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Risk Factors, Intracranial Aneurysm/epidemiology, Humans, Subarachnoid Hemorrhage/epidemiology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, genetics, Neurology (clinical), aneurysmal subarachnoid hemorrhage, genetic, Cardiology and Cardiovascular Medicine
Abstract

Background: Recently, common genetic risk factors for intracranial aneurysm (IA) and aneurysmal subarachnoid hemorrhage (ASAH) were found to explain a large amount of disease heritability and therefore have potential to be used for genetic risk prediction. We constructed a genetic risk score to (1) predict ASAH incidence and IA presence (combined set of unruptured IA and ASAH) and (2) assess its association with patient characteristics. Methods: A genetic risk score incorporating genetic association data for IA and 17 traits related to IA (so-called metaGRS) was created using 1161 IA cases and 407 392 controls from the UK Biobank population study. The metaGRS was validated in combination with risk factors blood pressure, sex, and smoking in 828 IA cases and 68 568 controls from the Nordic HUNT population study. Furthermore, we assessed association between the metaGRS and patient characteristics in a cohort of 5560 IA patients. Results: Per SD increase of metaGRS, the hazard ratio for ASAH incidence was 1.34 (95% CI, 1.20–1.51) and the odds ratio for IA presence 1.09 (95% CI, 1.01–1.18). Upon including the metaGRS on top of clinical risk factors, the concordance index to predict ASAH hazard increased from 0.63 (95% CI, 0.59–0.67) to 0.65 (95% CI, 0.62–0.69), while prediction of IA presence did not improve. The metaGRS was statistically significantly associated with age at ASAH (β=−4.82×10 −3 per year [95% CI, −6.49×10 −3 to −3.14×10 −3 ]; P =1.82×10 −8 ), and location of IA at the internal carotid artery (odds ratio=0.92 [95% CI, 0.86–0.98]; P =0.0041). Conclusions: The metaGRS was predictive of ASAH incidence, although with limited added value over clinical risk factors. The metaGRS was not predictive of IA presence. Therefore, we do not recommend using this metaGRS in daily clinical care. Genetic risk does partly explain the clinical heterogeneity of IA warranting prioritization of clinical heterogeneity in future genetic prediction studies of IA and ASAH.

Published
2023

23. Genetic determinants of chromatin reveal prostate cancer risk mediated by context-dependent gene regulation

Author

Sylvan C. Baca, Cassandra Singler, Soumya Zacharia, Ji-Heui Seo, Tunc Morova, Faraz Hach, Yi Ding, Tommer Schwarz, Chia-Chi Flora Huang, Jacob Anderson, André P. Fay, Cynthia Kalita, Stefan Groha, Mark M. Pomerantz, Victoria Wang, Simon Linder, Christopher J. Sweeney, Wilbert Zwart, Nathan A. Lack, Bogdan Pasaniuc, David Y. Takeda, Alexander Gusev, Matthew L. Freedman, Chemical Biology, Lack, Nathan Alan (ORCID 0000-0001-7399-5844 & YÖK ID 120842), Baca, Sylvan C., Singler, Cassandra, Zacharia, Soumya, Seo, Ji-Heui, Morova, Tunc, Hach, Faraz, Ding, Yi, Schwarz, Tommer, Huang, Chia-Chi Flora, Anderson, Jacob, Fay, Andre P., Kalita, Cynthia, Groha, Stefan, Pomerantz, Mark M., Wang, Victoria, Linder, Simon, Sweeney, Christopher J., Zwart, Wilbert, Pasaniuc, Bogdan, Takeda, David Y., Gusev, Alexander, Freedman, Matthew L., and School of Medicine

Subjects
Male, Urologic Diseases, Genetics and heredity, Aging, Quantitative Trait Loci, SDG 3 – Goede gezondheid en welzijn, Polymorphism, Single Nucleotide, Medical and Health Sciences, Article, SDG 3 - Good Health and Well-being, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Polymorphism, Aetiology, Cancer, Prevention, Prostate Cancer, Human Genome, Prostatic Neoplasms, Single Nucleotide, Biological Sciences, Chromatin, Gene Expression Regulation, Cancer risk, Cohort analysis, Controlled study, Developmental gene, Genome-Wide Association Study, Biotechnology, Developmental Biology
Abstract

Many genetic variants affect disease risk by altering context-dependent gene regulation. Such variants are difficult to study mechanistically using current methods that link genetic variation to steady-state gene expression levels, such as expression quantitative trait loci (eQTLs). To address this challenge, we developed the cistrome-wide association study (CWAS), a framework for identifying genotypic and allele-specific effects on chromatin that are also associated with disease. In prostate cancer, CWAS identified regulatory elements and androgen receptor-binding sites that explained the association at 52 of 98 known prostate cancer risk loci and discovered 17 additional risk loci. CWAS implicated key developmental transcription factors in prostate cancer risk that are overlooked by eQTL-based approaches due to context-dependent gene regulation. We experimentally validated associations and demonstrated the extensibility of CWAS to additional epigenomic datasets and phenotypes, including response to prostate cancer treatment. CWAS is a powerful and biologically interpretable paradigm for studying variants that influence traits by affecting transcriptional regulation. Cistrome-wide association study (CWAS) is an approach for nominating variants that impact traits through effects on chromatin state. CWAS performed on 307 prostate cistromes identifies candidate loci for prostate cancer and androgen-related traits., This work is supported by grants from the PhRMA Foundation and the Kure It Cancer Research Foundation (S.C.B.). The androgen deprivation GWAS was supported in part by the National Cancer Institute of the National Institutes of Health under award numbers U10CA180820, U10CA180794 and UG1CA233180 (C.J.S.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We are grateful to the E3805: CHAARTED investigators; the patients who participated in the trial; the Prostate Cancer Foundation Mazzone Awards; and Sanofi for partial financial support and supplying docetaxel for early use (C.J.S.). In addition, we acknowledge Public Health Service grants CA180794, CA180820, CA23318, CA66636, CA21115, CA49883, CA16116, CA21076, CA27525, CA13650, CA14548, CA35421, CA32102, CA31946, CA04919, CA107868 and CA184734 (C.J.S.). We are grateful for the generous support of Rebecca and Nathan Milikowsky and Debbie and Bob First (S.C.B.).

Published
2022

24. Pan-European survey on the implementation of robotic and laparoscopic minimally invasive liver surgery

Author

Frederik Berrevoet, Carolijn L.M.A. Nota, Luca Aldrighetti, Ronald M. van Dam, Emir Hoti, Jeroen Hagendoorn, Maurice J. W. Zwart, Rutger-Jan Swijnenburg, Burak Görgec, R. Fichtinger, Marcel J. van der Poel, David Fuks, Bjørn Edwin, Mohammed Abu Hilal, Marc G. Besselink, Abdullah Arabiyat, Graduate School, Surgery, CCA - Cancer Treatment and Quality of Life, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, CCA -Cancer Center Amsterdam, Radiology and Nuclear Medicine, Zwart, M. J. W., Gorgec, B., Arabiyat, A., Nota, C. L. M., van der Poel, M. J., Fichtinger, R. S., Berrevoet, F., van Dam, R. M., Aldrighetti, L., Fuks, D., Hoti, E., Edwin, B., Besselink, M. G., Abu Hilal, M., Hagendoorn, J., Swijnenburg, R. -J., RS: NUTRIM - R2 - Liver and digestive health, MUMC+: MA Heelkunde (9), and RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy

Subjects
Liver surgery, CLINICAL-OUTCOMES, medicine.medical_specialty, RESECTION, IMPACT, HEPATECTOMY, Liver resections, Resection, Robotic Surgical Procedures, Pan european, Medicine and Health Sciences, Hepatectomy, Humans, Minimally Invasive Surgical Procedures, Medicine, Robotic surgery, Hepatology, business.industry, General surgery, Gastroenterology, Center volume, surgical procedures, operative, Liver, EXPERIENCE, Laparoscopy, business
Abstract

BACKGROUND: Laparoscopic and robotic minimally invasive liver surgery (MILS) is gaining popularity. Recent data and views on the implementation of laparoscopic and robotic MILS throughout Europe are lacking.METHODS: An anonymous survey consisting of 46 questions was sent to all members of the European-African Hepato-Pancreato-Biliary Association.RESULTS: The survey was completed by 120 surgeons from 103 centers in 24 countries. Median annual center volume of liver resection was 100 [IQR 50-140]. The median annual volume of MILS per center was 30 [IQR 16-40]. For minor resections, laparoscopic MILS was used by 80 (67%) surgeons and robotic MILS by 35 (29%) surgeons. For major resections, laparoscopic MILS was used by 74 (62%) surgeons and robotic MILS by 33 (28%) surgeons. The majority of the surgeons stated that minimum annual volume of MILS per center should be around 21-30 procedures/year. Of the surgeons performing robotic surgery, 28 (70%) felt they missed specific equipment, such as a robotic-CUSA. Seventy (66%) surgeons provided a formal MILS training to residents and fellows. In 5 years' time, 106 (88%) surgeons felt that MILS would have superior value as compared to open liver surgery.CONCLUSION: In the participating European liver centers, MILS comprised about one third of all liver resections and is expected to increase further. Laparoscopic MILS is still twice as common as robotic MILS. Development of specific instruments for robotic liver parenchymal transection might further increase its adoption.

Published
2022

25. Double-strand break toxicity is chromatin context independent

Author

Anoek Friskes, Lisa Koob, Lenno Krenning, Tesa M Severson, Emma S Koeleman, Xabier Vergara, Michael Schubert, Jeroen van den Berg, Bastiaan Evers, Anna G Manjón, Stacey Joosten, Yongsoo Kim, Wilbert Zwart, René H Medema, and Pathology

Subjects
DNA Repair, Genetics, Humans, RNA, DNA Breaks, Double-Stranded, CRISPR-Cas Systems, Chromatin, Lamins
Abstract

Cells respond to double-strand breaks (DSBs) by activating DNA damage response pathways, including cell cycle arrest. We have previously shown that a single double-strand break generated via CRISPR/Cas9 is sufficient to delay cell cycle progression and compromise cell viability. However, we also found that the cellular response to DSBs can vary, independent of the number of lesions. This implies that not all DSBs are equally toxic, and raises the question if the location of a single double-strand break could influence its toxicity. To systematically investigate if DSB-location is a determinant of toxicity we performed a CRISPR/Cas9 screen targeting 6237 single sites in the human genome. Next, we developed a data-driven framework to design CRISPR/Cas9 sgRNA (crRNA) pools targeting specific chromatin features. The chromatin context was defined using ChromHMM states, Lamin-B1 DAM-iD, DNAseI hypersensitivity, and RNA-sequencing data. We computationally designed 6 distinct crRNA pools, each containing 10 crRNAs targeting the same chromatin state. We show that the toxicity of a DSB is highly similar across the different ChromHMM states. Rather, we find that the major determinants of toxicity of a sgRNA are cutting efficiency and off-target effects. Thus, chromatin features have little to no effect on the toxicity of a single CRISPR/Cas9-induced DSB.

Published
2022

26. Venous resection for pancreatic cancer, a safe and feasible option? A systematic review and meta-analysis

Author

E.S. Zwart, B.S. Yilmaz, A. Halimi, R. Ahola, B. Kurlinkus, J. Laukkarinen, and G.O. Ceyhan

Subjects
Pancreatic Neoplasms, Mesenteric Veins, Pancreatectomy, Hepatology, Portal Vein, Endocrinology, Diabetes and Metabolism, Gastroenterology, Humans, Pancreaticoduodenectomy, Retrospective Studies
Abstract

In pancreatic ductal adenocarcinoma patients with suspected venous infiltration, a R0 resection is most of the time not possible without venous resection (VR). To investigate this special kind of patients, this meta-analysis was conducted to compare mortality, morbidity and long-term survival of pancreatic resections with (VR+) and without venous resection (VR-).A systematic search was performed in Embase, Pubmed and Web of Science. Studies which compared over twenty patients with VR + to VR-for PDAC with ≥1 year follow up were included. Articles including arterial resections were excluded. Statistical analysis was performed with the random effect Mantel-Haenszel test and inversed variance method. Individual patient data was compared with the log-rank test.Following a review of 6403 papers by title and abstract and 166 by full text, a meta-analysis was conducted of 32 studies describing 2216 VR+ and 5380 VR-. There was significantly more post-pancreatectomy hemorrhage (6.5% vs. 5.6%), R1 resections (36.7% vs. 28.6%), N1 resections (70.3% vs. 66.8%) and tumors were significantly larger (34.6 mm vs. 32.8 mm) in patients with VR+. Of all VR + patients, 64.6% had true pathological venous infiltration. The 90-day mortality, individual patient data for overall survival and pooled multivariate hazard ratio for overall survival were similar.VR is a safe and feasible option in patients with pancreatic cancer and suspicion of venous involvement, since VR during pancreatic surgery has comparable overall survival and complication rates.

Published
2022

27. The effect of COVID-19 on transplant function and development of CLAD in lung transplant patients

Author

Elizabeth Roosma, Johanna P. van Gemert, Auke E.S. de Zwart, Coretta C. van Leer-Buter, Merel E. Hellemons, Elize M. Berg, Bart Luijk, Rogier A.S. Hoek, Diana A. van Kessel, Onno W. Akkerman, Huib A.M. Kerstjens, Erik A.M. Verschuuren, C. Tji Gan, Pulmonary Medicine, Microbes in Health and Disease (MHD), Groningen Research Institute for Asthma and COPD (GRIAC), and Groningen Institute for Organ Transplantation (GIOT)

Subjects
Pulmonary and Respiratory Medicine, Transplantation, Spirometry, Forced Expiratory Volume, Vital Capacity, COVID-19, Humans, Surgery, Cardiology and Cardiovascular Medicine, Lung, Lung Transplantation, Retrospective Studies
Abstract

Background: Concerns have been raised on the impact of coronavirus disease (COVID-19) on lung transplant (LTx) patients. The aim of this study was to evaluate the transplant function pre- and post-COVID-19 in LTx patients. Methods: Data were retrospectively collected from LTx patients with confirmed COVID-19 from all 3 Dutch transplant centers, between February 2020 and September 2021. Spirometry results were collected pre-COVID-19, 3- and 6-months post infection. Results: Seventy-four LTx patients were included. Forty-two (57%) patients were admitted, 19 (26%) to the intensive care unit (ICU). The in-hospital mortality was 20%. Twelve out of 19 ICU patients died (63%), a further 3 died on general wards. Patients with available spirometry (78% at 3 months, 65% at 6 months) showed a significant decline in mean forced expiratory volume in 1 second (FEV1) (ΔFEV1 138 ± 39 ml, p = 0.001), and forced vital capacity (FVC) (ΔFVC 233 ±74 ml, p = 0.000) 3 months post infection. Lung function improved slightly from 3 to 6 months after COVID-19 (ΔFEV1 24 ± 38 ml; ΔFVC 100 ± 46 ml), but remained significantly lower than pre-COVID-19 values (ΔFEV1 86 ml ± 36 ml, p = 0.021; ΔFVC 117 ± 35 ml, p = 0.012). FEV1/FVC was > 0.70. Conclusions: In LTx patients COVID-19 results in high mortality in hospitalized patients. Lung function declined 3 months after infection and gradually improved at 6 months, but remained significantly lower compared to pre-COVID-19 values. The more significant decline in FVC than in FEV1 and FEV1/FVC > 70%, suggested a more restrictive pattern.

Published
2022

28. A novel risk score to identify the need for triple antithrombotic therapy in patients with atrial fibrillation undergoing percutaneous coronary intervention: a post hoc analysis of the RE-DUAL PCI trial

Author

Zwart, Bastiaan, Bor, Willem Lambertus, de Veer, Anne Johanna Wilhelmina Maria, Mahmoodi, Bakhtawar Khan, Kelder, Johannes Christiaan, Lip, Gregory Y.H., Bhatt, Deepak L., Cannon, Christopher P., Ten Berg, Jurriën Maria, Cardiologie, and RS: Carim - B04 Clinical thrombosis and Haemostasis

Subjects
Stroke/etiology, Platelet Aggregation Inhibitors/therapeutic use, Myocardial Infarction, Hemorrhage, risk stratification, antithrombotic treatment, Brain Ischemia, Percutaneous Coronary Intervention, Fibrinolytic Agents, Risk Factors, Atrial Fibrillation, Myocardial Infarction/etiology, Humans, Hemorrhage/etiology, atrial fibrillation, METAANALYSIS, Percutaneous Coronary Intervention/adverse effects, stent thrombosis, Fibrinolytic Agents/therapeutic use, percutaneous coronary intervention, DABIGATRAN, Anticoagulants, Thrombosis, EFFICACY, Stroke, myocardial infarction, Anticoagulants/therapeutic use, SAFETY, Drug Therapy, Combination, Cardiology and Cardiovascular Medicine, Atrial Fibrillation/complications, Thrombosis/etiology, Platelet Aggregation Inhibitors
Abstract

BACKGROUND: Current guidelines recommend treating atrial fibrillation (AF) patients who undergo percutaneous coronary intervention (PCI) with triple antithrombotic therapy (TAT) for up to one month in patients at high thrombotic risk. It is unclear how to select these high-risk patients. AIMS: The aim of this study was to identify patients at high thrombotic risk who might benefit from TAT over double antithrombotic therapy (DAT). METHODS: This study was a post hoc subanalysis of the RE-DUAL PCI trial. A Cox proportional hazards model was built by stepwise selection of plausible predictor variables for a composite ischaemic endpoint, defined as cardiovascular death, myocardial infarction (MI), stent thrombosis (ST) or ischaemic stroke. The effect of TAT versus DAT was calculated for those patients with the highest proportion of predicted thrombotic risk. A simplified risk score was constructed based on beta-coefficients. RESULTS: For 209 patients (7.7%) the composite ischaemic endpoint occurred during the first year. The simplified risk score contained six variables. In patients with a score ≥5 (n=154, 5.7%), a significant reduction in the composite of MI and ST was observed with TAT versus DAT (6.3% vs 21.0%, p=0.041), without a penalty in terms of bleeding. In patients at low thrombotic risk, a significant increase in bleeding was observed without a reduction of ischaemic events. CONCLUSIONS: Our findings support the use of DAT in the majority of patients. A small subgroup of patients might benefit from TAT and we propose a novel clinical risk score to select these patients.

Published
2022

29. Respiratory Syncytial Virus, Human Metapneumovirus, and Parainfluenza Virus Infections in Lung Transplant Recipients

Author

Auke de Zwart, Annelies Riezebos-Brilman, Gerton Lunter, Judith Vonk, Allan R Glanville, Jens Gottlieb, Nitipong Permpalung, Huib Kerstjens, Jan-Willem Alffenaar, and Erik Verschuuren

Subjects
Microbiology (medical), Paramyxoviridae Infections, viruses, virus diseases, Respiratory Syncytial Virus Infections, Transplant Recipients, Parainfluenza Virus 1, Human, Parainfluenza Virus 2, Human, Infectious Diseases, Respiratory Syncytial Virus, Human, Ribavirin, Humans, Metapneumovirus, Prospective Studies, Lung, Respiratory Tract Infections, Retrospective Studies
Abstract

Background Respiratory syncytial virus (RSV), parainfluenza virus (PIV), and human metapneumovirus (hMPV) are increasingly associated with chronic lung allograft dysfunction (CLAD) in lung transplant recipients (LTR). This systematic review primarily aimed to assess outcomes of RSV/PIV/hMPV infections in LTR and secondarily to assess evidence regarding the efficacy of ribavirin. Methods Relevant databases were queried and study outcomes extracted using a standardized method and summarized. Results Nineteen retrospective and 12 prospective studies were included (total 1060 cases). Pooled 30-day mortality was low (0–3%), but CLAD progression 180–360 days postinfection was substantial (pooled incidences 19–24%) and probably associated with severe infection. Ribavirin trended toward effectiveness for CLAD prevention in exploratory meta-analysis (odds ratio [OR] 0.61, [0.27–1.18]), although results were highly variable between studies. Conclusions RSV/PIV/hMPV infection was followed by a high CLAD incidence. Treatment options, including ribavirin, are limited. There is an urgent need for high-quality studies to provide better treatment options for these infections.

Published
2022

30. The value of post-operative chemotherapy after chemoradiotherapy in patients with high-risk locally advanced rectal cancer-results from the RAPIDO trial

Author

Dijkstra, E A, Zwart, W H, Nilsson, P J, Putter, H, Roodvoets, A G H, Meershoek-Klein Kranenbarg, E, Frödin, J E, Nygren, P, Østergaard, L, Kersten, C, Verbiené, I, Cervantes, A, Hendriks, M P, Capdevila, J, Edhemovic, I, van de Velde, C J H, Marijnen, C A M, van Etten, B, Hospers, G A P, Glimelius, B, and Guided Treatment in Optimal Selected Cancer Patients (GUTS)

Subjects
post-operative chemotherapy, Cancer Research, oncological outcomes, propensity score stratification, Neoadjuvant Therapy/methods, Rectal Neoplasms/drug therapy, Infant, Disease-Free Survival, Chemoradiotherapy/methods, adjuvant chemotherapy, Neoplasm Recurrence, Local/drug therapy, Oncology, locally advanced rectal cancer, Humans
Abstract

BACKGROUND: Pre-operative chemoradiotherapy (CRT) rather than radiotherapy (RT) has resulted in fewer locoregional recurrences (LRRs), but no decrease in distant metastasis (DM) rate for patients with locally advanced rectal cancer (LARC). In many countries, patients receive post-operative chemotherapy (pCT) to improve oncological outcomes. We investigated the value of pCT after pre-operative CRT in the RAPIDO trial.PATIENTS AND METHODS: Patients were randomised between experimental (short-course RT, chemotherapy and surgery) and standard-of-care treatment (CRT, surgery and pCT depending on hospital policy). In this substudy, we compared curatively resected patients from the standard-of-care group who received pCT (pCT+ group) with those who did not (pCT- group). Subsequently, patients from the pCT+ group who received at least 75% of the prescribed chemotherapy cycles (pCT ≥75% group) were compared with patients who did not receive pCT (pCT-/- group). By propensity score stratification (PSS), we adjusted for the following unbalanced confounders: age, clinical extramural vascular invasion, distance to the anal verge, ypT stage, ypN stage, residual tumour, serious adverse event (SAE) and/or readmission within 6 weeks after surgery and SAE related to pre-operative CRT. Cumulative probability of disease-free survival (DFS), DM, LRR and overall survival (OS) was analysed by Cox regression.RESULTS: In total, 396/452 patients had a curative resection. The number of patients in the pCT+, pCT >75%, pCT- and pCT-/- groups was 184, 112, 154 and 149, respectively. The PSS-adjusted analyses for all endpoints demonstrated hazard ratios between approximately 0.7 and 0.8 (pCT+ versus pCT-), and 0.5 and 0.8 (pCT ≥75% versus pCT-/-). However, all 95% confidence intervals included 1.CONCLUSIONS: These data suggest a benefit of pCT after pre-operative CRT for patients with high-risk LARC, with approximately 20%-25% improvement in DFS and OS and 20%-25% risk reductions in DM and LRR. Compliance with pCT additionally reduces or improves all endpoints by 10%-20%. However, differences are not statistically significant.

Published
2023

31. Extensive androgen receptor enhancer heterogeneity in primary prostate cancers underlies transcriptional diversity and metastatic potential

Author

Jeroen Kneppers, Tesa M. Severson, Joseph C. Siefert, Pieter Schol, Stacey E. P. Joosten, Ivan Pak Lok Yu, Chia-Chi Flora Huang, Tunç Morova, Umut Berkay Altıntaş, Claudia Giambartolomei, Ji-Heui Seo, Sylvan C. Baca, Isa Carneiro, Eldon Emberly, Bogdan Pasaniuc, Carmen Jerónimo, Rui Henrique, Matthew L. Freedman, Lodewyk F. A. Wessels, Nathan A. Lack, Andries M. Bergman, Wilbert Zwart, Chemical Biology, Immunoengineering, Lack, Nathan Alan (ORCID 0000-0001-7399-5844 & YÖK ID 120842), Altıntaş, Umut Berkay, Kneppers, J., Severson, T.M., Siefert, J.C., Schol, P., Joosten, S.E.P., Yu, I.P.L., Huang, C.F., Morova, T., Giambartolomei, C., Seo, J.H., Baca, S.C., Carneiro, I., Emberly, E., Pasaniuc, B., Jerónimo, C., Henrique, R., Freedman, M.L., Wessels, L.F.A., Bergman, A.M., Zwart, W., Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), School of Medicine, Graduate School of Sciences and Engineering, and Department of Computational Sciences and Engineering

Subjects
Male, Multidisciplinary, Nucleic Acid, Prostatic Neoplasms/genetics, Androgen/genetics, Prostate, General Physics and Astronomy, Prostatic Neoplasms, General Chemistry, Regulatory Sequences, Nucleic Acid, SDG 3 – Goede gezondheid en welzijn, Receptors, Androgen/genetics, General Biochemistry, Genetics and Molecular Biology, Chromatin, Medicine, Biochemistry, SDG 3 - Good Health and Well-being, Receptors, Androgen, Receptors, Humans, Prostatic neoplasms, Receptors, androgen, Regulatory sequences, nucleic acid, Regulatory Sequences
Abstract

Androgen receptor (AR) drives prostate cancer (PCa) development and progression. AR chromatin binding profiles are highly plastic and form recurrent programmatic changes that differentiate disease stages, subtypes and patient outcomes. While prior studies focused on concordance between patient subgroups, inter-tumor heterogeneity of AR enhancer selectivity remains unexplored. Here we report high levels of AR chromatin binding heterogeneity in human primary prostate tumors, that overlap with heterogeneity observed in healthy prostate epithelium. Such heterogeneity has functional consequences, as somatic mutations converge on commonly-shared AR sites in primary over metastatic tissues. In contrast, less-frequently shared AR sites associate strongly with AR-driven gene expression, while such heterogeneous AR enhancer usage also distinguishes patients’ outcome. These findings indicate that epigenetic heterogeneity in primary disease is directly informative for risk of biochemical relapse. Cumulatively, our results illustrate a high level of AR enhancer heterogeneity in primary PCa driving differential expression and clinical impact., We would like to acknowledge the NKI Genomics Core Facility for Illumina sequencing and bioinformatics support and the NKI Research High-Performance Computing (RHPC) facility for computational infrastructure. We express gratitude to all members of the Zwart and Bergman lab, and members of the NKI Oncogenomics division for helpful scientific discussion. This work was supported by the Prostate Cancer Foundation (21CHAL04), Department of Defense (W81XWH-21-1-0234, W81XWH-19-1-0565), Oncode Institute and Alpe d’HuZes/KWF Dutch Cancer Society (10084).

Published
2022

32. Prediction of Drug–Drug Interactions After Esketamine Intranasal Administration Using a Physiologically Based Pharmacokinetic Model

Author

Marie-Emilie Willemin, Peter Zannikos, Geert Mannens, Loeckie de Zwart, and Jan Snoeys

Subjects
Pharmacology, Ticlopidine, Pharmaceutical Preparations, Cytochrome P-450 CYP3A, Humans, Computer Simulation, Drug Interactions, Ketamine, Pharmacology (medical), Prospective Studies, Models, Biological, Administration, Intranasal
Abstract

A physiologically based pharmacokinetic (PBPK) modeling approach for esketamine and its metabolite noresketamine after esketamine intranasal administration was developed to aid the prediction of drug-drug interactions (DDIs) during the clinical development of esketamine nasal spray (SPRAVATOThe intranasal PBPK (IN-PBPK) models for esketamine/noresketamine were constructed in SimcypThe simulated and observed (171 healthy volunteers) plasma pharmacokinetic profiles of intranasal esketamine/noresketamine showed a good match. The relative contributions of different cytochromes P450 (CYPs), mainly CYP3A4 and CYP2B6, involved in esketamine/noresketamine clearance was captured correctly in the IN-PBPK model using the DDI clinical studies of intranasal esketamine with clarithromycin and rifampicin and a published DDI study of oral esketamine with ticlopidine. The induction potential of esketamine toward CYP3A4 was also well captured. Inhibition of intranasal esketamine in the presence of ticlopidine was predicted to be not clinically relevant. Different scenarios tested with esketamine as a CYP3A4 perpetrator of midazolam also predicted the absence of clinically relevant CYP3A4 interactions.This PBPK model of the intranasal route adequately described the pharmacokinetics and DDI of intranasal esketamine/noresketamine with potential perpetrator and victim drugs. This work was used to support regulatory submissions of SPRAVATO

Published
2022

33. Albumin, oral contraceptives, and venous thromboembolism risk in astronauts

Author

Sara R. Zwart, Serena M. Auñón-Chancellor, Martina Heer, M. Mark Melin, and Scott M. Smith

Subjects
Male, Contraceptives, Oral, Combined, Risk Factors, Physiology, Physiology (medical), Astronauts, Humans, Transferrins, Female, Venous Thromboembolism, Serum Albumin, Research Article
Abstract

A venous thromboembolism (VTE) event occurred in a female astronaut during long-duration spaceflight. Multiple factors may have contributed to this risk, including the use of combined (progestin + estrogen) oral contraceptives (cOC). Biochemistry data from 65 astronauts were evaluated for associations with cOC use and with sex. The female astronauts who used cOCs had lower concentrations of serum albumin and higher concentrations of transferrin, a protein involved in the clotting cascade, than the male astronauts and the female astronauts who were not taking cOCs (P < 0.001). The women who used cOCs had higher serum concentrations of the acute phase reactant ceruloplasmin and cortisol during flight (P < 0.001) than the men and the women who were not taking cOCs; they also had higher calculated whole blood viscosity than women not taking cOCs (P < 0.001). Lower circulating concentrations of albumin, higher concentrations of transferrin, and elevated markers of inflammation all could contribute to an increased risk of VTE during spaceflight. These changes, in association with a higher blood viscosity, can directly affect endothelial glycocalyx integrity and hypercoagulability status, both of which contribute to VTE risk in terrestrial populations. NEW & NOTEWORTHY We report here evidence of an association between oral contraceptive use and serum albumin, among other factors, which potentially increase the risk of venous thromboembolism in astronauts. These findings highlight potential risks to astronaut health while providing potential alternative countermeasures for decreasing VTE risk during spaceflight. These findings also highlight an underrecognized potential mechanism for hypoalbuminemia to increase VTE risk in terrestrial populations.

Published
2022

34. Pilot study on VF-waveform based algorithms for early detection of acute myocardial infarction during out-of-hospital cardiac arrest

Author

Jos, Thannhauser, Joris, Nas, Koen, van der Sluijs, Hans, Zwart, Menko-Jan, de Boer, Niels, van Royen, Judith, Bonnes, Marc, Brouwer, ACS - Atherosclerosis & ischemic syndromes, and Mathematical Systems Theory

Subjects
Amsacrine, Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], Electric Countershock, Myocardial Infarction, Vascular damage Radboud Institute for Molecular Life Sciences [Radboudumc 16], Pilot Projects, Acute myocardial infarction, Emergency Nursing, Cardiac arrest, Cardiopulmonary Resuscitation, Electrocardiography, All institutes and research themes of the Radboud University Medical Center, Machine learning, Emergency Medicine, Humans, Acute coronary syndrome, Ventricular fibrillation, Cardiology and Cardiovascular Medicine, Algorithms, Out-of-Hospital Cardiac Arrest, Waveform analysis
Abstract

Introduction: On-scene detection of acute coronary occlusion (ACO) during ongoing ventricular fibrillation (VF) may facilitate patient-tailored triage and treatment during cardiac arrest. Experimental studies have demonstrated the diagnostic potential of the amplitude spectrum area (AMSA) of the VF-waveform to detect myocardial infarction (MI). In follow-up, we performed this clinical pilot study on VF-waveform based discriminative models to diagnose acute MI due to ACO in real-world VF-patients. Methods: In our registry of VF-patients transported to a tertiary hospital (Nijmegen, The Netherlands), we studied patients with high-quality VF-registrations. We calculated VF-characteristics prior to the first shock, and first-to-second shock changes (Δ-characteristics). Primary aim was to assess the discriminative ability of the AMSA to detect patients with ACO. Secondarily, we investigated the discriminative value of adding ΔAMSA-measures using machine learning algorithms. Model performances were assessed using C-statistics. Results: In total, there were 67 VF-patients with and 34 without an ACO, and baseline characteristics did not differ significantly. Based on the AMSA prior to the first defibrillation attempt, discrimination between ACO and non-ACO was possible, with a C-statistic of 0.66 (0.56–0.75). The discriminative model using AMSA + ΔAMSA yielded a C-statistic of 0.80 (0.69–0.88). Conclusion: These clinical pilot data confirm previous experimental findings that early detection of MI using VF-waveform analysis seems feasible, and add insights on the diagnostic impact of accounting for first-to-second shock changes in VF-characteristics. Confirmative studies in larger cohorts and with a variety of VF-algorithms are warranted to further investigate the potential of this innovative approach.

Published
2022

35. Self-testing for the detection of SARS-CoV-2 infection with rapid antigen tests for people with suspected COVID-19 in the community

Author

Carla R.S. Nagel-Imming, Joep J.J.M. Stohr, Vivian F. Zwart, Adam Meijer, Wouter van den Bijllaardt, Jean-Luc Murk, Femke van den Oetelaar, Ariene Rietveld, Marjolein F.Q. Kluytmans-van den Bergh, Jaco J. Verweij, Suzan D. Pas, Gabriel Goderski, Kim H. Gan, Marloes Hellwich, and Jan Kluytmans

Subjects
Microbiology (medical), medicine.medical_specialty, 2019-20 coronavirus outbreak, Rapid antigen detection test, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Self-testing, Sensitivity and Specificity, COVID-19 Testing, Antigen, Internal medicine, parasitic diseases, medicine, Humans, Severe acute respiratory syndrome coronavirus 2, Antigens, Viral, Public health, Coronavirus disease 2019, SARS-CoV-2, business.industry, Viral culture, COVID-19, General Medicine, Odds ratio, Infectious Diseases, Positive culture, Original Article, business
Abstract

Objectives To evaluate the performance of nasal mid-turbinate self-testing using rapid antigen detection tests (RDT) for persons with suspected coronavirus disease 2019 (COVID-19) in the community. Self-testing for COVID-19 infection with lateral flow assay severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RDT, provides rapid results and could enable frequent and extensive testing in the community, thereby improving the control of SARS-CoV-2. Methods Participants visiting a municipal SARS-CoV-2 testing centre, received self-testing kits containing either the BD Veritor System (BD-RDT) or Roche SARS-CoV-2 antigen detection test (Roche-RDT). Oro-nasopharyngeal swabs were collected from the participants for quantitative RT-PCR (qRT-PCR) testing. As a proxy for contagiousness, viral culture was performed on a selection of qRT-PCR positive samples to determine the Ct-value at which the chance of a positive culture dropped below 0.5 (Ct-value cut-off). Sensitivity and specificity of self-testing were compared to qRT-PCR with a Ct-value below the Ct value cut-off. Determinants independently associated with a false-negative self-test result were determined. Results A total of 3201 participants were included (BD-RDT n = 1595; Roche-RDT n = 1606). Sensitivity and specificity of self-testing compared with the qRT-PCR results with a Ct-value below the Ct-value cut-off were 78.4% (95% CI 73.2%–83.5%) and 99.4% (95% CI 99.1%–99.7%), respectively. A higher age was independently associated with a false-negative self-testing result with an odds ratio of 1.024 (95% CI 1.003–1.044). Conclusions Self-testing using currently available RDT has a high specificity and relatively high sensitivity to identify individuals with a high probability of contagiousness.

Published
2022

36. The Multimodal Management of Locally Advanced Rectal Cancer

Author

Wouter H. Zwart, Alexandra Hotca, Geke A.P. Hospers, Karyn A. Goodman, Julio Garcia-Aguilar, and Guided Treatment in Optimal Selected Cancer Patients (GUTS)

Subjects
Treatment Outcome, Rectal Neoplasms, Quality of Life, Humans, Neoplasms, Second Primary, General Medicine, Chemoradiotherapy, Prospective Studies, Neoplasm Recurrence, Local, Watchful Waiting, Neoadjuvant Therapy
Abstract

In the past 40 years, the treatment of locally advanced rectal cancer has evolved with the addition of radiotherapy or chemoradiotherapy and providing (neo)adjuvant systemic chemotherapy to major surgery. However, recent trends have focused on improving our ability to risk-stratify patients and tailoring treatment to achieve the best oncologic outcome while limiting the impact on long-term quality of life. Therefore, there has been increasing interest in pursuing a watch-and-wait approach to achieve organ preservation. Several retro- and prospective studies suggest safety of the watch-and-wait approach, though it is still considered controversial due to limited clinical evidence, concerns about tumor regrowth, and subsequent distant progression. To further reduce treatment, MRI risk stratification, together with patient characteristics and patient preferences, can guide personalized treatment and reserve radiation and chemotherapy for a select patient population. Ultimately, improved options for reassessment during neoadjuvant treatment may allow for more adaptive therapy options based on treatment response. This article provides an overview of some major developments in the multimodal treatment of locally advanced rectal cancer. It reviews some relevant, controversial issues of the watch-and-wait approach and opportunities to personally tailor and reduce treatment. It also reviews the overall neoadjuvant treatment, including total neoadjuvant therapy trials, and how to best optimize for a potential complete response. Finally, it provides an algorithm as an example of how such a personalized, tailored, adaptive, and reduced treatment could look like in the future.

Published
2022

37. Nationwide confidential enquiries into maternal deaths because of obstetric hemorrhage in the Netherlands between 2006 and 2019

Author

Cornette, J.M.J., Ramler, Paul I., Beenakkers, I. C. M., Bloemenkamp, KWM, van der Bom, JG (Anske), Braams-Lisman, B. A. M., Kallianidis, A. F., Kuppens, Simone M.I., Rietveld, Anna L., Schaap, Timme, Schutte, Joke M., Stekelenburg, Jelle, Zwart, Joost J., van den Akker, Thomas, Obstetrics and gynaecology, Athena Institute, Network Institute, APH - Global Health, Public Health Research (PHR), and Obstetrics & Gynecology

Subjects
maternal mortality, MORTALITY, education, Obstetrics and Gynecology, Hemorrhage, General Medicine, PREVENTABILITY, Obstetrics, confidential enquiry, postpartum hemorrhage, SDG 3 - Good Health and Well-being, Pregnancy, Maternal Death, Humans, lessons learned, Female, Maternal Health Services, obstetric hemorrhage, improvable care, Netherlands
Abstract

Introduction: Obstetric hemorrhage-related deaths are rare in high income countries. Yet, with increasing incidences of obstetric hemorrhage in these countries, it is of utmost importance to learn lessons from each obstetric hemorrhage-related death to improve maternity care. Our objective was to calculate the obstetric hemorrhagerelated maternal mortality ratio (MMR), assess causes of obstetric hemorrhage-related deaths, and identify lessons learned.Material and methods: Nationwide mixed-methods prospective case-series with confidential enquiries into maternal deaths due to obstetric hemorrhage in the Netherlands from January 1, 2006 to December 31, 2019.Results: The obstetric hemorrhage-related MMR in the Netherlands in 2006–2019was 0.7 per 100 000 livebirths and was not statistically significantly different compared with the previous MMR of 1.0 per 100 000 livebirths in 1993–2005 (odds ratio 0.70, 95% confidence interval 0.38–1.30). Leading underlying cause of hemorrhage was retained placenta. Early recognition of persistent bleeding, prompt involvement of a senior clinician and timely management tailored to the cause of hemorrhage with attention to coagulopathy were prominent lessons learned. Also, timely recourse to surgical interventions, including hysterectomy, in case other management options fail to stop bleeding came up as an important lesson in several obstetric hemorrhagerelated deaths.Conclusions: The obstetric hemorrhage-related MMR in the Netherlands in 2006–2019 has not substantially changed compared to the MMR of the previous enquiry in1993–2005. Although obstetric hemorrhage is commonly encountered by maternity care professionals, it is important to remain vigilant for possible adverse maternal outcomes and act upon an ongoing bleeding following birth in a more timely and adequate manner. Our confidential enquiries still led to important lessons learned with clinical advice to professionals as how to improve maternity care and avoid maternal deaths. Drawing lessons from maternal deaths should remain a qualitative and moral imperative.

Published
2022

38. Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Author

Niamh Mullins, JooEun Kang, Adrian I. Campos, Jonathan R.I. Coleman, Alexis C. Edwards, Hanga Galfalvy, Daniel F. Levey, Adriana Lori, Andrey Shabalin, Anna Starnawska, Mei-Hsin Su, Hunna J. Watson, Mark Adams, Swapnil Awasthi, Michael Gandal, Jonathan D. Hafferty, Akitoyo Hishimoto, Minsoo Kim, Satoshi Okazaki, Ikuo Otsuka, Stephan Ripke, Erin B. Ware, Andrew W. Bergen, Wade H. Berrettini, Martin Bohus, Harry Brandt, Xiao Chang, Wei J. Chen, Hsi-Chung Chen, Steven Crawford, Scott Crow, Emily DiBlasi, Philibert Duriez, Fernando Fernández-Aranda, Manfred M. Fichter, Steven Gallinger, Stephen J. Glatt, Philip Gorwood, Yiran Guo, Hakon Hakonarson, Katherine A. Halmi, Hai-Gwo Hwu, Sonia Jain, Stéphane Jamain, Susana Jiménez-Murcia, Craig Johnson, Allan S. Kaplan, Walter H. Kaye, Pamela K. Keel, James L. Kennedy, Kelly L. Klump, Dong Li, Shih-Cheng Liao, Klaus Lieb, Lisa Lilenfeld, Chih-Min Liu, Pierre J. Magistretti, Christian R. Marshall, James E. Mitchell, Eric T. Monson, Richard M. Myers, Dalila Pinto, Abigail Powers, Nicolas Ramoz, Stefan Roepke, Vsevolod Rozanov, Stephen W. Scherer, Christian Schmahl, Marcus Sokolowski, Michael Strober, Laura M. Thornton, Janet Treasure, Ming T. Tsuang, Stephanie H. Witt, D. Blake Woodside, Zeynep Yilmaz, Lea Zillich, Rolf Adolfsson, Ingrid Agartz, Tracy M. Air, Martin Alda, Lars Alfredsson, Ole A. Andreassen, Adebayo Anjorin, Vivek Appadurai, María Soler Artigas, Sandra Van der Auwera, M. Helena Azevedo, Nicholas Bass, Claiton H.D. Bau, Bernhard T. Baune, Frank Bellivier, Klaus Berger, Joanna M. Biernacka, Tim B. Bigdeli, Elisabeth B. Binder, Michael Boehnke, Marco P. Boks, Rosa Bosch, David L. Braff, Richard Bryant, Monika Budde, Enda M. Byrne, Wiepke Cahn, Miguel Casas, Enrique Castelao, Jorge A. Cervilla, Boris Chaumette, Sven Cichon, Aiden Corvin, Nicholas Craddock, David Craig, Franziska Degenhardt, Srdjan Djurovic, Howard J. Edenberg, Ayman H. Fanous, Jerome C. Foo, Andreas J. Forstner, Mark Frye, Janice M. Fullerton, Justine M. Gatt, Pablo V. Gejman, Ina Giegling, Hans J. Grabe, Melissa J. Green, Eugenio H. Grevet, Maria Grigoroiu-Serbanescu, Blanca Gutierrez, Jose Guzman-Parra, Steven P. Hamilton, Marian L. Hamshere, Annette Hartmann, Joanna Hauser, Stefanie Heilmann-Heimbach, Per Hoffmann, Marcus Ising, Ian Jones, Lisa A. Jones, Lina Jonsson, René S. Kahn, John R. Kelsoe, Kenneth S. Kendler, Stefan Kloiber, Karestan C. Koenen, Manolis Kogevinas, Bettina Konte, Marie-Odile Krebs, Mikael Landén, Jacob Lawrence, Marion Leboyer, Phil H. Lee, Douglas F. Levinson, Calwing Liao, Jolanta Lissowska, Susanne Lucae, Fermin Mayoral, Susan L. McElroy, Patrick McGrath, Peter McGuffin, Andrew McQuillin, Sarah E. Medland, Divya Mehta, Ingrid Melle, Yuri Milaneschi, Philip B. Mitchell, Esther Molina, Gunnar Morken, Preben Bo Mortensen, Bertram Müller-Myhsok, Caroline Nievergelt, Vishwajit Nimgaonkar, Markus M. Nöthen, Michael C. O’Donovan, Roel A. Ophoff, Michael J. Owen, Carlos Pato, Michele T. 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J., Wasserman, D., Coon, H., Demontis, D., Docherty, A. R., Kuo, P. -H., Mann, J. J., Renteria, M. E., Stein, M. B., Willour, V., Psychiatry, Biological Psychology, APH - Methodology, APH - Mental Health, APH - Health Behaviors & Chronic Diseases, AMS - Sports, AMS - Ageing & Vitality, APH - Personalized Medicine, Amsterdam Neuroscience - Complex Trait Genetics, Complex Trait Genetics, Institute for Molecular Medicine Finland, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Genomics of Neurological and Neuropsychiatric Disorders, HUS Psychiatry, Department of Public Health, Clinicum, Nuorisopsykiatria, Faculty Common Matters (Faculty of Social Sciences), Samuli Olli Ripatti / Principal Investigator, Complex Disease Genetics, Biostatistics Helsinki, Anna Keski-Rahkonen / Principal Investigator, Elisabeth Ingrid Maria Widen / Principal Investigator, Genomic Discoveries and Clinical Translation, Internal medicine, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Digital Health, Mullins N., Kang J., Campos A.I., Coleman J.R.I., Edwards A.C., Galfalvy H., Levey D.F., Lori A., Shabalin A., Starnawska A., Su M.-H., Watson H.J., Adams M., Awasthi S., Gandal M., Hafferty J.D., Hishimoto A., Kim M., Okazaki S., Otsuka I., Ripke S., Ware E.B., Bergen A.W., Berrettini W.H., Bohus M., Brandt H., Chang X., Chen W.J., Chen H.-C., Crawford S., Crow S., DiBlasi E., Duriez P., Fernandez-Aranda F., Fichter M.M., Gallinger S., Glatt S.J., Gorwood P., Guo Y., Hakonarson H., Halmi K.A., Hwu H.-G., Jain S., Jamain S., Jimenez-Murcia S., Johnson C., Kaplan A.S., Kaye W.H., Keel P.K., Kennedy J.L., Klump K.L., Li D., Liao S.-C., Lieb K., Lilenfeld L., Liu C.-M., Magistretti P.J., Marshall C.R., Mitchell J.E., Monson E.T., Myers R.M., Pinto D., Powers A., Ramoz N., Roepke S., Rozanov V., Scherer S.W., Schmahl C., Sokolowski M., Strober M., Thornton L.M., Treasure J., Tsuang M.T., Witt S.H., Woodside D.B., Yilmaz Z., Zillich L., Adolfsson R., Agartz I., Air T.M., Alda M., Alfredsson L., Andreassen O.A., Anjorin A., Appadurai V., Soler Artigas M., Van der Auwera S., Azevedo M.H., Bass N., Bau C.H.D., Baune B.T., Bellivier F., Berger K., Biernacka J.M., Bigdeli T.B., Binder E.B., Boehnke M., Boks M.P., Bosch R., Braff D.L., Bryant R., Budde M., Byrne E.M., Cahn W., Casas M., Castelao E., Cervilla J.A., Chaumette B., Cichon S., Corvin A., Craddock N., Craig D., Degenhardt F., Djurovic S., Edenberg H.J., Fanous A.H., Foo J.C., Forstner A.J., Frye M., Fullerton J.M., Gatt J.M., Gejman P.V., Giegling I., Grabe H.J., Green M.J., Grevet E.H., Grigoroiu-Serbanescu M., Gutierrez B., Guzman-Parra J., Hamilton S.P., Hamshere M.L., Hartmann A., Hauser J., Heilmann-Heimbach S., Hoffmann P., Ising M., Jones I., Jones L.A., Jonsson L., Kahn R.S., Kelsoe J.R., Kendler K.S., Kloiber S., Koenen K.C., Kogevinas M., Konte B., Krebs M.-O., Landen M., Lawrence J., Leboyer M., Lee P.H., Levinson D.F., Liao C., Lissowska J., Lucae S., Mayoral F., McElroy S.L., McGrath P., McGuffin P., McQuillin A., Medland S.E., Mehta D., Melle I., Milaneschi Y., Mitchell P.B., Molina E., Morken G., Mortensen P.B., Muller-Myhsok B., Nievergelt C., Nimgaonkar V., Nothen M.M., O'Donovan M.C., Ophoff R.A., Owen M.J., Pato C., Pato M.T., Penninx B.W.J.H., Pimm J., Pistis G., Potash J.B., Power R.A., Preisig M., Quested D., Ramos-Quiroga J.A., Reif A., Ribases M., Richarte V., Rietschel M., Rivera M., Roberts A., Roberts G., Rouleau G.A., Rovaris D.L., Rujescu D., Sanchez-Mora C., Sanders A.R., Schofield P.R., Schulze T.G., Scott L.J., Serretti A., Shi J., Shyn S.I., Sirignano L., Sklar P., Smeland O.B., Smoller J.W., Sonuga-Barke E.J.S., Spalletta G., Strauss J.S., Swiatkowska B., Trzaskowski M., Turecki G., Vilar-Ribo L., Vincent J.B., Volzke H., Walters J.T.R., Shannon Weickert C., Weickert T.W., Weissman M.M., Williams L.M., Wray N.R., Zai C.C., Ashley-Koch A.E., Beckham J.C., Hauser E.R., Hauser M.A., Kimbrel N.A., Lindquist J.H., McMahon B., Oslin D.W., Qin X., Mattheisen M., Abdellaoui A., Adams M.J., Agerbo E., Andlauer T.F.M., Bacanu S.-A., Baekvad-Hansen M., Beekman A.T.F., Bryois J., Buttenschon H.N., Bybjerg-Grauholm J., Cai N., Christensen J.H., Clarke T.-K., Colodro-Conde L., Couvy-Duchesne B., Crawford G.E., Davies G., Derks E.M., Direk N., Dolan C.V., Dunn E.C., Eley T.C., Escott-Price V., Hassan Kiadeh F.F., Finucane H.K., Frank J., Gaspar H.A., Gill M., Goes F.S., Gordon S.D., Weinsheimer S.M., Wellmann J., Willemsen G., Wu Y., Xi H.S., Yang J., Zhang F., Arolt V., Boomsma D.I., Dannlowski U., de Geus E.J.C., Depaulo J.R., Domenici E., Domschke K., Esko T., Grove J., Hall L.S., Hansen C.S., Hansen T.F., Herms S., Hickie I.B., Homuth G., Horn C., Hottenga J.-J., Hougaard D.M., Howard D.M., Jansen R., Jorgenson E., Knowles J.A., Kohane I.S., Kraft J., Kretzschmar W.W., Kutalik Z., Li Y., Lind P.A., MacIntyre D.J., MacKinnon D.F., Maier R.M., Maier W., Marchini J., Mbarek H., Middeldorp C.M., Mihailov E., Milani L., Mondimore F.M., Montgomery G.W., Mostafavi S., Nauck M., Ng B., Nivard M.G., Nyholt D.R., O'Reilly P.F., Oskarsson H., Hayward C., Heath A.C., Lewis G., Li Q.S., Madden P.A.F., Magnusson P.K., Martin N.G., McIntosh A.M., Metspalu A., Mors O., Nordentoft M., Paciga S.A., Pedersen N.L., Painter J.N., Pedersen C.B., Pedersen M.G., Peterson R.E., Peyrot W.J., Posthuma D., Quiroz J.A., Qvist P., Rice J.P., Riley B.P., Mirza S.S., Schoevers R., Schulte E.C., Shen L., Sigurdsson E., Sinnamon G.C.B., Smit J.H., Smith D.J., Stefansson H., Steinberg S., Streit F., Strohmaier J., Tansey K.E., Teismann H., Teumer A., Thompson W., Thomson P.A., Thorgeirsson T.E., Traylor M., Treutlein J., Trubetskoy V., Uitterlinden A.G., Umbricht D., der Auwera S.V., van Hemert A.M., Viktorin A., Visscher P.M., Wang Y., Webb B.T., Perlis R.H., Porteous D.J., Schaefer C., Stefansson K., Tiemeier H., Uher R., Werge T., Lewis C.M., Breen G., Borglum A.D., Sullivan P.F., O'Connell K.S., Coombes B., Qiao Z., Als T.D., Borte S., Charney A.W., Drange O.K., Gandal M.J., Hagenaars S.P., Ikeda M., Kamitaki N., Krebs K., Panagiotaropoulou G., Schilder B.M., Sloofman L.G., Winsvold B.S., Won H.-H., Abramova L., Adorjan K., Al Eissa M., Albani D., Alliey-Rodriguez N., Antilla V., Antoniou A., Baek J.H., Bauer M., Beins E.C., Bergen S.E., Birner A., Boen E., Brum M., Brumpton B.M., Brunkhorst-Kanaan N., Byerley W., Cairns M., Cervantes P., Cruceanu C., Cuellar-Barboza A., Cunningham J., Curtis D., Czerski P.M., Dale A.M., Dalkner N., David F.S., Dobbyn A.L., Douzenis A., Elvsashagen T., Ferrier I.N., Fiorentino A., Foroud T.M., Forty L., Frei O., Freimer N.B., Frisen L., Gade K., Garnham J., Gelernter J., Gizer I.R., Gordon-Smith K., Greenwood T.A., Ha K., Haraldsson M., Hautzinger M., Heilbronner U., Hellgren D., Holmans P.A., Huckins L., Johnson J.S., Kalman J.L., Kamatani Y., Kittel-Schneider S., Koromina M., Kranz T.M., Kranzler H.R., Kubo M., Kupka R., Kushner S.A., Lavebratt C., Leber M., Lee H.-J., Levy S.E., Lewis C., Lundberg M., Magnusson S.H., Maihofer A., Malaspina D., Maratou E., Martinsson L., McGregor N.W., McKay J.D., Medeiros H., Millischer V., Moran J.L., Morris D.W., Muhleisen T.W., O'Brien N., O'Donovan C., Olde Loohuis L.M., Oruc L., Papiol S., Pardinas A.F., Perry A., Pfennig A., Porichi E., Raj T., Rapaport M.H., Regeer E.J., Rivas F., Roth J., Roussos P., Ruderfer D.M., Senner F., Sharp S., Shilling P.D., Slaney C., Sobell J.L., Artigas M.S., Spijker A.T., Stein D.J., Terao C., Toma C., Tooney P., Tsermpini E.-E., Vawter M.P., Vedder H., Xi S., Xu W., Kay Yang J.M., Young A.H., Young H., Zandi P.P., Zhou H., HUNT All-In Psychiatry, Babadjanova G., Backlund L., Bengesser S., Blackwood D.H.R., Carr V.J., Catts S., Dikeos D., Etain B., Ferentinos P., Gawlik M., Gershon E.S., Henskens F., Hillert J., Hong K.S., Hultman C.M., Hveem K., Iwata N., Jablensky A.V., Kirov G., Lochner C., Loughland C., Mathews C.A., McMahon F.J., Michie P., Mowry B., Neale B.M., Nievergelt C.M., Oedegaard K.J., Olsson T., Pantelis C., Patrinos G.P., Reininghaus E.Z., Saito T., Schall U., Schalling M., Scott R.J., Weickert C.S., Stordal E., Vaaler A.E., Vieta E., Waldman I.D., Zwart J.-A., Nurnberger J.I., Stahl E.A., Di Florio A., Adan R.A.H., Ando T., Aschauer H., Baker J.H., Bencko V., Birgegard A., Boden J.M., Boehm I., Boni C., Perica V.B., Buehren K., Bulik C.M., Burghardt R., Carlberg L., Cassina M., Clementi M., Cone R.D., Courtet P., Crowley J.J., Danner U.N., Davis O.S.P., de Zwaan M., Dedoussis G., Degortes D., DeSocio J.E., Dick D.M., Dina C., Dmitrzak-Weglarz M., Martinez E.D., Duncan L.E., Egberts K., Mattingsdal M., McDevitt S., Meulenbelt I., Micali N., Mitchell J., Mitchell K., Monteleone P., Monteleone A.M., Munn-Chernoff M.A., Nacmias B., Navratilova M., Ntalla I., Olsen C.M., O'Toole J.K., Padyukov L., Palotie A., Pantel J., Papezova H., Parker R., Pearson J.F., Ehrlich S., Escaramis G., Espeseth T., Estivill X., Farmer A., Favaro A., Fischer K., Floyd J.A.B., Focker M., Foretova L., Forzan M., Franklin C.S., Gambaro G., Giuranna J., Giusti-Rodriquez P., Gonidakis F., Gordon S., Mayora M.G., Guillaume S., Hanscombe K.B., Hatzikotoulas K., Hebebrand J., Helder S.G., Henders A.K., Herpertz-Dahlmann B., Herzog W., Hinney A., Horwood L.J., Hubel C., Petersen L.V., Purves K.L., Raevuori A., Reichborn-Kjennerud T., Ricca V., Ripatti S., Ritschel F., Roberts M., Rybakowski F., Santonastaso P., Scherag A., Schmidt U., Schork N.J., Schosser A., Seitz J., Slachtova L., Slagboom P.E., Slof-Op 't Landt M.C.T., Slopien A., Soranzo N., Sorbi S., Southam L., Steen V.W., Huckins L.M., Hudson J.I., Imgart H., Inoko H., Janout V., Jordan J., Julia A., Kalsi G., Kaminska D., Kaprio J., Karhunen L., Karwautz A., Kas M.J.H., Kennedy M.A., Keski-Rahkonen A., Kiezebrink K., Kim Y.-R., Kirk K.M., Klareskog L., Knudsen G.P.S., Larsen J.T., Le Hellard S., Leppa V.M., Lichtenstein P., Lin B.D., Lundervold A., Luykx J., Maj M., Mannik K., Marsal S., Stuber G.D., Szatkiewicz J.P., Tachmazidou I., Tenconi E., Tortorella A., Tozzi F., Tsitsika A., Tyszkiewicz-Nwafor M., Tziouvas K., van Elburg A.A., van Furth E.F., Wade T.D., Wagner G., Walton E., Whiteman D.C., Wichmann H.E., Widen E., Yao S., Zeggini E., Zerwas S., Zipfel S., Jungkunz M., Dietl L., Schwarze C.E., Dahmen N., Schott B.H., Mobascher A., Crivelli S., Dennis M.F., Harvey P.D., Carter B.W., Huffman J.E., Jacobson D., Madduri R., Olsen M.K., Pestian J., Gaziano J.M., Muralidhar S., Ramoni R., Beckham J., Chang K.-M., O'Donnell C.J., Tsao P.S., Breeling J., Huang G., Romero J.P.C., Moser J., Whitbourne S.B., Brewer J.V., Aslan M., Connor T., Argyres D.P., Stephens B., Brophy M.T., Humphries D.E., Selva L.E., Do N., Shayan S., Cho K., Pyarajan S., Hauser E., Sun Y., Zhao H., Wilson P., McArdle R., Dellitalia L., Mattocks K., Harley J., Zablocki C.J., Whittle J., Jacono F., Gutierrez S., Gibson G., Hammer K., Kaminsky L., Villareal G., Kinlay S., Xu J., Hamner M., Mathew R., Bhushan S., Iruvanti P., Godschalk M., Ballas Z., Ivins D., Mastorides S., Moorman J., Gappy S., Klein J., Ratcliffe N., Florez H., Okusaga O., Murdoch M., Sriram P., Yeh S.S., Tandon N., Jhala D., Aguayo S., Cohen D., Sharma S., Liangpunsakul S., Oursler K.A., Whooley M., Ahuja S., Constans J., Meyer P., Greco J., Rauchman M., Servatius R., Gaddy M., Wallbom A., Morgan T., Stapley T., Sherman S., Ross G., Tsao P., Strollo P., Boyko E., Meyer L., Gupta S., Huq M., Fayad J., Hung A., Lichy J., Hurley R., Robey B., Striker R., Erlangsen A., Kessler R.C., Porteous D., Ursano R.J., Wasserman D., Coon H., Demontis D., Docherty A.R., Kuo P.-H., Mann J.J., Renteria M.E., Stein M.B., and Willour V.

Subjects
LD SCORE REGRESSION, Genome-wide association study, Suicide, Attempted, 3124 Neurology and psychiatry, 0302 clinical medicine, Risk Factors, Insomnia, Suicide attempt, GWAS, Suïcidi, Depression (differential diagnoses), Cause of death, Psychiatry, 0303 health sciences, Factors de risc en les malalties, Mental Disorders, Genetic Correlation, Genome-wide Association Study, Pleiotropy, Polygenicity, Suicide, Suicide Attempt, DEPRESSION, 3. Good health, Genetic correlation, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Depressive Disorder, Major, Mental illness, Cohort, SEX, medicine.symptom, Human, medicine.medical_specialty, Risk factors in diseases, BF, Locus (genetics), BEHAVIORS, Psykiatri, EVENTS, 03 medical and health sciences, SDG 3 - Good Health and Well-being, medicine, ddc:610, GENOME-WIDE ASSOCIATION, IDEATION, Socioeconomic status, METAANALYSIS, Biological Psychiatry, 030304 developmental biology, business.industry, Risk Factor, Genetic architecture, THOUGHTS, RC0321, business, Malalties mentals, 030217 neurology & neurosurgery
Abstract

Statistical analyses were carried out on the NL Genetic Cluster Computer (http://www.geneticcluster.org) hosted by SURFsara and the Mount Sinai high performance computing cluster (http://hpc.mssm.edu), which is supported by the Office of Research Infrastructure of the National Institutes of Health (Grant Nos. S10OD018522 and S10OD026880). This work was conducted in part using the resources of the Advanced Computing Center for Research and Education at Vanderbilt University, Nashville, TN. This work was funded by the National Institutes of Health (Grant Nos. R01MH116269 and R01MH121455 [to DMR]), NIGMS of the National Institutes of Health (Grant No. T32GM007347 [to JK]), and the Brain & Behavior Research Foundation (NARSAD Young Investigator Award No. 29551 [to NM])., BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders., Office of Research Infrastructure of the National Institutes of Health S10OD018522 S10OD026880, United States Department of Health & Human Services, National Institutes of Health (NIH) - USA R01MH116269 R01MH121455, NIH National Institute of General Medical Sciences (NIGMS) T32GM007347 NARSAD 29551

Published
2022

39. The impact of body mass index and height on risk for primary tumours of the spinal cord, spinal meninges, spinal and peripheral nerves in 1.7 million norwegian women and men: a prospective cohort study

Author

Anamaria Gheorghiu, Cathrine Brunborg, Tom B. Johannesen, Eirik Helseth, John A. Zwart, and Markus K. H. Wiedmann

Subjects
Adult, Male, Glioma, Hematology, General Medicine, Body Height, Body Mass Index, Cohort Studies, Meninges, Oncology, Risk Factors, Meningeal Neoplasms, Humans, Female, Radiology, Nuclear Medicine and imaging, Peripheral Nerves, Prospective Studies, Spinal Cord Neoplasms
Abstract

Primary tumours of the spinal cord, spinal meninges, spinal and peripheral nerves comprise a heterogenous group of pathology, dominantly represented by meningioma, nerve sheath tumours (NST) and glioma. Body height and body mass index (BMI) are risk factors for certain brain tumour subgroups, but no other study has specifically assessed height and BMI in relation to primary tumours of the spine and peripheral nerves in women and men.In this prospective population-based cohort study height and weight were measured in 1.7 million adult Norwegian women and men at baseline. Incident cases of primary tumours arising from the spinal cord, spinal meninges, spinal and peripheral nerves during follow-up were identified by linkage to the National Cancer Registry. Tumour risk was assessed by Cox regression analyses in relation to height and BMI.During 49 million person-years of follow-up, 857 primary tumours of the spinal cord, spinal meninges, spinal and peripheral nerves were identified. Overweight and obesity were not associated with risk for all tumours or any tumour subgroup. Height was positively associated with risk for all tumours (HR per 10 cm increase: 1.30, 95% CI 1.16-1.46). The association between height and tumour risk varied between tumour subgroups: while height was not significantly associated with NST, height increased the risk for meningioma (HR 1.42, 95% CI 1.13-1.78) and glioma (HR 1.56, 95% CI 1.06-2.28). The strongest association between height and tumour risk was found for the glioma subgroup of ependymoma in women (HR 3.38, 95% CI 1.64-6.94).This study could not identify overweight and obesity as risk factors for primary tumours of the spinal cord, spinal meninges, spinal and peripheral nerves in women or men. Increasing body height was associated with increased tumour risk overall, but not universal for all tumour subgroups.Importance of the studyPrimary tumours of the spinal cord, spinal meninges, spinal and peripheral nerves have received little focus in epidemiologic studies, although the incidence and histo-pathological tumour subgroups differ significantly from primary brain tumours. Risk factors for these tumours have hardly been assessed in previous studies. Height, overweight and obesity are known risk factors for several cancers, including certain brain tumour subgroups, such as meningioma.This is the first study to report the association between height, overweight and obesity and primary tumours of the spinal cord, spinal meninges, spinal and peripheral nerves. This includes tumour subgroups of meningioma, nerve sheath tumour, glioma and the most common spinal glioma subgroup of ependymoma. While overweight and obesity were not associated with either of the tumour subgroups, an association between increasing body height and risk for spinal meningioma and glioma, including ependymoma, was found. Nerve sheath tumour risk was not associated with increasing body height.

Published
2022

40. Physiologically‐based pharmacokinetic modeling to evaluate in vitro‐to‐in vivo extrapolation for intestinal P‐glycoprotein inhibition

Author

Raymond Evers, Shinji Yamazaki, and Loeckie de Zwart

Subjects
Quinidine, Adult, Male, Physiologically based pharmacokinetic modelling, Digoxin, endocrine system diseases, Metabolic Clearance Rate, RM1-950, Pharmacology, Models, Biological, Article, Young Adult, Pharmacokinetics, In vivo, medicine, polycyclic compounds, Humans, Pharmacology (medical), Computer Simulation, Drug Interactions, ATP Binding Cassette Transporter, Subfamily B, Member 1, P-glycoprotein, biology, Dose-Response Relationship, Drug, integumentary system, Chemistry, Research, Transporter, Articles, Middle Aged, In vitro, female genital diseases and pregnancy complications, Dabigatran, Intestines, carbohydrates (lipids), Verapamil, Modeling and Simulation, Area Under Curve, biology.protein, Female, Therapeutics. Pharmacology, Itraconazole, medicine.drug
Abstract

As one of the key components in model‐informed drug discovery and development, physiologically‐based pharmacokinetic (PBPK) modeling linked with in vitro‐to‐in vivo extrapolation (IVIVE) is widely applied to quantitatively predict drug–drug interactions (DDIs) on drug‐metabolizing enzymes and transporters. This study aimed to investigate an IVIVE for intestinal P‐glycoprotein (Pgp, ABCB1)‐mediated DDIs among three Pgp substrates, digoxin, dabigatran etexilate, and quinidine, and two Pgp inhibitors, itraconazole and verapamil, via PBPK modeling. For Pgp substrates, assuming unbound Michaelis‐Menten constant (K m) to be intrinsic, in vitro‐to‐in vivo scaling factors for maximal Pgp‐mediated efflux rate (J max) were optimized based on the clinically observed results without co‐administration of Pgp inhibitors. For Pgp inhibitors, PBPK models utilized the reported in vitro values of Pgp inhibition constants (K i), 1.0 μM for itraconazole and 2.0 μM for verapamil. Overall, the PBPK modeling sufficiently described Pgp‐mediated DDIs between these substrates and inhibitors with the prediction errors of less than or equal to ±25% in most cases, suggesting a reasonable IVIVE for Pgp kinetics in the clinical DDI results. The modeling results also suggest that Pgp kinetic parameters of both the substrates (K m and J max) and the inhibitors (K i) are sensitive to Pgp‐mediated DDIs, thus being key for successful DDI prediction. It would also be critical to incorporate appropriate unbound inhibitor concentrations at the site of action into PBPK models. The present results support a quantitative prediction of Pgp‐mediated DDIs using in vitro parameters, which will significantly increase the value of in vitro studies to design and run clinical DDI studies safely and effectively.

Published
2022

41. Current Practices, Gap Analysis, and Proposed Workflows for PBPK Modeling of Cytochrome P450 Induction: An Industry Perspective

Author

Tamara D. Cabalu, Mengyao Li, Kenichi Umehara, Dermot F. McGinnity, Neil Parrott, Kunal S Taskar, Arian Emami Riedmaier, Micaela B Reddy, Hugues Chanteux, Martin E. Dowty, Justine Badée, Jialin Mao, Jayaprakasam Bolleddula, Loeckie de Zwart, Jessica Rehmel, Dwaipayan Mukherjee, Chandra Prakash, Niresh Hariparsad, Masakatsu Kotsuma, Diane Ramsden, Karthik Venkatakrishnan, Venkatesh Pilla Reddy, and Kushal Shah

Subjects
Pharmacology, Physiologically based pharmacokinetic modelling, Knowledge management, Computer science, business.industry, Drug-drug interaction, Pharmacokinetic modeling, Survey result, Gap analysis, Models, Biological, Workflow, Cytochrome P-450 Enzyme System, Cytochrome P-450 CYP3A, Humans, Computer Simulation, Drug Interactions, Pharmacology (medical), business
Abstract

The International Consortium for Innovation and Quality (IQ) Physiologically Based Pharmacokinetic (PBPK) Modeling Induction Working Group (IWG) conducted a survey across participating companies around general strategies for PBPK modeling of induction, including experience with its utility to address various questions, regulatory interactions, and regulatory acceptance. The results highlight areas where PBPK modeling is used with high confidence and identifies opportunities where confidence is lower and further evaluation is needed. To enhance the survey results, the PBPK-IWG also collected case studies and analyzed recent literature examples where PBPK models were applied to predict CYP3A induction-mediated drug-drug interactions. PBPK modeling of induction has evolved and progressed significantly, proving to have great potential to accelerate drug discovery and development. With the aim of enabling optimal use for new molecular entities that are either substrates and/or inducers of CYP3A, the PBPK-IWG proposes initial workflows for PBPK application, discusses future trends, and identifies gaps that need to be addressed.

Published
2021

42. Icosapent Ethyl Reduces Ischemic Events in Patients With a History of Previous Coronary Artery Bypass Grafting: REDUCE-IT CABG

Author

Subodh Verma, Deepak L. Bhatt, Ph. Gabriel Steg, Michael Miller, Eliot A. Brinton, Terry A. Jacobson, Nitish K. Dhingra, Steven B. Ketchum, Rebecca A. Juliano, Lixia Jiao, Ralph T. Doyle, Craig Granowitz, C. Michael Gibson, Duane Pinto, Robert P. Giugliano, Matthew J. Budoff, R. Preston Mason, Jean-Claude Tardif, Christie M. Ballantyne, Fabrice M.A.C. Martens, Astrid Schut, Brian Olshansky, Mina Chung, Al Hallstrom, Lesly Pearce, Cyrus Mehta, Rajat Mukherjee, Anjan K. Chakrabarti, Eli V. Gelfand, Megan Carroll Leary, Duane S. Pinto, Yuri B. Pride, Steven Ketchum, Ramakrishna Bhavanthula, Gertrude Chester, Christina Copland, Katelyn Diffin, Ralph Doyle, Kurt Erz, Alex Giaquinto, Paula Glanton, Angela Granger, Richard H. Iroudayassamy, Rebecca Juliano, James Jin, Dimitry Klevak, Hardik Panchal, Robert Wang, Shin-Ru Wang, Gerard Abate, Peggy J. Berry, Rene Braeckman, Declan Doogan, Anne Elson, Amy HauptmannBaker, Isabel Lamela, Catherine Lubeck, Mehar Manku, Sabina Murphy, Monica Sanford, William Stirtan, Paresh Soni, Arnaud Bastien, Demetria Foster, Evangelito Gascon, Judith Johnson, Lasbert Latona, Gang Liu, Sandra Palleja, Nelly Sanjuan, Jimmy Shi, William Stager, Mukund Venkatakrishnan, Ahmed Youssef-Agha, Julie Zhu, Leela Aertker, Suresh Ankolekar, Lisa Goldberg, Natasa Rajicic, Jianfen Shu, Heng Zou, Magdy Mikhail, Gamil Dawood, N. Mathew Koshy, Sandip K. Mukherjee, Rafik Abadier, Andrea L. Lawless, William P. McGuinn, Howard Weintraub, Kathryn Rohr, Edmund Claxton, Robert J. Weiss, Terry D. Klein, Mani Nallasivan, Stephen Crowley, Marilyn King, Anthony D. Alfieri, David Fitz-Patrick, Irving Loh, Nolan J. Mayer, Rakesh Prashad, Samuel Lederman, Debra Weinstein, Harold E. Bays, Keith Chu, Alireza Maghsoudi, Paul D. Thompson, Jeff Carstens, Anna Chang, Kenneth R. Cohen, Julius Dean, Howard S. Ellison, Bernard Erickson, Enrique A. Flores, Daniel W. Gottlieb, Paul Grena, John R. Guyton, Peter H. Jones, John M. Joseph, Norman E. Lepor, Sam Lerman, Robert D. Matheney, Theodore R. Pacheco, Michael B. Russo, John Rubino, Edward S. Pereira, Albert A. Seals, Eduardo Viera, Alan D. Steljes, Jason Thompson, Shaival Kapadia, Michael McIvor, Jorge E. Salazar, Jose O. Santiago, Ralph Vicari, Martin R. Berk, William A. Kaye, Marcus McKenzie, David Podlecki, Brian D. Snyder, Stephen Nash, David M. Herrington, Wallace Johnson, Joseph R. Lee, Ronald Blonder, Alpa M. Patel, Ramon Castello, Susan Greco, Dean J. Kereiakes, Venkatesh K. Nadar, Mark Nathan, Ranganatha P. Potu, Robert Sangrigoli, Richard Smalling, Mitchell Davis, Robert Braastad, James McCriskin, Kunal Bodiwala, Joe L. Hargrove, Mark W. Graves, George Emlein, Raegan W. Durant, James W. Clower, Rohit Arora, Narendra Singh, Lisa Warsinger Martin, W Herbert Haught, Marc P. Litt, Michael D. Klein, Peter Hoagland, Michael Goldstein, Marco S. Mazzella, Daniel H. Dunker, Brian H. Kahn, Carlos S. Ince, Frank A. McGrew, Jay Lee, David Pan, Salman A. Khan, Uri Elkayam, Wasim Deeb, Anne C. Goldberg, Christopher S. Brown, Wayne N. Leimbach, Thomas S. Backer, David R. Sutton, Joel Gellman, Anu R. George, Alan S. Hoffman, Mark Kates, Kishlay Anand, Robert Bear, Brendan J. Cavanaugh, Ramon G. Reyes, Rodolfo Sotolongo, Kenneth Sabatino, Kevin Gallagher, Ehab Sorial, Chris Geohas, Kathleen E. Magness, Bernard P. Grunstra, Frederik A. Martin, William S. Knapp, Mel E. Lucas, John J. Champlin, Jason Demattia, Patrick H. Peters, Judith Kirstein, William J. Randall, Cezar S. Staniloae, Jennifer G. Robinson, Alexander Adler, Christopher Case, Andrew J. Kaplan, Gregory F. Lakin, Krishan K. Goyle, Michael J. DiGiovanna, Chester L. Fisher, Michael Lillestol, Michael Robinson, Robert G. Perry, Lawrence S. Levinson, Brian G. Everhart, Robert D. Madder, Earl F. Martin, Earl E. Martin, Imtiaz Alam, Jose Mari L. Elacion, Robina Poonawala, Taddese T. Desta, Jerome A. Robinson, Gilbert J. Martinez, Jakkidi S. Reddy, Jeffrey D. Wayne, Samuel Mujica Trenche, Westbrook I. Kaplan, Rubin H. Saavedra, Michael D. DiGregorio, Barry D. Bertolet, Neil J. Fraser, Terence T. Hart, Ronald J. Graf, David A. Jasper, Michael Dunn, Dan A. Streja, David J. Strobl, Nan Jiang, Vicki Kalen, Richard Mascolo, Mercedes B. Samson, Michael Stephens, Bret M. Bellard, Mario Juarez, Patrick J. McCarthy, John B. Checton, Michael Stillabower, Edward Goldenberg, Amin H. Karim, Naseem Jaffrani, Robert C. Touchon, Erich R. Fruehling, Clayton J. Friesen, Pradipta Chaudhuri, Frank H. Morris, Robert E. Broker, Rajesh J. Patel, Susan Hole, Randall P. Miller, Francisco G. Miranda, Sadia Dar, Shawn N. Gentry, Paul Hermany, Charles B. Treasure, Miguel E. Trevino, Raimundo Acosta, Anthony Japour, Samuel J. Durr, Thomas Wang, Om P. Ganda, Perry Krichmar, James L. Arter, Douglas Jacoby, Michael A. Schwartz, Amer Al-Karadsheh, Nelson E. Gencheff, John A. Pasquini, Richard Dunbar, Sarah Kohnstamm, Hector F. Lozano, Francine K. Welty, Thomas L. Pitts, Brian Zehnder, Salah El Hafi, Mark A. King, Arnold Ghitis, Marwan M. Bahu, Hooman Ranjbaran Jahromi, Ronald P. Caputo, Robert S. Busch, Michael D. Shapiro, Suhail Zavaro, Munib Daudjee, Shahram Jacobs, Vipul B. Shah, Frank Rubalcava, Mohsin T. Alhaddad, Henry Lui, Raj T. Rajan, Fadi E. Saba, Mahendra Pai N Gunapooti, Tshiswaka B. Kayembe, Timothy Jennings, Robert A. Strzinek, Michael H. Shanik, Pradeep K. Singh, Alastair C. Kennedy, Howard Rubenstein, Ramin Manshadi, Joanne Ladner, Lily Kakish, Ashley Kakish, Amy L. Little, Jaime Gerber, Nancy J. Hinchion, Janet Guarino, Denise Raychok, Susan Budzinski, Kathleen Kelley-Garvin, April Beckord, Jessica Schlinder, Arthur Schwartzbard, Stanley Cobos, Deborah Freeman, David Abisalih, Dervilla McCann, Kylie Guy, Jennifer Chase, Stacey Samuelson, Madeline Cassidy, Marissa Tardif, Jaime Smith, Brenna Sprout, Nanette Riedeman, Julie Goza, Lori Johnson, Chad Kraske, Sheila Hastings, Chris Dutka, Stephanie Smith, Toni McCabe, Kathleen Maloney, Paul Alfieri, Vinay Hosemane, Chanhsamone Syravanh, Cindy Pau, April Limcoiloc, Tabitha Carreira, Taryn S. Kurosawa, Razmig Krumian, Krista Preston, Ashraf Nashed, Daria Schneidman-Fernandez, Jack Patterson, John Tsakonas, Jennifer Esaki, Lynn Sprafka, Porous Patel, Brian Mitchell, Erin M. Ross, Donna Miller, Akash Prashad, Kristina M. Feyler, Natasha Juarbe, Sandra Herrera, Sarah M. Keiran, Becky Whitehead, Whitney Asher, Coury Hobbs, Abbey Elie, Jean Brooks, Amanda L. Zaleski, Brenda Foxen, Barb Lapke, Philippa Wright, Bristol Pavol, Gwen Carangi, Marla Turner, Katharine W. Sanders, Rikita S. Delamar, Virginia L. Wilson, Sarah M. Harvel, Alison M. Cartledge, Kaitlyn R. Bailey, Kathleen Mahon, Timothy Schuchard, Jen Humbert, Mark C. Hanson, Michael P. Cecil, James S. Abraham, Lorie Benedict, Claudia Slayton, Curtis S. Burnett, Rachel W. Ono-Lim, Sharon Budzinski, Shubi A. Khan, Sharon Goss, Terry Techmanski, Farida Valliani, Rimla Joseph, Edith Flores, Laurn Contreras, Ana Aguillon, Carrie-Ann Silvia, Maria Martin, Edmund K. Kerut, Leslie W. Levenson, Louis B. Glade, Brian J. Cospolich, Maureen W. Stein, Stephen P. LaGuardia, Thelma L. Sonza, Tracy M. Fife, Melissa Forschler, Jasmyne Watts, Judy Fritsch, Emese Futchko, Sarah Utech, Scott B. Baker, Miguel F. Roura, Scott A. Segel, James S. Magee, Cathy Jackson, Rebecca F. Goldfaden, Liudmila Quas, Elizabeth C. Ortiz, Michael Simpson, Robert Foster, Christopher Brian, James Trimm, Michael Bailey, Brian Snoddy, Van Reeder, Rachel Wilkinson, Harold Settle, Cynthia Massey, Angela Maiola, Michele Hall, Shelly Hall, Wanda Hall, Mark Xenakis, Janet Barrett, Giovanni Campanile, David Anthou, Susan F. Neill, Steven Karas, Enrique Polanco, Norberto Schechtman, Grace Tischner, Kay Warren, Cynthia St Cyr, Menna Kuczinski, Latrina Alexander, Maricruz Ibarra, Barry S. Horowitz, Jaime Steinsapir, Jeanette Mangual-Coughlin, Brittany Mooney, Precilia Vasquez, Kathleen Rodkey, Alexandria Biberstein, Christine Ignacio, Irina Robinson, Marcia Hibberd, Lisa B. Hoffman, Daniel J. Murak, Raghupathy Varavenkataraman, Theresa M. Ohlson Elliott, Linda A. Cunningham, Heather L. Palmerton, Sheri Poole, Jeannine Moore, Helene Wallace, Ted Chandler, Robert Riley, Farah Dawood, Amir Azeem, Michael Cammarata, Ashleigh Owen, Shivani Aggarwal, Waqas Qureshi, Mohamed Almahmoud, Abdullahi Oseni, Adam Leigh, Erin Barnes, Adam Pflum, Amer Aladin, Karen Blinson, Vickie Wayne, Lynda Doomy, Michele Wall, Valerie Bitterman, Cindi Young, Rachel Grice, Lioubov Poliakova, Jorge Davalos, David Rosenbaum, Mark Boulware, Heather Mazzola, J. Russell Strader, Russell Linsky, David Schwartz, Elizabeth Graf, Alicia Gneiting, Melissa Palmblad, Ashley Donlin, Emily Ensminger, Hillary Garcia, Dawn Robinson, Carolyn Tran, Jeffrey Jacqmein, Darlene Bartilucci, Michael Koren, Barbara Maluchnik, Melissa Parks, Jennifer Miller, Cynthia DeFosse, Albert B. Knouse, Amy Delancey, Stephanie Chin, Thomas Stephens, Mag Sohal, Juana Ingram, Swarooparani Kumar, Heather Foley, Nina Smith, Vera McKinney, Linda Schwarz, Judith Moore, Hildreth Vernon Anderson, Stefano Sdringola-Maranga, Ali Denktas, Elizabeth Turrentine, Rhonda Patterson, John Marshall, Terri Tolar, Donna Patrick, Pamela Schwartzkopf, Anthony M. Fletcher, Frances R. Harris, Sherry Clements, Tiffany Brown, William Smith, Stacey J. Baehl, Robin Fluty, Daniel VanHamersveld, Dennis Breen, Nancy Bender, Beverly Stafford, Tamika Washington, Margaret N. Pike, Mark A. Stich, Evyan Jawad, Amin Nadeem, Jill Nyland, Rhonda Hamer, Kendra Calhoun, Charlotte Mall, Samuel Cadogan, Kati Raynes, Richard Katz, Lorraine Marshall, Rashida Abbas, Jay L. Dinerman, John T. Hartley, Beth Lamb, Lisa Eskridge, Donna Raymond, Kristy Clemmer, Denise M. Fine, Paula Beardsley, Janet Werner, Bette Mahan, Courtney VanTol, Robert Herman, Christine Raiser-Vignola, Felicia McShan, Stefanie A. Neill, David R. Blick, Michael J. Liston, Denetta K. Nelson, Sandra K. Dorrell, Patricia Wyman, Ambereen Quraishi, Fernando Ferro, Frank Morris, Vicki J. Coombs, Autumn M. Mains, Austin A. Campbell, Jeanne Phelps, Cheryl A. Geary, Ellen G. Sheridan, Jean M. Downing, Arie Swatkowski, Tish Redden, Brian Dragutsky, Susan Thomas, Candace Mitchell, Diana Barker, Elanie Turcotte, Deborah Segerson, Jill Guy, Karena De La Mora, Jennifer Hong, Dennis Do, Rose Norris, Faisal Khan, Hector Montero, Stacy Kelly-White, Alan Cleland, Rosalyn Alcalde-Crawford, Melissa Morgan, Brijmohan Sarabu, Megan Minor, Shweta Kamat, Stephanie M. Estes, Nancee Harless, Alicia Disney, Jodi L. Pagano, Chad M. Alford, Noel W. Bedwell, Warren D. Hardy, Kevin DeAndrade, Jessica G. Elmore, Eric Auerbach, Anthony W. Haney, Miriam H. Brooks, Jose Torres, Lois Roper, Terry Backer, Katie Backer, John G. Evans, Ricardo A. Silva, Lorraine H. Dajani, Veronica Yousif, Tammy Ross, Sion K. Roy, Ronald Oudiz, Sajad Hamal, Ferdinand Flores, Amor Leahy, Debra Ayer, Swapna George, Chrisi Carine Stewart, Elvira Orellana, Cristina Boccalandro, Mary Rangel, Suzanne Hennings, Carl Vanselow, Teri Victor, Darlene Birdwell, Paul Haas, Anthony Sandoval, Gina Ciavarella, Caroline Saglam, Amy Bird, Keith Beck, Brian Poliquin, David Dominguez, Brittany Tenorio, Harvonya Perkins, Esther San Roman, Paris Bransford, Christy Lowrance, Marcy Broussard, Mary Ellis, Bobbi Skiles, Jessica Hamilton, Kathryn Hall, Diego Olvera, Julee A. Hartwell, Nevien Sorial, Mary Rickman, Kevin Berman, Nirav Mehta, Annie Laborin, Rodger Rothenberger, Sarah Beauvilliers, Kathy Morrell, Michael P. Schachter, Cindy L. Perkins, Elizabeth A. Gordon, Jennifer Lauer, Kim Bichsel, Kelly Oliver, Leslie J. Mellor, Candice Demattia, Jennifer Schomburg, Yenniffer Moreno, Eduardo Mansur-Garza, Lena Rippstein, Lorie Chacon, Andrea Pena, Michelle King, Susan Richardson, Annette Jessop, Nicole Tucker, Whitney Royer, Gilbert Templeton, Ann Moell, Christine Weller, Melissa J. Botts, Gretel Hollon, Elsa Homberg-Pinassi, Paula Forest, Aref Bin Abhulhak, Devona Chun-Furlong, Deborah Harrington, Emily Harlynn, Marjorie Schmitt, Constance Shelsky, Patricia Feldick, Mary Cherrico, Courtney Jagle, Nicholas Warnecke, Debra Myer, Deanna J. Ruder, Albina Underwood, Alan Rauba, George Carr, Barbara Oberhaus, Jessica Vanderfeltz, Mary Jo Stucky-Heil, Dale R. Gibson, Vonnie Fuentes, Kimberly L. Talbot, William C. Simon, Katlyn J. Grimes, Christina R. Wheeler, Cassaundra Shultz, Rhonda A. Metcalf, Jennifer L. Hill, Michelle R. Oliver, Basharat Ahmad, Fouzal Azeem, Abdul Rahim, George H. Freeman, Dawn Bloch, Heather Freeman, Jamie Brown, Sarah Rosbach, Pamela Melander, Nick Taralson, Alex Liu, Katlyn Harms, Mahfouz Michale, Jose Lopez, Maria Revoredo, Shari Edevane, Sarah Shawley, Timothy L. Jackson, Michael J. Oliver, Dina DeSalle, Patricia J. Matlock, Ionna M. Beraun, Heather Hendrix, Garrett Bromley, Ashley Niemerski, Gabby Teran, Sonia Guerrero, Murtaza Marvi, Zehra Palanpurwala, Andrea Torres, Patty Gloyd, Michelle Conger, Aziz Laurent, Olia Nayor, Catalina S. Villanueva, Munira Khambati, Tabetha J. Mumford, Melanie J. Castillo, Taddese Desta, Jerome Robinson, La Shawn Woods, Anita Bahri, Nancy Herrera, Cecilia Casaclang, Jeffrey R. Unger, Geraldine Martinez, Mia K. Moon, Stephen M. Mohaupt, Larry Sandoval, Louisito Valenzuela, Victora Ramirez, Nelly Mata, Veronica Avila, Marisol Patino, Cynthia Montano-Pereira, Omar Barnett, William M. Webster, Lorraine M. Christensen, Leighna Bofman, Melanie Livingston, Stacey Adams, Joseph Hobbs, Leesa Koskela, Mia Katz, Samuel Mujica-Trenche, Franklin Cala, Noreen T. Rana, Jennifer Scarlett, Milagros Cala Anaya, Marsha R. Jones, Kelly D. Hollis, Debbie Roth, Kristin Eads, Tina Watts, Judy Perkins, Alice Arnold, Daniel C. Ginsberg, Denise Quinn, Nicole Cureton, David B. Fittingoff, Mohammed I. Iqbal, Stephen R. White, Edith Sisneros, Michelle Ducca, David Streja, Danny Campos, Jennifer L. Boak, Farzeen Amir, Felice Anderson, James J. Kmetzo, Mary O. Bongarzone, Dawn Scott, Mary Grace De Leon, Cynthia Buda, William Graettinger, Michelle Alex, Erika Hess, James Govoni, Melissa Bartel, Travis L. Monchamp, Julie S. Roach, Sara Gibson, Amy M. Allfrey, Kristen Timpy, Kathy Bott, Karin A. Soucy, Jean Willis, Cecilia A. Valerio, Anusha Chunduri, Rebecca Coker, Nicole Vidrine, Ellen A. Thompson, Mark A. Studeny, Melissa K. Marcum, Tammy S. Monway, Douglas L. Kosmicki, Melissa J. Kelley, Corey M. Godfrey, Susan L. Krenk, Randy R. Holcomb, Deb K. Baehr, Mary K. Trauernicht, David Rowland Lowry, Betty Bondy Herts, Jeanne E Phelps, Jean-Marie Downing, Carol Gamer Dignon, Elisabeth S. Cockrill, Pravinchandra G. Chapla, Diane Fera, Margaret Chang, Patricia Fredette, Tamie Ashby, Renee Bergin, Zebediah A. Stearns, David B. Ware, Rachael M. Boudreaux, Joanna Rodriguez, Robert McKenzie, Amanda Huber, Rebecca Sommers, Heather Rowe, Stacy McLallen, Michale Haynes, Ashley Adamson, Janice Henderson, Lori McClure, Beverly A. Harris, Laura Ference, Sue Meissner-Dengler, Lisa Treasure, Doreen Nicely, Timothy L. Light, Tracey A. Osborn, Kimberly J. Mai, Pablo Vivas, Jose Rios, Dunia Rodriguez, Roger DeRaad, James Walder, Oscar Bailon, Denice Hockett, Debbie Anderson, Kelli McIntosh, Amber Odegard, Andrew Shepherd, Mary Seifert, Laurence Kelley, Rajendra Shetty, Michael Castine, David Brill, Gregory Fisher, Nicole Richmond, Kathleen Gray, Patricia Miller, Charlene Coneys, Yarixa Chanza, Monica Sumoza, Victoria M. Caudill, Kelly D. Harris, Courtney A. Manion, Melody J. Lineberger-Moore, Julie J. Wolfe, Barbara J. Rosen, Patricia DiVito, Janet L. Moffat, Christina Michaelis, Prashant Koshy, Diana Perea, Ghaith Al Yacoub, Stephanie Sadeghi, Thomas D. LeGalley, Rudolph F. Evonich, William J. Jean, Gary M. Friesen, John M. Pap, David A. Pesola, Mark D. Cowan, Kristofer M. Dosh, Dianna Larson, Adele M. Price, Jodi A. Nease, Jane E. Anderson, Lori A. Piggott, Robert Iwaoka, Kevin Sharkey, Edward McMillan, Laurie Lowder, Latisha Morgan, Kyle Davis, Tara Caldwell, Erica Breglio, Jasmine Summers, Rachel Poulimas, Muhammad Zahid, Hamid Syed, Maria Escobar, Jacob Levy, Rahma Warsi, Carol Ma, Puxiao Cen, Kimberly A. Cawthon, Delores B. Barnes, Deanna G. Allen, Margaret L. Warrington, Carol R. Stastny, Robin J. Michaels, Mohamad Saleh, John Sorin, Sunny Rathod, Urakay Juett, Steven Spencer, Aziza Keval, Jill McBride, Shane Young, Catherine Baxter, Carol Rasmussen, Shari L. Coxe, Luis Campos, Shahin Tavackoli, Diana Beckham, Darlynee Sanchez, Karanjit Basrai, Dorian Helms, Erica Clinton, Kasie Smith, Henry Cusnir, Mary Klaus Clark, Madhavagopal V. Cherukuri, Ameta Scarfaru, Stephen D. Nash, Loretta C. Grimm, Anna Grace, Kylie McElheran, Dino Subasic, Zedrick Buhay, Janet Litvinoff, Deepak Shah, Shannon Cervantes, Freda Usher, Farra Yasser, Theodore Trusevich, Ronnie L. Garcia, Jamison Wyatt, Rahul Bose, Holllilyn Miska, Traci Spivey, Amy B. Wren, Katie E. Vance, Lani L. Holman, Pam Gibbons, Elaine Eby, Sandra Shepard, Soratree Charoenthongtrakul, Brett Snodgrass, Mohammed Nazem, Shelly Keteenburg, Prathima Murthy, Frederic Prater, Ashley Rumfelt, Christina Eizensmits, Lisa Iannuzzi, Pourus R. Patel, Clellia Bergamino, Elizabeth McFeaters, Botros Rizk, Emiljia Pflaum, Danny Kalish, Rex Ambatali, Mona Ameli, Delaina Sanguinetti, Rakesh Vaidya, Martinus A.W. Broeders, Dorman Henrikus, Adrianus F.M. Kuijper, Nadea Al-Windy, Michael Magro, Karim Hamraoui, Ismail Aksoy, Guy L.J. Vermeiren, H.W.O. Roeters van Lennep, Gerard Hoedemaker, Johannes Jacobus Remmen, Kjell Bogaard, Dirk van der Heijden, Nicole MJ Knufman, Joost Frederiks, Johannes Willem Louwerenburg, Piet van Rossum, Johannes Milhous, Peter van der Meer, Arno van der Weerdt, Rob Breedveld, Mitran Keijzers, Walter Hermans, Ruud van de Wal, Peter A.G. Zwart, Marc M.J.M. van der Linden, Gerardus Zwiers, Dirk J. Boswijk, Jan Geert Tans, Jacob van Eck, Maarten V. Hessen, Barnabas J.B. Hamer, Stieneke Zoet-Nugteren, Lucien Theunissen, E.A. van Beek, Remco Nijmeijer, Pieter R. Nierop, Gerard Linssen, H.P. Swart, Timo Lenderink, Gerard L. Bartels, Frank den Hartog, Brian J. Berg van den, Wouter van Kempen, Susanne Kentgens, Gloria M. Rojas Lingan, Martinus M. Peeters, Hilligje Keterberg, Melchior Nierman, Annemieke K. den Hollander, Jacqueline Hoogendijk, Christine Voors-Pette, Vicdan Kose, Peter Viergever, Larysa Yena, Viktor Syvolap, Mykola P. Kopytsya, Olga Barna, Svitlana S. Panina, Mykhailo I. Lutai, Oxana V. Shershnyova, Iryna Luzkiv, Larysa S. Bula, Sergii Zotov, Ivan Vyjhovaniuk, Olena Lysunets, Volodymyr I. Koshlia, Nataliya Sydor, Myroslava F. Vayda, Olexiy Ushakov, Mykola Rishko, Viktor P. Shcherbak, Yevgeniya Svyshchenko, Vira Tseluyko, Andriy Yagensky, Viktoriia I. Zolotaikina, Olga Godlevska, Larysa Ivanova, Olena Koval, Olena I. Mitchenko, Galyna Y. Kardash, Yurii S. Rudyk, Mykola Stanislavchuk, Volodymyr Ivanovych Volkov, Olena G. Karlinskaya, Susanna A. Tykhonova, Nikolay Vatutin, Ganna Smirnova, Volodymyr M. Kovalenko, Viktor Lizogub, Denys Sebov, Oleksandr Dyadyk, Svetlana Andrievskaya, Mykola P. Krasko, Alexander N. Parkhomenko, Lidiya Horbach, Iryna G. Kupnovytska, Tetyana Pertseva, Oleksandr Karpenko, Dmytro Reshotko, Svitlana V. Zhurba, Leonid Rudenko, Viktoriia Yu Zharinova, Valerii B. Shatylo, Yuriy I. Karpenko, Mariya A. Orynchak, Tatiana R. Kameneva, Elena Zherlitsina, Diana N. Alpenidze, Grigoriy P. Arutyunov, Elena Baranova, Boris Bart, Dmitriy I. Belenkiy, Svetlana A. Boldueva, Elena A. Demchenko, Vera V. Eltishcheva, Alexander M. Gofman, Boris M. Goloshchekin, Ivan Gennadyevich Gordeev, Nikolay Gratsianskiy, Gadel Kamalov, Niyaz R. Khasanov, Irina M. Kholina, Zhanna D. Kobalava, Elena V. Kobeleva, Alexandra O. Konradi, Victor A. Kostenko, Andrey Dmitrievich Kuimov, Polina Y. Ermakova, Sofia K. Malyutina, Alexey V. Panov, Natalia V. Polezhaeva, Olga Reshetko, Nataliya P. Shilkina, Sergey B. Shustov, Elena A. Smolyarchuk, Raisa I. Stryuk, Elena Yurievnar Solovieva, Andrey V. Susekov, Natalia Vezikova, Svetlana N. Ivanova, Alexander A. Petrov, Vladimir O. Konstantinov, Alina S. Agafina, Victor Gurevich, Konstantin N. Zrazhevskiy, Tatiana V. Supryadkina, Nikita B. Perepech, Vadim L. Arkhipovskiy, Dmitry Yu Butko, Irina A. Zobenko, Olga V. Orlikova, Viktor Mordovin, Olga L. Barbarash, Anastasiya Lebedeva, Vladimir Nosov, Oleg V. Averkov, Elena P. Pavlikova, Yuri B. Karpov, Marina Lvovna Giorgadze, Oleg A. Khrustalev, Mikhail Arkhipov, Tatiana A. Raskina, Julia V. Shilko, Yulia Samoilova, Elena D. Kosmacheva, Sergey V. Nedogoda, Kathleen Coetzee, Lesley J. Burgess, F.C.R. Theron, Iftikhar O. Ebrahim, Gerbrand A. Haasbroek, Maria Pretorius, Julien S. Trokis, Dorothea V. Urbach, Mark J. Abelson, Adrian R. Horak, Aysha E. Badat, Ellen M. Makotoko, Hendrik Du Toit Theron, Padaruth Ramlachan, Clive H. Corbett, Ismail H. Mitha, Hendrik F.M. Nortje, Dirkie J. Jansen van Rensburg, Peter J. Sebastian, F.C.J. Bester, Louis J. van Zyl, Brian L. Rayner, Elżbieta Błach, Magda Dąbrowska, Grzegorz Kania, Agata E. Kelm-Warchol, Leszek P. Kinasz, Janusz Korecki, Mariusz Kruk, Ewa Laskowska-Derlaga, Andrzej Madej, Krzysztof Saminski, Katarzyna Wasilewska, Katarzyna Szymkowiak, Małgorzata Wojciechowska, Natalia Piorowska, Andrzej Dyczek, Rajpal K. Abhaichand, Ramesh B. Byrapaneni, Basavanagowdappa Hattur, Malipeddi Bhaskara Rao, Nitin Ghaisas, Sujit Shankar Kadam, Jugal B. Gupta, Santhosh M. Jayadev, V.A. Kothiwale, Atul Mathur, Vijay Bhaskar, Ravi K. Aluri, Udaya P. Ponangi, Mukesh K. Sarna, Sunil Sathe, Manish K. Sharma, Jilendra Pal Singh Sawhney, Chakrabhavi B. Keshavamurthy, Arun Srinivas, Hemant P. Thacker, A. Sharda, Johny Joseph, Sunil Dwivedi, Viswanathan Mohan, Rajendra K. Premchand, Jacques Bedard, Jean Bergeron, Ronald Collette, David Crowley, Richard Dumas, Sam Henein, Geoff Moran, William F. O’Mahony, Michael O’Mahony, Sammy Chan, Mark H. Sherman, Graham C. Wong, Brian D. Carlson, Milan K. Gupta, David Borts, Sean R. Peterson, Martyn Chilvers, Allan J. Kelly, Jean C. Gregoire, Simon Kouz, Josep Rodés Cabau, Minodora Andor, Mircea Cinteza, Radu Ciudin, Radu I. Cojan, Roxana O. Darabont, Dan-Lucian Dumitrascu, Carmen Fierbinteanu-Braticievici, Ana Gabriela Fruntelata, Constantin Militaru, Bogdon E. Minescu, Doina Luminita Serban, Florin Mitu, Dorel Nastase Melicovici, Ovidiu Petrascu, Octavian M. Pirvu, Cristian Podoleanu, Calin Pop, Rodica-Valentina V. Stanescu-Cioranu, Adrian Tase, Cristina Voiculet, Constantine N. Aroney, Anthony M. Dart, Timothy Davis, Karam Kostner, David N. O’Neal, Peter W. Purnell, Bhuwanendu B. Singh, David R. Sullivan, Peter Thompson, Gerald F. Watts, Adam F. Blenkhorn, John V. Amerena, Rafeeq Samie, Randall Hendriks, Joseph Proietto, Nikolai Petrovsky, Alan Whelan, David Colquhoun, Russell S. Scott, Simon C. Young, Tammy Pegg, Samuel JS Wilson, Andrew W. Hamer, Richard A. Luke, Hamish H. Hart, Gerard P. Devlin, Gerard T. Wilkins, Ian F. Ternouth, Samraj Nandra, Bruno S. Loeprich, Nicole McGrath, Stuart L. Tie, Rob J. Bos, Alexandra Wils, Tamara Jacobs, Erik A. Badings, Lillian A. Ebels-Tuinbeek, Mayke L. Scholten, Esther Bayraktar-Verver, Debby Zweers, Manoek Schiks, Carolien Kalkman, Tineke Tiemes, Jeanette Mulderij, Katarzyna Dabrowska, Wilma Wijnakker, Riny Van de Loo, Jeanne de Graauw, Giny Reijnierse, Mirjam van der Zeijst, Mariska Scholten, Henk R. Hofmeijer, Antoinette van Dijk-van der Zanden, Dineke J. van Belle, Jan Van Es, Gera Van Buchem, Wendy Zijda, Harald Verheij, Linnea Oldenhof-Janssen, Martina Bader, Marije Löwik, Sandra Stuij, Pascal Vantrimpont, Krista van Aken, Karen Hamilton, Han Blömer, Gabriela van Laerhoven, Raymond Tukkie, Maarten Janssen, Gerard Verdel, Jon Funke Küpper, Bob van Vlies, Caroline Kalkman, Joke Vooges, Marinella Vermaas, Rachel Langenberg, Niek Haenen, Frans Smeets, Arko Scheepmaker, Marcel Grosfeld, Ilvy Van Lieshout, Marleen van den Berg, Marian Wittekoek, Petra Mol, Antionette Stapel, Margaretha Sierevogel, Nancy van der Ven, Annemiek Berkelmans, Eric Viergever, Hanneke Kramer, Wilma Engelen, Karen V. Houwelingen, Thierry X. Wildbergh, Arend Mosterd, Coriet Hobé-Rap, Marjan van Doorn, Petra Bunschoten, Michel Freericks, Mireille Emans, Petra Den Boer-Penning, Els Verlek, Christine Freericks, Cornelis de Nooijer, Christina Welten, Ingrid Groenenberg, Claudia van der Horst, Esther Vonk, Geert Tjeerdsma, Gerard M. Jochemsen, Corinne van Daalen, Ingrid Y. Danse, Lucy Kuipers, Anke Pieterse, Antonius Oomen, Daan de Waard, Willem Jan Flu, Zusan Kromhout, Petra Van der Bij, Rob Feld, Brigitta Hessels-Linnemeijer, Rob Lardinois, Jan L. Posma, Zwanette R. Aukema-Wouda, Marjolijn Hendriks-van Woerden, Desiree van Wijk, Driek P. Beelen, Ingrid H. Hendriks, Jan J. Jonker, Stefanie Schipperen, Vicdan Köse, Gloria Rojas, Linda Goedhart, Hanneke van Meurs, Jacqueline Rijssemus, Lindy Swinkels-Diepenmaat, Marloes de Louw-Jansen, Dominique Bierens-Peters, Willem W. van Kempen, Marianne E. Wittekoek, Irmaina Agous, Geert Schenk, Janneke Wittekoek, Kevin Cox, Deborah F. Julia, Jan J.C. Jonker, Roel Janssen, Melchor Nierman, Hilligje Katerberg, Irene van der Haar, Willem W. Van Kempen, Taco van Mesdag, Leyda M. Alvarez Costa, Manon Schensema, Salomé Zweekhorst, Deborah Font Julia, Lauri Hanewinckel, Joyce Olsthoorn, Johan C. Berends, Arie C. van der Spek, Roy van der Berg, Rob J. Timmermann, Ingrid Boerema, Iryna Mudruk, Anna Khrystoforova, Serhii Kyselov, Yaroslava V. Hilova, Pavlo Logoida, Nataliia A. Sanina, Ilona P. Golikova, Olena O. Nemchyna, Ivan I. Isaichikov, Olga B. Potapova, Iurii V. Gura, Larysa Berestetska, Olena O. Kulianda, Oleksandr Tantsura, Oleksandr S. Kulbachuk, Volodymyr Petsentiy, Ihor Biskub, Tetyana Handych, Oleg Lagkuti, Alyna Gagarina, Taras Chendey, Oksana F. Bilonko, Olena Matova, Larysa Bezrodna, Olena Yarynkina, Tetiana Ovdiienko, Volodymyr Randchenko, Maryna Mospan, Olena Butko, Olga Romanenko, Mykhailo Pavelko, Iryna Sichkaruk, Svitlana O. Lazareva, Olena A. Kudryk, Inessa M. Koltsun, Tetiana Magdalits, Sergei Zadorozhniy, Kira Kompaniiets, Andrii Ivanov, Sergiy Romanenko, Pavlo Kaplan, Vadym Y. Romanov, Oksana P. Mykytyuk, Nataliia S. Zaitseva, Sergiy N. Pyvovar, Lyudmyla Burdeuna, Emerita Serdobinska, Tatiana I. Shevchenko, Igor I. Ivanytskyi, Olena V. Khyzhnyak, Nataliya Kalinkina, Olena Keting, Olena Sklyanna, Olga Kashanska, Anna Shevelok, Marina Khristichenko, Ievgenii Y. Titov, Danilenko O. Oleksander, Nataliia S. Polenova, Nataliia Altunina, Viktoriia Kororaieva, Stanislav Zborovskiy, Leonid Kholopov, Iurii Suliman, Lanna Lukashenko, Stanislav Shvaykin, Olexandr M. Glavatskiy, Roman O. Sychov, Roman L. Kulynych, Oleksandr A. Skarzhevskyi, Nataliia V. Dovgan, Marta Horbach, Olga Cherkasova, Iryna Tyshchenko, Liudmyla Todoriuk, Svitlana Kizim, Nataliia Brodi, Oleksandr Ivanko, Olga Garbarchuk, Liudmyla Alieksieieva, Tetiana L. Shandra, Olena Beregova, Larisa An Bodretska, Svitlana S. Naskalova, Ivanna A. Antoniuk-Shcheglova, Olena V. Bondarenko, Natalia G. Andreeva, Iryna I. Vakalyuk, Olha S. Chovganyuk, Nataliya R. Artemenko, Kiril A. Maltsev, Natalia Kalishevich, Natalia G. Kondratyeva, Svetlana A. Nikitina, Maria V. Martjanova, Anna V. Sokolova, Dmitrii O. Dragunov, Olga Kolesnik, Vera Larina, Oxana V. Tsygankova, Maria Ivanova, Illia A. Karpov, Elena M. Aronova, Ekaterina S. Vedernikova, Ekaterina I. Lubinskaya, Taras Y. Burak, Sergey I. Skichko, Farhad Rasulev, Ekaterina B. Soldatova, Alexander L. Fenin, Ilya I. Laptev, Elena E. Luchinkina, Alexandr Akatov, Natalia V. Polenova, Natalia N. Slavina, Irina N. Korovnika, Marina Yu Prochorova, Regina Shakirova, Elena N. Andreicheva, Olga A. Krasnova, Tinatin V. Lobzhanidze, Tatiana B. Dmitrova, Viktoriya V. Stakhiv, Maria I. Pechatnikova, Alexandra V. Panova, Maria Y. Tipikina, Oxana P. Rotar, Nikolay A. Bokovin, Saule K. Karabalieva, Farid Y. Tumarov, Elena V. Vasileva, Natalya Gennadevna Lozhkina, Ekaterina V. Filippova, Alisa I. Sharkaeva, Ekanerina V. Filippova Deilik, Natalia Yu Tolkacheva, Elena N. Domracheva, Andrey N. Ryabikov, Inga T. Abesadze, Marianna Z. Alugishvili, Elena P. Nikolaeva, Nadezda V. Smirnova, Valentina I. Rodionova, Polina V. Dolovstaya, Igor E. Yunonin, Sergey V. Kadin, Tatyana S. Sveklina, Anna V. Bushmanova, Elena L. Barkova, Irina S. Gomova, Yana V. Brytkova, Tatiana B. Ivanova, Marina Y. Zubareva, Inga Skopets, Lybov A. Galashevskaya, Emilia D. Butinskaya, Olga G. Gusarova, Natalia B. Kalishevich, Yana R. Pavlova, Marianna P Serebrenitskaya, Vitalina F. Grygorieva, Gulnara R. Kuchaeva, Inna A. Vasileva, Gulnara I. Ospanova, Yulia V. Vahrusheva, Irina A. Semenova, Irina E.E. Mikhailova, Olga O. Kvasova, Valeria D. Shurygina, Alexey E. Rivin, Alexey O. Savelyev, Alexey A. Savelyev, Olesya O. Milyaeva, Nadezhda N. Lapshina, Ninel A. Lantsova, Pavel V. Alexandrov, Evgeniy A. Orlikov, Alla Falkovskaya, Tatiana Ripp, Sergei Triss, Stanislav Pekarskiy, Sitkova Ekaterina, Evgeniya N. Zhuravleva, Olga Perova, Galina Kovaleva, Liubov Koroleva, Lydia Mishchenko, Boris P. Garshin, Svetlana A. Kutuzova, Lyudmila I. Provotorova, Igor P. Zadvorny, Olga V. Okhapkina, Anatoly O. Khrustalev, Tatiana Suvorova, Elena S. Shaf, Varvara A. Vershinina, Andrey A. Kozulin, Oxana A. Oleynik, Irina Y. Martynova, Natalia V. Kizhvatova, Alla S. Salasyuk, Vera V. Tsoma, Alla A. Ledyaeva, Elena V. Chumachek, S.C. Blignaut, Tersia Y. Alexander, Chano Du Plessis, Thirumani Govender, Samatha M. Du Toit, Leya Motala, Areesh Gassiep, Christina Naude (Smit), Marli Terblanche, Marlien Snoer (Kruger), Berenice Pillay, De Vries Basson, Marisa E. Theron, Bianca Fouche, Mareli E. Coetzee, Pieter Odendall, Frederik H. Van Wijk, Anna-Mari Conradie, Trudie Van der Westhuizen, Carine Tredoux, Mohamed S. Mookdam, Andie J. Van der Merwe, Karin Snyman, Gerda Smal, Yvonne De Jager, Thomas A. Mabin, Annusca King, Lindy L. Henley, Brenda M. Zwane, Jane Robinson, Marinda Karsten, Andonia M. Page, Valerie Nsabiyumva, Charmaine Krahenbuhl, Jaiprakash D. Patel, Yunus E. Motala, Ayesha Dawood, Nondumiso B. Koza, Lenore M.S. Peters, Shavashni Ramlachan, Wilhelm J. Bodenstein, Pierre Roux, Lizelle Fouche, Cecilia M. Boshoff, Haroon M. Mitha, Fathima Khan, Henry P. Cyster, Helen Cyster, E. C. Wessels, Florence J. Jacobs, Melanie A. Sebastian, Deborah A. Sebastian, Nadia Mahomed, Ignatius P. Immink, Celia Cotzee, Tanja Cronje, Madele Roscher, Maria Le Roux, Yvonne A. Trinder, Renata Wnętrzak-Michalska, Magdalena Piszczek, Andrzej Piela, Ewa Czernecka, Dorota Knychas, Alina Walczak, Izabella Gładysz, Katarzyna Filas, Ewelina Kiluk, Krzysztof Świgło, Iwona Jędrzejczyk, Kamila Łuczyńska, Katarzyna Tymendorf, Wojciech Piesiewicz, Wojciech L. Kinasz, Stefan Samborski, Ilona Bartuś, Gramzyna Latocha Korecka, Ewa Gulaj, Jolanta Sopa, Bogusław Derlaga, Marcin Baisiak, Allicia Kowalisko, Edyta Stainszewska-Marasazlek, Bartosz Szafran, Malgorzata Swiatkiewicz, Artur Racewicz, Sławomir Grycel, Jerzy Supronik, Sylwia Walendziuk, Magdalena Tarantowicz, Agata Stasiak, Anna Sidorowicz-Białynicka, Marek Dwojak, Ewa Jaźwińska-Tarnawska, Katarzyna Kupczyk, Kamila Martowska, Kamila Kulon, Katarzyna Gajda, Bivin Wilson, Krithika Velusamy, Swaidha S. Sadhiq, Bhavani Siddeshi, M. Bhanukumar, Abhishek Srivatsav, Madhan Ramesh, Sri Harsha Chalasani, Mini Johnson, Prashanth Gopu, Jeesa George, Sowmya Reddy, Swetha Tessy Thara Eleena, Damodara Rao Kodem, Haritha N. Nakkella, Padma Kumari Mandula, Anjan Kumar Vuriya, Syamala Rajana, Aruna Kale, Tiwari Rajeev, Raina Jain, Vipin Jain, Srilakshmi Mandayam Adhyapak, Lumin Sheeba, Uma C R, Ramya R, Aditya V. Kulkarni, M.S. Ganachari, Ruma Sambrekar, Mohammad Bilal, Kalyan Chakravarthy, Ravi Badhavath, Sravan Kumar, Meenakshi Simhadri, Farooque Salamuddin, Venkat Prasad, Vivek Dwivedi, Sudha Sarna, Tilak Arora, Deepak Chawla, Archana Sathe, Chaware Gayatree, Ajeet Nanda, Ram Avtar, Jyoti Sharma, Vaibhavi P S, Sasirekha D, Deepthi Kobbajji, Ramya Ningappa, Shwetha Shree, Chandrashekar K, Nandini M R, Sowjanya S, Devika I G, Yashaswini N, Sonika G, Rathna L, Priyanka R, Rupal J. Shrimanker, Lakshmi Vinutha Reddy, K. Sumathi, Babitha Devi, Bina N. Naik, Rohini Manjunath, Rajeshwari Ashok, Tony V. Kunjumon, Jesline Thomas, Shaik Samdhani, Kasthuri Selvam, Poongothai Subramani, Nandakumar Parthasarathy, Nirmal K. Bohra, Anvesh K. Gatla, Cheryl Horbatuk, Julie Sills, E B. Davey, Liz Paramonczyk, Olga Racanelli, Sandy Strybosch, Andre Belanger, Jean Palardy, Alicia Schiffrin, Sylvie Gauthier, Norman Kalyniuk, Shawn D. Whatley, Heather Lappala, Grishma Patel, Matthew Reeve, Catherine Moran, Jody Everitt, Teresa Ferrari, Christine Bouffard, Jirir Frohlich, Gordon Francis, John Mancini, Gregory Bondy, Debbie DeAngelis, Patricia Fulton, David W. Blank, Angela Lombardo, Mylène Roy, Jackie Chow, Hyman Fox, William J. Grootendorst, Angela Hutchinson, Sharon M. Chan, Christie Fitzgerald, Lynn Wilkins, Rebecca L. Raymond, Arlene Reyes, Lavoie Marc André, Denis Fortin, Hélène Ouimet, Thanh-Thao Tôn-Nu, Martine Dussureault, Marie-Hélène Blain, Madeleine Roy, Nathalie Kopajko, Chantal Fleury, Karine Maheux, Gabriela Valentina Ciobotaru, Maria C. Constantinescu, Carmen-Lucia Gherghinescu, Ana-Maria Avram, Ioan Manitiu, Aura Sinpetrean, Lucian Pop, Delia Lupu, Radu Usvat, Ana Petrisor, Nicoleta Dumitru, Camelia Moruju, Adelina Gheorghita, Magda V. Mitu, Cosmin Macarie, Ana Maria Pop, Maria-Catalina Diaconu, Iulia Grancea, Mihaela Cosma, Mihaela Crisan, Elizabeth Herron, Paul Nestel, Sally B. Kay, Kaye S. Carter, Imran Badshah, Ashley Makepeace, Jocelyn Drinkwater, Michelle England, Azette Rafei, Kylie Patterson, Alicia Jenkins, Sybil McAuley, Sue M. Kent, Joy E. Vibert, Leonie Perrett, Thomas David, Samantha L. Kaye, Monika O’Connor, Nimalie J. Perera, Nicole T. Lai, Kerry A. Kearins, Christinia Dicamillo, Heather Anderson, Louise Ferguson, Sharon D. Radtke, Charles T. Thamarappillil, Janice M. Boys, Anita K. Long, Toni Shanahan, Michael Nyguyen, Nicole Forrest, Gill Tulloch, Della Greenwell, Sarah L. Price, Aye N. Tint, Priya K. Sumithran, Tamara L. Debreceni, Lisa Walker, Mary Caruana, Kira Edwards, Maria Stathopoulos, Cilla Haywood, Dimitar Sajkov, Sharen Pringle, Anne Tabner, Kathrina Bartolay, Chamindi Abeyratne, Kylie Bragg, Patrick Mulhern, Peter Purnell, Lyn Williams, Jane Hamlyn, Aurelia Connelly, Jan Hoffman, Samantha Bailey, Jane Kerr, Zarnia Morrison, Sarah Maeder, Roberta McEwan, Prasanna Kunasekera, Patrice McGregor, Jo Young, Sharon Berry, Rick Cutfield, Michelle Choe, Catherine McNamara, Narrinder K. Shergill, Petra Crone, Miles G. Williams, Keith Dyson, Diana H. Schmid, Audrey C. Doak, Melissa Spooner, Colin Edwards, Anne Turner, Grainne M. McAnnalley, Raewyn A. Fisher, Fraser B. Hamilton, Denis H. Friedlander, Melissa R. Kirk, Jayne E. Scales, Marguerite A. McLelland, Neelam A. Dalman, Cathy E. Vickers, Carolyn Jackson, Wendy Coleman, Phillip I. Garden, and Wendy F. Arnold

Subjects
Male, medicine.medical_specialty, Rate ratio, Double-Blind Method, Ischemia, Risk Factors, Physiology (medical), Internal medicine, medicine, Clinical endpoint, Humans, Myocardial infarction, Coronary Artery Bypass, Stroke, Aged, business.industry, Unstable angina, Hazard ratio, Absolute risk reduction, Middle Aged, medicine.disease, Eicosapentaenoic Acid, Number needed to treat, Cardiology, Female, Cardiology and Cardiovascular Medicine, business
Abstract

Background: Despite advances in surgery and pharmacotherapy, there remains significant residual ischemic risk after coronary artery bypass grafting surgery. Methods: In REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial), a multicenter, placebo-controlled, double-blind trial, statin-treated patients with controlled low-density lipoprotein cholesterol and mild to moderate hypertriglyceridemia were randomized to 4 g daily of icosapent ethyl or placebo. They experienced a 25% reduction in risk of a primary efficacy end point (composite of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina) and a 26% reduction in risk of a key secondary efficacy end point (composite of cardiovascular death, myocardial infarction, or stroke) when compared with placebo. The current analysis reports on the subgroup of patients from the trial with a history of coronary artery bypass grafting. Results: Of the 8179 patients randomized in REDUCE-IT, a total of 1837 (22.5%) had a history of coronary artery bypass grafting, with 897 patients randomized to icosapent ethyl and 940 to placebo. Baseline characteristics were similar between treatment groups. Randomization to icosapent ethyl was associated with a significant reduction in the primary end point (hazard ratio [HR], 0.76 [95% CI, 0.63–0.92]; P =0.004), in the key secondary end point (HR, 0.69 [95% CI, 0.56–0.87]; P =0.001), and in total (first plus subsequent or recurrent) ischemic events (rate ratio, 0.64 [95% CI, 0.50–0.81]; P =0.0002) compared with placebo. This yielded an absolute risk reduction of 6.2% (95% CI, 2.3%–10.2%) in first events, with a number needed to treat of 16 (95% CI, 10–44) during a median follow-up time of 4.8 years. Safety findings were similar to the overall study: beyond an increased rate of atrial fibrillation/flutter requiring hospitalization for at least 24 hours (5.0% vs 3.1%; P =0.03) and a nonsignificant increase in bleeding, occurrences of adverse events were comparable between groups. Conclusions: In REDUCE-IT patients with a history of coronary artery bypass grafting, treatment with icosapent ethyl was associated with significant reductions in first and recurrent ischemic events. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01492361.

Published
2021

43. Differential response to prolonged amoxicillin treatment: long-term resilience of the microbiome versus long-lasting perturbations in the gut resistome

Author

Achal Dhariwal, Lars Christian Haugli Bråten, Kjersti Sturød, Gabriela Salvadori, Ahmed Bargheet, Heidi Åmdal, Roger Junges, Dag Berild, John-Anker Zwart, Kjersti Storheim, and Fernanda Cristina Petersen

Subjects
Microbiology (medical), Feces, Infectious Diseases, Microbiota, Gastroenterology, Humans, Amoxicillin, Microbiology, Gastrointestinal Microbiome, Anti-Bacterial Agents
Abstract

The collateral impact of antibiotics on the microbiome has attained increasing attention. However, the ecological consequences of long-term antibiotic exposure on the gut microbiome, including antibiotic resistance, are still limited. Here, we investigated long-term exposure effects to amoxicillin on the human gut microbiome and resistome. Fecal samples were collected from 20 patients receiving 3-months of amoxicillin or placebo treatment as part of a Norwegian multicenter clinical trial on chronic low back pain (AIM study). Samples were collected at baseline, last day of treatment, and 9 months after antibiotic cessation. The abundance and diversity of microbial and resistome composition were characterized using whole shotgun and functional metagenomic sequencing data. While the microbiome profiles of placebo subjects were stable over time, discernible changes in diversity and overall microbiome composition were observed after amoxicillin treatment. In particular, health-associated short-chain fatty acid producing species significantly decreased in proportion. However, these changes were short-lived as the microbiome showed overall recovery 9 months post-treatment. On the other hand, exposure to long-term amoxicillin was associated with an increase in total antimicrobial resistance gene load and diversity of antimicrobial resistance genes, with persistent changes even at 9 months post-treatment. Additionally, beta-lactam resistance was the most affected antibiotic class, suggesting a targeted response to amoxicillin, although changes at the gene level varied across individuals. Overall, our results suggest that the impact of prolonged amoxicillin exposure was more explicit and long-lasting in the fecal resistome than in microbiome composition. Such information is relevant for designing rational administration guidelines for antibiotic therapies.

Published
2022

44. Impact of diet on human nutrition, immune response, gut microbiome, and cognition in an isolated and confined mission environment

Author

Grace L, Douglas, Diane, DeKerlegand, Holly, Dlouhy, Nathan, Dumont-Leblond, Eden, Fields, Martina, Heer, Stephanie, Krieger, Satish, Mehta, Bridgette V, Rooney, Manolito G, Torralba, Sara E, Whiting, Brian, Crucian, Hernan, Lorenzi, Scott M, Smith, Millennia, Young, and Sara R, Zwart

Subjects
Cognition, Multidisciplinary, Fatty Acids, Omega-3, Immunity, Animals, Humans, Space Flight, Gastrointestinal Microbiome, Diet
Abstract

Long-duration spaceflight impacts human physiology, including well documented immune system dysregulation. The space food system has the potential to serve as a countermeasure to maladaptive physiological changes during spaceflight. However, the relationship between dietary requirements, the food system, and spaceflight adaptation requires further investigation to adequately define countermeasures and prioritize resources on future spaceflight missions. We evaluated the impact of an enhanced spaceflight diet, with increased quantity and variety of fruits, vegetables, fish, and other foods rich in flavonoids and omega-3 fatty acids, compared to a standard spaceflight diet on multiple health and performance outcomes in 16 subjects over four 45-day closed chamber missions in the NASA Human Exploration Research Analog (HERA). Subjects consuming the enhanced spaceflight diet had lower cholesterol levels, lower stress (i.e. cortisol levels), better cognitive speed, accuracy, and attention, and a more stable microbiome and metatranscriptome than subjects consuming the standard diet. Although no substantial changes were observed in the immune response, there were also no immune challenges, such as illness or infection, so the full benefits of the diet may not have been apparent in these analog missions. These results indicate that a spaceflight diet rich in fruits, vegetables, and omega-3 fatty acids produces significant health and performance benefits even over short durations. Further investigation is required to fully develop dietary countermeasures to physiological decrements observed during spaceflight. These results will have implications for food resource prioritization on spaceflight missions.

Published
2022

45. MYC promotes immune-suppression in triple-negative breast cancer via inhibition of interferon signaling

Author

Dario Zimmerli, Chiara S. Brambillasca, Francien Talens, Jinhyuk Bhin, Renske Linstra, Lou Romanens, Arkajyoti Bhattacharya, Stacey E. P. Joosten, Ana Moises Da Silva, Nuno Padrao, Max D. Wellenstein, Kelly Kersten, Mart de Boo, Maurits Roorda, Linda Henneman, Roebi de Bruijn, Stefano Annunziato, Eline van der Burg, Anne Paulien Drenth, Catrin Lutz, Theresa Endres, Marieke van de Ven, Martin Eilers, Lodewyk Wessels, Karin E. de Visser, Wilbert Zwart, Rudolf S. N. Fehrmann, Marcel A. T. M. van Vugt, Jos Jonkers, Guided Treatment in Optimal Selected Cancer Patients (GUTS), and Damage and Repair in Cancer Development and Cancer Treatment (DARE)

Subjects
Multidisciplinary, General Physics and Astronomy, Triple Negative Breast Neoplasms, General Chemistry, General Biochemistry, Genetics and Molecular Biology, Proto-Oncogene Proteins c-myc, Mice, Lymphocytes, Tumor-Infiltrating, Cell Line, Tumor, Tumor Microenvironment, Animals, Humans, Interferons, Signal Transduction
Abstract

The limited efficacy of immune checkpoint inhibitor treatment in triple-negative breast cancer (TNBC) patients is attributed to sparse or unresponsive tumor-infiltrating lymphocytes, but the mechanisms that lead to a therapy resistant tumor immune microenvironment are incompletely known. Here we show a strong correlation between MYC expression and loss of immune signatures in human TNBC. In mouse models of TNBC proficient or deficient of breast cancer type 1 susceptibility gene (BRCA1), MYC overexpression dramatically decreases lymphocyte infiltration in tumors, along with immune signature remodelling. MYC-mediated suppression of inflammatory signalling induced by BRCA1/2 inactivation is confirmed in human TNBC cell lines. Moreover, MYC overexpression prevents the recruitment and activation of lymphocytes in both human and mouse TNBC co-culture models. Chromatin-immunoprecipitation-sequencing reveals that MYC, together with its co-repressor MIZ1, directly binds promoters of multiple interferon-signalling genes, resulting in their downregulation. MYC overexpression thus counters tumor growth inhibition by a Stimulator of Interferon Genes (STING) agonist via suppressing induction of interferon signalling. Together, our data reveal that MYC suppresses innate immunity and facilitates tumor immune escape, explaining the poor immunogenicity of MYC-overexpressing TNBCs.

Published
2022

46. Rare SLC13A1 variants associate with intervertebral disc disorder highlighting role of sulfate in disc pathology

Author

Bjornsdottir, Gyda, Stefánsdóttir, Lilja, Thorleifsson, Gudmar, Sulem, Patrick, Norland, Kristjan, Ferkingstad, Egil, Oddsson, Asmundur, Zink, Florian, Lund, Sigrun H., Nawaz, Muhammad S., Bragi Walters, G., Skuladottir, Astros Th., Gudjonsson, Sigurjon A., Einarsson, Gudmundur, Halldorsson, Gisli H., Bjarnadottir, Valgerdur, Sveinbjornsson, Gardar, Helgadottir, Anna, Styrkársdóttir, Unnur, Gudmundsson, Larus J., Pedersen, Ole B., Hansen, Thomas Folkmann, Werge, Thomas, Banasik, Karina, Troelsen, Anders, Skou, Soren T., Thørner, Lise Wegner, Erikstrup, Christian, Nielsen, Kaspar Rene, Mikkelsen, Susan, Andersen, Steffen, Brunak, Søren, Burgdorf, Kristoffer, Hjalgrim, Henrik, Jemec, Gregor, Jennum, Poul, Johansson, Per Ingemar, Nielsen, Kasper Rene, Nyegaard, Mette, Bruun, Mie Topholm, Pedersen, Ole Birger, Dinh, Khoa Manh, Sørensen, Erik, Ostrowski, Sisse R., Johansson, Pär Ingemar, Gudbjartsson, Daniel F., Stefansson, Hreinn, Þorsteinsdóttir, Unnur, Larsen, Margit Anita Hørup, Didriksen, Maria, Sækmose, Susanne, Zeggini, Eleftheria, Hatzikotoulas, Konstantinos, Southam, Lorraine, Gilly, Arthur, Barysenka, Andrei, van Meurs, Joyce B. J., Boer, Cindy G., Uitterlinden, André G., Jonsson, Helgi, Ingvarsson, Thorvaldur, Esko, Tõnu, Mägi, Reedik, Teder-Laving, Maris, Ikegawa, Shiro, Terao, Chikashi, Takuwa, Hiroshi, Meulenbelt, Ingrid, Coutinho de Almeida, Rodrigo, Kloppenburg, Margreet, Tuerlings, Margo, Slagboom, P. Eline, Nelissen, Rob R. G. H. H., Valdes, Ana M., Mangino, Massimo, Tsezou, Aspasia, Zengini, Eleni, Alexiadis, George, Babis, George C., Cheah, Kathryn S. E., Wu, Tian T., Samartzis, Dino, Cheung, Jason Pui Yin, Sham, Pak Chung, Kraft, Peter, Kang, Jae Hee, Hveem, Kristian, Zwart, John-Anker, Luetge, Almut, Skogholt, Anne Heidi, Johnsen, Marianne B., Thomas, Laurent F., Winsvold, Bendik, Gabrielsen, Maiken E., Lee, Ming Ta Michael, Zhang, Yanfei, Lietman, Steven A., Shivakumar, Manu, Smith, George Davey, Tobias, Jonathan H., Hartley, April, Gaunt, Tom R., Zheng, Jie, Wilkinson, J. Mark, Steinberg, Julia, Morris, Andrew P., Jonsdottir, Ingileif, Bjornsson, Aron, Olafsson, Ingvar H., Ulfarsson, Elfar, Blondal, Josep, Vikingsson, Arnor, Brunak, Soren, Ullum, Henrik, Thorsteinsdottir, Unnur, Thorgeirsson, Thorgeir E., Stefansson, Kari, Consortium, DBDS Genetic, Consortium, GO, and Internal Medicine

Subjects
Science, General Physics and Astronomy, Intervertebral Disc Degeneration, Intervertebral Disc/metabolism, Bone and Bones/metabolism, Bone and Bones, General Biochemistry, Genetics and Molecular Biology, health services administration, Humans, Sodium Sulfate Cotransporter/genetics, Intervertebral Disc, 3' Untranslated Regions, health care economics and organizations, Sodium Sulfate Cotransporter, Symporters/genetics, Multidisciplinary, Symporters, Sulfates, General Chemistry, equipment and supplies, Intervertebral Disc Degeneration/genetics, Intervertebral Disc Displacement/genetics, Sulfates/metabolism, population characteristics, human activities, Intervertebral Disc Displacement, Genome-Wide Association Study
Abstract

Back pain is a common and debilitating disorder with largely unknown underlying biology. Here we report a genome-wide association study of back pain using diagnoses assigned in clinical practice; dorsalgia (119,100 cases, 909,847 controls) and intervertebral disc disorder (IDD) (58,854 cases, 922,958 controls). We identify 41 variants at 33 loci. The most significant association (ORIDD = 0.92, P = 1.6 × 10−39; ORdorsalgia = 0.92, P = 7.2 × 10−15) is with a 3’UTR variant (rs1871452-T) in CHST3, encoding a sulfotransferase enzyme expressed in intervertebral discs. The largest effects on IDD are conferred by rare (MAF = 0.07 − 0.32%) loss-of-function (LoF) variants in SLC13A1, encoding a sodium-sulfate co-transporter (LoF burden OR = 1.44, P = 3.1 × 10−11); variants that also associate with reduced serum sulfate. Genes implicated by this study are involved in cartilage and bone biology, as well as neurological and inflammatory processes.

Published
2022

47. Care for Language

Author

Hub Zwart and WP ESPhil

Subjects
Vocabulary, Health (social science), Health Policy, media_common.quotation_subject, Continental philosophy of language, Bioethics, Ambiguity, Etymology and ethics, Morals, Philosophical methodology, Epistemology, Philosophy, SDG 3 - Good Health and Well-being, Argument, Historicity, Continental bioethics, Humans, Meaning (existential), Sociology, Autonomy, media_common, Language, Original Research
Abstract

Emphasizing the importance of language is a key characteristic of philosophical reflection in general and of bioethics in particular. Rather than trying to eliminate the historicity and ambiguity of language, a continental approach to bioethics will make conscious use of it, for instance by closely studying the history of the key terms we employ in bioethical debates. Continental bioethics entails a focus on the historical vicissitudes of the key signifiers of the bioethical vocabulary, urging us to study the history of terms such as “bioethics,” “autonomy,” “privacy,” and “consensus.” Instead of trying to define such terms as clearly and unequivocally as possible, a continental approach rather requires us to take a step backwards, tracing the historical backdrop of the words currently in vogue. By comparing the original meanings of terms with their current meanings, and by considering important moments of transition in their history, obfuscated dimensions of meaning can be retrieved. Thus, notwithstanding a number of methodological challenges involved in etymological exercises, they may foster moral articulacy and enhance our ability to come to terms with moral dilemmas we are facing.

Published
2021

48. Intermediate-dose versus low-dose low-molecular-weight heparin in pregnant and post-partum women with a history of venous thromboembolism (Highlow study): an open-label, multicentre, randomised, controlled trial

Author

Ingrid M Bistervels, Andrea Buchmüller, Hanke M G Wiegers, Fionnuala Ní Áinle, Bernard Tardy, Jennifer Donnelly, Peter Verhamme, Anne F Jacobsen, Anette T Hansen, Marc A Rodger, Maria T DeSancho, Roman G Shmakov, Nick van Es, Martin H Prins, Céline Chauleur, Saskia Middeldorp, Eline S van den Akker, Mireille N Bekker, Thomas van Bemmel, Laurent Bertoletti, Julie Blanc, Suzanne M Bleker, Aude Bourtembourg-Matras, Florence Bretelle, Bridgette Byrne, Francis Couturaud, Pierre Delorme, Elise S Eerenberg, Maureen TM Franssen, Jens Fuglsang, Wessel Ganzevoort, François Goffinet, Jiska M de Haan-Jebbink, Wieteke Heidema, Monique A Hertzberg, Marcel MC Hovens, Menno V Huisman, Leonie de Jong-Speksnijder, Pieter-Willem Kamphuisen, Denis J O'Keeffe, Karine Lacut, Josje Langenveld, M Simone Lunshof, Caroline P Martens, Adel Merah, Emmanuelle Le Moigne, Dimitri NM Papatsonis, Gilles Pernod, Franck Perrotin, Edith Peynaud-Debayle, Fabrice Pierre, Geneviève Plu Bureau, Tiphaine Raia-Barjat, Robbert JP Rijnders, Roger Rosario, Marc Ruivard, Jeannot Schmidt, Marieke Sueters, Thomas Vanassche, Marie-Noëlle Varlet, Alexandre J Vivanti, Matthieu Y van der Vlist, Lucet F van der Voet, Karlijn C Vollebregt, Johanna IP de Vries, Sabina de Weerd, Peter E Westerweel, Lia DE Wijnberger, Marije ten Wolde, Paula F Ypma, Catherine Zuily-Lamy, Joost J Zwart, Alexandra Benachi, Gaël Beucher, Holy Bezanahary, Karin de Boer, Marjon A. de Boer, Frantz Bousquet, Henk A. Bremer, Luc Bressollette, Aurélie Brossard, Cécile Chau, Brian Cleary, Fabienne Comte, Thomas Corsini, Anne Coustel, Barbara Debaveye, Raoul Desbrière, Cécile Duvillard, Astrid Eckman, Jeroen Eikenboom, Antoine Elias, Laura M. Faber, Emile Ferrari, Denis Gallot, Emilie Gauchotte, Ingrid Gaugler, Abby E. Geerlings, Audrey O'Gorman, Vincent Grobost, Pieter-Kees de Groot, David P. van der Ham, Brenda Hermsen, Kim Kamphorst, Alan Karovitch, Gunilla Kleiverda, Aiste Kloster, Annemarieke Koops, Inneke Krabbendam, Marieke J.H.A. Kruip, Saskia Kuipers, Judith van Laar, Damien Laneelle, Suzanne Lima, Peter MacMahon, Laurent Mandelbrot, Claudia A. van Meir, Caroline Menez, Leonard P. Morssink, Nathalie Moulin, Eve Mousty, Matthieu Muller, Lucy Murphy, Kathelijne Peerlinck, Alma O'Reilly, Maartje de Reus, Magali Hilmi Le Roux, Kevin Ryan, Bettina Samren, Daniela Schippers, Nico Schuitemaker, Chloé Schweizer, Hanneke van der Straaten, Cécile Tromeur, Kristine Vanheule, Tamara Verhagen, Jantien Visser, Michael Watts, Wim J. van Wijngaarden, Mallory Woiski, Maartje Zelis, Obstetrics and gynaecology, AMS - Rehabilitation & Development, Amsterdam Reproduction & Development (AR&D), VU University medical center, Cardiology, ACS - Heart failure & arrhythmias, Graduate School, Vascular Medicine, ACS - Pulmonary hypertension & thrombosis, ARD - Amsterdam Reproduction and Development, ACS - Amsterdam Cardiovascular Sciences, CCA -Cancer Center Amsterdam, Obstetrics and Gynaecology, APH - Quality of Care, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, APH - Digital Health, ACS - Atherosclerosis & ischemic syndromes, RS: CAPHRI - R5 - Optimising Patient Care, MUMC+: KIO Kemta (9), Surgery, Public Health, Obstetrics & Gynecology, Hematology, and Epidemiology

Subjects
Low-Molecular-Weight/adverse effects, Male, Heparin, Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], Postpartum Period, Postpartum Hemorrhage, Heparin, Low-Molecular-Weight/adverse effects, Obstetrics and Gynecology, Anticoagulants, General Medicine, Venous Thromboembolism, Heparin, Low-Molecular-Weight, Pregnancy, Humans, Pulmonary Embolism/prevention & control, Female, Anticoagulants/adverse effects, Pulmonary Embolism, Venous Thromboembolism/drug therapy
Abstract

Item does not contain fulltext BACKGROUND: Pregnancy-related venous thromboembolism is a leading cause of maternal morbidity and mortality, and thromboprophylaxis is indicated in pregnant and post-partum women with a history of venous thromboembolism. The optimal dose of low-molecular-weight heparin to prevent recurrent venous thromboembolism in pregnancy and the post-partum period is uncertain. METHODS: In this open-label, randomised, controlled trial (Highlow), pregnant women with a history of venous thromboembolism were recruited from 70 hospitals in nine countries (the Netherlands, France, Ireland, Belgium, Norway, Denmark, Canada, the USA, and Russia). Women were eligible if they were aged 18 years or older with a history of objectively confirmed venous thromboembolism, and with a gestational age of 14 weeks or less. Eligible women were randomly assigned (1:1), before 14 weeks of gestational age, using a web-based system and permuted block randomisation (block size of six), stratified by centre, to either weight-adjusted intermediate-dose or fixed low-dose low-molecular-weight heparin subcutaneously once daily until 6 weeks post partum. The primary efficacy outcome was objectively confirmed venous thromboembolism (ie, deep-vein thrombosis, pulmonary embolism, or unusual site venous thrombosis), as determined by an independent central adjudication committee, in the intention-to-treat (ITT) population (ie, all women randomly assigned to treatment). The primary safety outcome was major bleeding which included antepartum, early post-partum (within 24 h after delivery), and late post-partum major bleeding (24 h or longer after delivery until 6 weeks post partum), assessed in all women who received at least one dose of assigned treatment and had a known end of treatment date. This study is registered with ClinicalTrials.gov, NCT01828697, and is now complete. FINDINGS: Between April 24, 2013, and Oct 31, 2020, 1339 pregnant women were screened for eligibility, of whom 1110 were randomly assigned to weight-adjusted intermediate-dose (n=555) or fixed low-dose (n=555) low-molecular-weight heparin (ITT population). Venous thromboembolism occurred in 11 (2%) of 555 women in the weight-adjusted intermediate-dose group and in 16 (3%) of 555 in the fixed low-dose group (relative risk [RR] 0·69 [95% CI 0·32-1·47]; p=0·33). Venous thromboembolism occurred antepartum in five (1%) women in the intermediate-dose group and in five (1%) women in the low-dose group, and post partum in six (1%) women and 11 (2%) women. On-treatment major bleeding in the safety population (N=1045) occurred in 23 (4%) of 520 women in the intermediate-dose group and in 20 (4%) of 525 in the low-dose group (RR 1·16 [95% CI 0·65-2·09]). INTERPRETATION: In women with a history of venous thromboembolism, weight-adjusted intermediate-dose low-molecular-weight heparin during the combined antepartum and post-partum periods was not associated with a lower risk of recurrence than fixed low-dose low-molecular-weight heparin. These results indicate that low-dose low-molecular-weight heparin for thromboprophylaxis during pregnancy is the appropriate dose for the prevention of pregnancy-related recurrent venous thromboembolism. FUNDING: French Ministry of Health, Health Research Board Ireland, GSK/Aspen, and Pfizer.

Published
2022

49. [Analysis of accidental falls and the integration in the chronicity programs of patients with amyotrophic lateral sclerosis]

Author

E, Castro-Rodríguez, R, Azagra-Ledesma, X, Gómez-Batiste Alertón, A, Aguyé-Batista, M, Zwart-Salmerón, R, Cabanas-Valdés, F M, Caballero-Gómez, and C, Clemente-Azagra

Subjects
Male, Noninvasive Ventilation, Amyotrophic Lateral Sclerosis, Quality of Life, Humans, Female, Accidental Falls, Motor Neuron Disease, Aged
Abstract

Amyotrophic lateral sclerosis (ALS) is the most common degenerative motor neuron disease. There is no curative treatment available, and these patients require multidisciplinary support to promote their comfort and quality of life.Longitudinal descriptive study in patients registered in primary care (PC), Costa de Ponent-Barcelona Institut Catala de la Salut to analyse emergency hospital visits, use of support devices and their integration into the primary care chronicity program. Variables were sex, age and evolution time, emergency visits, patients with percutaneous gastrostomy (PEG), non-invasive or invasive ventilation (NIV/VI), integration in the primary care chronicity program.81 patients, 49.4% male, mean age 65.6 years (±11.7), evolution time less than 2 years or equal to or greater than 2 years (42 and 58%, respectively). Of them, 47 (58.5%) made 107 consultations. The most frequent reasons for consultation were falls (26.8%), respiratory difficulties (23.3%), comorbidity (16.7%), eating problems (11%) and pain (10.2%) without differences by age or sex. Greater frequency (p0.001) was observed in patients with less than two years of evolution and significant increases in the use of NIV and PEG up to 51.9 and 35.8% respectively, as well as integration in primary care chronicity program of 61.7%.Accidental falls were the most frequent and potentially avoidable reason for hospital emergency visits in patients with ALS, especially in the first two years of the disease. Significant increases are detected in the use of support devices and in primary care chronicity program integration. It is necessary to increase home resources, especially in physiotherapy and occupational therapy.Análisis de las caídas accidentales y la integración en los programas de cronicidad de los pacientes con esclerosis lateral amiotrófica.Introducción. La esclerosis lateral amiotrófica (ELA) es la enfermedad degenerativa de las motoneuronas más frecuente. No dispone de tratamiento curativo y estos pacientes requieren un soporte multidisciplinar para favorecer su confort y calidad de vida. Pacientes y métodos. Estudio descriptivo longitudinal en pacientes registrados en atención primaria, Costa de Ponent-Barcelona, Institut Català de la Salut, para analizar las visitas urgentes hospitalarias, la utilización de dispositivos de soporte y su integración en el programa de atención a la cronicidad. Las variables fueron sexo, edad y tiempo de evolución, visitas urgentes, portadores de gastrostomía percutánea (PEG), ventilación no invasiva o invasiva (VNI/VI) e integración en el programa de atención a la cronicidad. Resultados. Se incluyó a 81 pacientes, un 49,4% varones, con una edad media de 65,6 años (±11,7), y un tiempo de evolución menor de 2 años o igual o mayor de 2 años (42 y 58%, respectivamente). De ellos, 47 (58,5%) realizaron 107 consultas. Los motivos de consulta más frecuentes fueron: caídas (26,8%), dificultades respiratorias (23,3%), comorbilidad (16,7%), problemas en la alimentación (11%) y dolor (10,2%), sin diferencias por edad o sexo. Se observó una mayor frecuentación (p menor de 0,001) en pacientes con menos de dos años de evolución e incrementos significativos en la utilización de la VNI y la PEG hasta el 51,9 y el 35,8%, respectivamente, así como integración en el programa de atención a la cronicidad del 61,7%. Conclusiones. El motivo más frecuente de consulta a urgencias hospitalarias de pacientes con ELA y potencialmente evitable fueron las caídas accidentales, especialmente en los primeros dos años de enfermedad. Se detectan incrementos significativos en la utilización de dispositivos de soporte y en la integración en el programa de atención a la cronicidad. Es necesario incrementar los recursos domiciliarios, especialmente en fisioterapia y terapia ocupacional.

Published
2022

50. Homing in on a Moving Target

Author

Nils Eickhoff, Andries M Bergman, and Wilbert Zwart

Subjects
Male, Neoplastic, Tumor, epigenetics, Prostatic Neoplasms/genetics, Androgen/genetics, Prostatic Neoplasms, prostate cancer, Chromatin, Cell Line, Gene Expression Regulation, Neoplastic, Endocrinology, Gene Expression Regulation, SDG 3 - Good Health and Well-being, Receptors, Androgen, Cell Line, Tumor, androgen receptor, Receptors, Humans, cistromic plasticity, Protein Binding
Abstract

The androgen receptor (AR) is the critical driver in prostate cancer and exerts its function mainly through transcriptional control. Recent advances in clinical studies and cell line models have illustrated that AR chromatin binding features are not static; rather they are highly variable yet reproducibly altered between clinical stages. Extensive genomic analyses of AR chromatin binding features in different disease stages have revealed a high degree of plasticity of AR chromatin interactions in clinical samples. Mechanistically, AR chromatin binding patterns are associated with specific somatic mutations on AR and other permutations, including mutations of AR-interacting proteins. Here we summarize the most recent studies on how the AR cistrome is dynamically altered in prostate cancer models and patient samples, and what implications this has for the identification of therapeutic targets to avoid the emergence of treatment resistance.

Published
2022

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