Publications by authors named "Janet Hall"

182 Publications

Prevalence of Hirsutism Among Reproductive-Aged African American Women.

J Womens Health (Larchmt) 2021 Sep 14. Epub 2021 Sep 14.

Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.

Hirsutism is the most common clinical symptom of hyperandrogenism, but racial and ethnic-specific thresholds have not been established. Our objective was to characterize hirsutism using self-report of hair growth in a large sample of African American women. The Study of Environment, Lifestyle, and Fibroids is a prospective community-based cohort study of African American women (23-34 at recruitment). A total of 1568 participants received the modified Ferriman-Gallwey (mFG) pictorial assessment and were asked if they were ever bothered by excess hair. We estimated the prevalence of hirsutism (mFG score ≥8) and associations of acne, polycystic ovary syndrome (PCOS), and menstrual cycle characteristics with hirsutism. We also explored hirsutism defined by the 95th percentile of scores in our cohort (mFG = 11) and a newly recommended criterion, mFG = 4. We could determine hirsutism status in 1556 women. Thirty-seven percent reported being bothered by excess hair, and 10% met the mFG criterion for hirsutism. History of severe facial acne was positively associated with hirsutism (prevalence ratio: 1.90; 95% confidence interval [CI]: 1.30-2.76), as was physician-diagnosed PCOS (2.22, 95% CI: 1.30-3.81). Women with irregular menstrual cycles were also more likely to report hirsutism (1.78, 95% CI: 1.00-3.18). Results were similar using mFG ≥11 and attenuated using mFG ≥4. Hirsutism prevalence was 10% in this community sample of African American women and was associated with PCOS, severe acne, and irregular menstrual cycles suggesting this represented hirsutism caused by hyperandrogenism. Ethnically diverse, population-based studies assessing the association between mFG score and androgen levels are needed to better understand the hirsutism threshold as a clinical marker of hyperandrogenism.
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http://dx.doi.org/10.1089/jwh.2021.0125DOI Listing
September 2021

Exploring the motivations of research participants who chose not to learn medically actionable secondary genetic findings about themselves.

Genet Med 2021 Jul 29. Epub 2021 Jul 29.

National Institutes of Health, Department of Bioethics; National Human Genome Research Institute, Bethesda, MD, USA.

Purpose: Proposals to return medically actionable secondary genetic findings (SFs) in the clinical and research settings have generated controversy regarding whether to solicit individuals' preferences about their "right not to know" genetic information. This study contributes to the debate by surveying research participants who have actively decided whether to accept or refuse SFs.

Methods: Participants were drawn from a large National Institutes of Health (NIH) environmental health study. Participants who had accepted SFs (n = 148) or refused SFs (n = 83) were given more detailed information about the types of SFs researchers could return and were given an opportunity to revise their original decision.

Results: Forty-one of 83 initial refusers (49.4%) opted to receive SFs following the informational intervention. Nearly 75% of these "reversible refusers" thought they had originally accepted SFs. The 50.6% of initial refusers who continued to refuse ("persistent refusers") demonstrated high levels of understanding of which SFs would be returned postintervention. The most prominent reason for refusing was concern about becoming worried or sad (43.8%).

Conclusion: This study demonstrates the need for a more robust informed consent process when soliciting research participants' preferences about receiving SFs. We also suggest that our data support implementing a default practice of returning SFs without actively soliciting preferences.
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http://dx.doi.org/10.1038/s41436-021-01271-1DOI Listing
July 2021

The Hypothalamic Pituitary Thyroid Axis and Sleep.

Curr Opin Endocr Metab Res 2021 Apr 24;17:8-14. Epub 2020 Oct 24.

Thyroid Tumors and Functional Thyroid Disorders Section, Metabolic Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, Maryland, USA.

Sleep has a bidirectional relationship with the hypothalamic-pituitary-thyroid (HPT) axis, and both these homeostatic processes are inter-dependent for robust physiological functioning. The quality and quantity of sleep influence the circadian pattern of TSH and thyroid hormone secretion. Short term sleep restriction significantly reduces the amplitude of nocturnal TSH secretion and may modulate active thyroid hormone secretion, likely through an increased sympathetic tone. Conversely, TSH and active thyroid hormone affect the quantity and architecture of sleep. For instance, low TSH values are permissive for slow wave sleep and maintenance of normal sleep architecture, while the hypo- or hyper-secretion of active thyroid hormones adversely affects the quality and quantity of sleep. Structural thyroid disorders may also be associated with an altered circadian clock - a phenomenon warranting further investigation. In this review, we aim to provide readers a comprehensive review on the associations between the HPT axis and sleep patterns.
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http://dx.doi.org/10.1016/j.coemr.2020.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315115PMC
April 2021

Institutional Review Board Preparedness for Disaster Research: a Practical Approach.

Curr Environ Health Rep 2021 06 11;8(2):127-137. Epub 2021 May 11.

Office of Director, National Institute of Environmental Health Sciences, Durham, NC, USA.

Purpose Of Review: Disasters are becoming more common and challenge national and global resiliency and response efforts. As a result, government agencies have increased interest in disaster research to understand their environmental impact and health-related consequences. With the research field greatly expanding, Institutional Review Boards (IRBs) are being asked to review research protocols aimed at assessing health risks, exposures, and outcomes from disaster survivors. Few IRBs have experience reviewing disaster research protocols. This article describes approaches for IRB preparedness in reviewing disaster research.

Recent Findings: From a human research protections perspective, primary attention has focused on vulnerability of individuals and/or populations affected by a disaster who may serve as research participants [3, 4]. From our review of the current literature, there is a lack of best practices and/or guidance for IRBs in the review of disaster research protocols. The growth of the disaster research field has brought more attention to potential ethical concerns of disaster research studies. Disaster survivors, responders, and those that assist in cleanup and remedial efforts may be left with significant unmet needs and long-term physical and emotional challenges as a result of their experiences. It is important for IRBs and investigators to collaboratively address how best to protect the welfare of individuals and communities affected by a disaster. A new approach is needed to systematically consider the various factors relevant to an assessment of human research protection issues following disasters.
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http://dx.doi.org/10.1007/s40572-021-00311-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111380PMC
June 2021

Scoping review of COVID-19-related systematic reviews and meta-analyses: can we really have confidence in their results?

Postgrad Med J 2021 Feb 26. Epub 2021 Feb 26.

NICHD, National Institutes of Health, Bethesda, Maryland, USA

Aim: The aim of this study was to systematically appraise the quality of a sample of COVID-19-related systematic reviews (SRs) and discuss internal validity threats affecting the COVID-19 body of evidence.

Design: We conducted a scoping review of the literature. SRs with or without meta-analysis (MA) that evaluated clinical data, outcomes or treatments for patients with COVID-19 were included.

Main Outcome Measures: We extracted quality characteristics guided by A Measurement Tool to Assess Systematic Reviews-2 to calculate a qualitative score. Complementary evaluation of the most prominent published limitations affecting the COVID-19 body of evidence was performed.

Results: A total of 63 SRs were included. The majority were judged as a critically low methodological quality. Most of the studies were not guided by a pre-established protocol (39, 62%). More than half (39, 62%) failed to address risk of bias when interpreting their results. A comprehensive literature search strategy was reported in most SRs (54, 86%). Appropriate use of statistical methods was evident in nearly all SRs with MAs (39, 95%). Only 16 (33%) studies recognised heterogeneity in the definition of severe COVID-19 as a limitation of the study, and 15 (24%) recognised repeated patient populations as a limitation.

Conclusion: The methodological and reporting quality of current COVID-19 SR is far from optimal. In addition, most of the current SRs fail to address relevant threats to their internal validity, including repeated patients and heterogeneity in the definition of severe COVID-19. Adherence to proper study design and peer-review practices must remain to mitigate current limitations.
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http://dx.doi.org/10.1136/postgradmedj-2020-139392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918809PMC
February 2021

Phenotypic continuum between Waardenburg syndrome and idiopathic hypogonadotropic hypogonadism in humans with SOX10 variants.

Genet Med 2021 04 13;23(4):629-636. Epub 2021 Jan 13.

Harvard Reproductive Sciences Center, The Reproductive Endocrine Unit and The Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.

Purpose: SOX10 variants previously implicated in Waardenburg syndrome (WS) have now been linked to Kallmann syndrome (KS), the anosmic form of idiopathic hypogonadotropic hypogonadism (IHH). We investigated whether SOX10-associated WS and IHH represent elements of a phenotypic continuum within a unifying disorder or if they represent phenotypically distinct allelic disorders.

Methods: Exome sequencing from 1,309 IHH subjects (KS: 632; normosmic idiopathic hypogonadotropic hypogonadism [nIIHH]: 677) were reviewed for SOX10 rare sequence variants (RSVs). The genotypic and phenotypic spectrum of SOX10-related IHH (this study and literature) and SOX10-related WS cases (literature) were reviewed and compared with SOX10-RSV spectrum in gnomAD population.

Results: Thirty-seven SOX10-associated IHH cases were identified as follows: current study: 16 KS; 4 nIHH; literature: 16 KS; 1 nIHH. Twenty-three IHH cases (62%; all KS), had ≥1 known WS-associated feature(s). Moreover, five previously reported SOX10-associated WS cases showed IHH-related features. Four SOX10 missense RSVs showed allelic overlap between IHH-ascertained and WS-ascertained cases. The SOX10-HMG domain showed an enrichment of RSVs in disease states versus gnomAD.

Conclusion: SOX10 variants contribute to both anosmic (KS) and normosmic (nIHH) forms of IHH. IHH and WS represent SOX10-associated developmental defects that lie along a unifying phenotypic continuum. The SOX10-HMG domain is critical for the pathogenesis of SOX10-related human disorders.
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http://dx.doi.org/10.1038/s41436-020-01051-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8335791PMC
April 2021

Environmental Factors Involved in Maternal Morbidity and Mortality.

J Womens Health (Larchmt) 2021 02 18;30(2):245-252. Epub 2020 Nov 18.

Office of Policy, Planning, and Evaluation, National Institute of Environmental Health Sciences, National Institutes of Health, U.S. Department of Health and Human Services, Durham, North Carolina, USA.

Nongenetic, environmental factors contribute to maternal morbidity and mortality through chemical exposures via air, water, soil, food, and consumer products. Pregnancy represents a particularly sensitive window of susceptibility during which physiological changes to every major organ system increase sensitivity to chemicals that can impact a woman's long-term health. Nonchemical stressors, such as low socioeconomic status, may exacerbate the effects of chemical exposures on maternal health. Racial/ethnic minorities are exposed disproportionately to both chemicals and nonchemical stressors, which likely contribute to the observed health disparities for maternal morbidities and mortality. Epidemiological studies linking exposures to adverse maternal health outcomes underscore the importance of environmental health impacts, and mechanistic studies in model systems reveal how chemicals perturb biological pathways and processes. Environmental stressors are associated with a variety of immediate maternal health impacts, including hypertensive disorders of pregnancy, fibroids, and infertility, as well as long-term maternal health impacts, such as higher risk of breast cancer and metabolic disorders. Identifying and reducing a pregnant woman's environmental exposures is not only beneficial to her offspring but also important to preserve her short- and long-term health.
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http://dx.doi.org/10.1089/jwh.2020.8855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891208PMC
February 2021

Depot Medroxyprogesterone Acetate Use and Blood Lead Levels in a Cohort of Young Women.

Environ Health Perspect 2020 11 18;128(11):117004. Epub 2020 Nov 18.

Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.

Background: Injectable contraceptive use is common, with 74 million users worldwide. Use of the injectable contraceptive depot medroxyprogesterone acetate (DMPA) is associated with bone mineral density loss. We hypothesize that increased bone resorption with DMPA use allows for mobilization of the toxic metal lead stored in bone to blood, presenting users with increased systemic exposure to lead.

Objective: The objective of our study was to investigate the association between current DMPA use and blood lead concentrations.

Methods: We conducted a cross-sectional analysis using enrollment data from the Study of Environment, Lifestyle & Fibroids (SELF), a cohort of 1,693 African-American women who were 23-35 years of age. Data on DMPA use were collected by computer-assisted telephone interview. Blood lead concentrations were measured in whole blood samples among 1,548 participants (91% of cohort). We estimated the adjusted percent difference in blood lead concentrations and 95% confidence intervals (CI) between current DMPA users and nonusers using multivariable linear regression.

Results: Geometric mean blood lead concentration was (95% CI: 0.67, 0.71). After adjustment, current DMPA users (7% of cohort) had blood lead concentrations that were 18% higher than those of nonusers (95% CI: 8%, 29%). Similar associations were observed with additional analyses to assess for potential bias from smoking, DMPA-induced amenorrhea, use of estrogen-containing contraceptives, having given birth in the prior year, and history of medical conditions or current medication use associated with bone loss.

Discussion: Our results indicate that current DMPA use is associated with increased blood lead concentrations. Further research, particularly in populations highly exposed to lead, is warranted to consider tradeoffs between the adverse effects of lead on human health and the importance of DMPA as a contraceptive option to prevent unintended pregnancy. https://doi.org/10.1289/EHP7017.
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http://dx.doi.org/10.1289/EHP7017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673223PMC
November 2020

PARP inhibitors and radiation potentiate liver cell death in vitro. Do hepatocellular carcinomas have an achilles' heel?

Clin Res Hepatol Gastroenterol 2020 Nov 9:101553. Epub 2020 Nov 9.

Univ Lyon, Université Claude Bernard Lyon 1, INSERM, CNRS, Centre Léon Bérard, Centre De Recherche En Cancérologie De Lyon, Lyon, 69008, France. Electronic address:

Background: A promising avenue for cancer treatment is exacerbating the deregulation of the DNA repair machinery that would normally protect the genome. To address the applicability of poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) combined with radiotherapy for the treatment of hepatocellular carcinoma (HCC) two approaches were used: firstly, the in vitro sensitivity to the PARPi Veliparib and Talazoparib +/- radiation exposure was determined in liver cell lines and the impact of the HBV X protein (HBx) that deregulates cellular DNA damage repair via SMC5/6 degradation was investigated. Secondly, PARP expression profiles and DNA damage levels using the surrogate marker gammaH2AX were assessed in a panel of control liver vs HCC tissues.

Methods: Cell cytotoxicity was measured by clonogenic survival or relative cell growth and the DNA damage response using immunological-based techniques in Hep3B, PLC/PRF/5, HepG2- and HepaRG-derived models. Transcriptome changes due to HBx expression vs SMC6 loss were assessed by RNA sequencing in HepaRG-derived models. PARP and PARG transcripts (qPCR) and PARP1, H2AX and gammaH2AX protein levels (RPPA) were compared in control liver vs HBV-, HCV-, alcohol- and non-alcoholic steatohepatitis-associated HCC (tumor/peritumor) tissues.

Results: PARPi cytotoxicity was significantly enhanced when combined with X-rays (2Gy) with Talazoparib having a greater impact than Veliparib in most in vitro models. HBx expression significantly lowered survival, probably driven by SMC5/6 loss based on the transcriptome analysis and higher DNA damage levels. PARP1 and PARP2 transcript levels were significantly higher in tumor than peritumor and control tissues. The HBV/HCV/alcohol-associated tumor tissues studied had reduced H2AX but higher gammaH2AX protein levels compared to peritumor and control tissues providing evidence of increased DNA damage during liver disease progression.

Conclusions: These proof-of-concept experiments support PARPi alone or combined with radiotherapy for HCC treatment, particularly for HBV-associated tumors, that warrant further investigation.
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http://dx.doi.org/10.1016/j.clinre.2020.09.014DOI Listing
November 2020

Insights into the Immunopathophysiology of Severe COVID-19 in Metabolic Disorders.

Ann Natl Acad Med Sci 2020 Apr;56(2):112-115

Section on Endocrinology & Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA.

COVID-19 has affected millions of people across the world but disproportionately and severely affects persons with metabolic disorders such as obesity, diabetes mellitus and hypertension. In this brief review, we discuss the pathways of immune dysregulation that may lead to severe COVID-19 in persons with metabolic conditions.
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http://dx.doi.org/10.1055/s-0040-1713346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571615PMC
April 2020

Hepatitis B virus preS2Δ38-55 variants: A newly identified risk factor for hepatocellular carcinoma.

JHEP Rep 2020 Oct 11;2(5):100144. Epub 2020 Jul 11.

INSERM U1052, CNRS 5286, Univ Lyon, Université Claude Bernard Lyon 1, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France.

Background & Aims: Although HBV is a major cause of death in Africa, its genetic variability has been poorly documented. This study aimed to address whether HBV genotype and surface gene variants are associated with HBV-related liver disease in The Gambia.

Methods: We conducted a case-control study nested in the Prevention of Liver Fibrosis and Cancer in Africa programme. Consecutive treatment-naive patients with chronic HBV infection and detectable viral load were recruited: 211 controls with no significant liver disease and 91 cases (56 cirrhosis and 35 HCC cases). HBV genotypes and surface gene variants were determined by Sanger sequencing or next-generation sequencing (NGS) in serum DNA. Aflatoxin B1 (AFB1)-specific codon 249 mutation was determined by NGS in circulating cell-free plasma DNA.

Results: In phylogenetic analysis, 85% of individuals carried HBV genotype E, 14% genotype A, and 1% A/E recombinant viruses. Surface gene variants were more frequently observed in cases (43% and 57% in cirrhosis and HCC cases, respectively) than controls (25%; <0.001), with preS2 deletions between nucleotides 38-55 (preS2Δ38-55) being the main genetic variant detected. In multivariable analysis, HBeAg seropositivity, low HBsAg levels, and HDV seropositivity were significantly associated with cirrhosis and HCC, whilst older age, higher viral load, genotype A, preS2Δ38-55, and AFB1 exposure were only associated with HCC. There was a multiplicative joint effect of preS2Δ38-55 variants with HBeAg seropositivity (odds ratio [OR] 43.1 [10.4-177.7]), high viral load >2,000 IU/ml (OR 22.7 [8.0-64.9]), HBsAg levels <10,000 IU/ml (OR 19.0 [5.5-65.3]), and AFB1 exposure (OR 29.3 [3.7-230.4]) on HCC risk.

Conclusions: This study identified a hotspot for HBV preS2 deletions as a strong independent factor for HCC in The Gambia, with HBV genotypes and AFB1 exposure contributing to the high liver cancer risk.

Lay Summary: Although HBV-related liver disease is highly prevalent in sub-Saharan Africa, the associated virological characteristics are poorly studied. Using clinical data from African patients chronically infected with HBV, an assessment of the virological variability (genotypes and mutations) and exposure to AFB1, a toxin often contaminating food, was carried out. Our results show that HBV genotypes, the presence of a highly prevalent mutant form of HBV, and AFB1 exposure contribute to the high liver cancer risk in this population.
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http://dx.doi.org/10.1016/j.jhepr.2020.100144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7452365PMC
October 2020

Prevalence of Diabetes and Hypertension and Their Associated Risks for Poor Outcomes in Covid-19 Patients.

J Endocr Soc 2020 Sep 21;4(9):bvaa102. Epub 2020 Jul 21.

Section on Endocrinology & Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland.

Coronavirus disease 2019 (Covid-19) has affected millions of people and may disproportionately affect those with hypertension and diabetes. Because of inadequate methods in published systematic reviews, the prevalence of diabetes and hypertension and associated risks of poor outcomes in Covid-19 patients are unknown. We searched databases from December 1, 2019, to April 6, 2020, and selected observational peer-reviewed studies in English of patients with Covid-19. Independent reviewers extracted data on study participants, interventions, and outcomes and assessed risk of bias, and the certainty of evidence. We included 65 (15 794 participants) observational studies at moderate to high risk of bias. Overall prevalence of diabetes and hypertension was 12% (95% confidence interval [CI], 10-15; n = 12 870; : 89%), and 17% (95% CI, 13-22; n = 12 709; : 95%), respectively. In severe Covid-19, the prevalence of diabetes and hypertension were 18% (95% CI, 16-20; n = 1099; : 0%) and 32% (95% CI, 16-54; n = 1078; : 63%), respectively. Unadjusted relative risk for intensive care unit admission and mortality were 1.96 (95% CI, 1.19-3.22; n = 8890; : 80%;  = .008) and 2.78 (95% CI, 1.39-5.58; n = 2058; : 75%;  = .0004) for diabetics; and 2.95 (95% CI, 2.18-3.99; n = 1737; : 0%;  < .001) and 2.39 (95% CI, 1.54-3.73; n = 3107; : 66%;  < .001) for hypertensives. Neither diabetes (1.50; 95% CI, 0.90-2.50; n = 1991; : 74%;  = .119) nor hypertension (1.48; 95% CI, 0.99-2.23; n = 2023; : 69%;  = .058) was associated with severe Covid-19. In conclusion, the risk of intensive care unit admission and mortality for patients with diabetes or hypertension who developed Covid-19 is increased compared with those without these comorbidities.

Prospero Registration Number: CRD42020176582.
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http://dx.doi.org/10.1210/jendso/bvaa102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454711PMC
September 2020

Increased Burden of Rare Sequence Variants in GnRH-Associated Genes in Women With Hypothalamic Amenorrhea.

J Clin Endocrinol Metab 2021 03;106(3):e1441-e1452

National Institute of Environmental Health Sciences, National Institutes of Health (NIH), Research Triangle Park, North Carolina.

Context: Functional hypothalamic amenorrhea (HA) is a common, acquired form of hypogonadotropic hypogonadism that occurs in the setting of energy deficits and/or stress. Variability in individual susceptibility to these stressors, HA heritability, and previous identification of several rare sequence variants (RSVs) in genes associated with the rare disorder, isolated hypogonadotropic hypogonadism (IHH), in individuals with HA suggest a possible genetic contribution to HA susceptibility.

Objective: We sought to determine whether the burden of RSVs in IHH-related genes is greater in women with HA than controls.

Design: We compared patients with HA to control women.

Setting: The study was conducted at secondary referral centers.

Patients And Other Participants: Women with HA (n = 106) and control women (ClinSeq study; n = 468).

Interventions: We performed exome sequencing in all patients and controls.

Main Outcome Measure(s): The frequency of RSVs in 53 IHH-associated genes was determined using rare variant burden and association tests.

Results: RSVs were overrepresented in women with HA compared with controls (P = .007). Seventy-eight heterozygous RSVs in 33 genes were identified in 58 women with HA (36.8% of alleles) compared to 255 RSVs in 41 genes among 200 control women (27.2%).

Conclusions: Women with HA are enriched for RSVs in genes that cause IHH, suggesting that variation in genes associated with gonadotropin-releasing hormone neuronal ontogeny and function may be a major determinant of individual susceptibility to developing HA in the face of diet, exercise, and/or stress.
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http://dx.doi.org/10.1210/clinem/dgaa609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947783PMC
March 2021

Endocrine Conditions and COVID-19.

Horm Metab Res 2020 Jul 8;52(7):471-484. Epub 2020 Jun 8.

Section on Endocrinology & Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH), Bethesda, Maryland, USA.

COVID-19 was declared a global pandemic by the WHO and has affected millions of patients around the world. COVID-19 disproportionately affects persons with endocrine conditions, thus putting them at an increased risk for severe disease. We discuss the mechanisms that place persons with endocrine conditions at an additional risk for severe COVID-19 and review the evidence. We also suggest precautions and management of endocrine conditions in the setting of global curfews being imposed and offer practical tips for uninterrupted endocrine care.
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http://dx.doi.org/10.1055/a-1172-1352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417289PMC
July 2020

The COronavirus Pandemic Epidemiology (COPE) Consortium: A Call to Action.

Cancer Epidemiol Biomarkers Prev 2020 07 5;29(7):1283-1289. Epub 2020 May 5.

Social & Scientific Systems, Durham, North Carolina.

The rapid pace of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; COVID-19) pandemic presents challenges to the real-time collection of population-scale data to inform near-term public health needs as well as future investigations. We established the COronavirus Pandemic Epidemiology (COPE) consortium to address this unprecedented crisis on behalf of the epidemiology research community. As a central component of this initiative, we have developed a COVID Symptom Study (previously known as the COVID Symptom Tracker) mobile application as a common data collection tool for epidemiologic cohort studies with active study participants. This mobile application collects information on risk factors, daily symptoms, and outcomes through a user-friendly interface that minimizes participant burden. Combined with our efforts within the general population, data collected from nearly 3 million participants in the United States and United Kingdom are being used to address critical needs in the emergency response, including identifying potential hot spots of disease and clinically actionable risk factors. The linkage of symptom data collected in the app with information and biospecimens already collected in epidemiology cohorts will position us to address key questions related to diet, lifestyle, environmental, and socioeconomic factors on susceptibility to COVID-19, clinical outcomes related to infection, and long-term physical, mental health, and financial sequalae. We call upon additional epidemiology cohorts to join this collective effort to strengthen our impact on the current health crisis and generate a new model for a collaborative and nimble research infrastructure that will lead to more rapid translation of our work for the betterment of public health.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357669PMC
July 2020

Cadmium Exposure and Ovarian Reserve in Women Aged 35-49 Years: The Impact on Results From the Creatinine Adjustment Approach Used to Correct for Urinary Dilution.

Am J Epidemiol 2021 01;190(1):116-124

Cadmium is toxic to the ovaries in animal studies, but its association with diminished ovarian reserve in women is not established. We investigated urinary cadmium, a biomarker of long-term exposure, in relation to diminished ovarian reserve, as indicated by elevated serum follicle-stimulating hormone concentrations (≥10 IU/L), in women aged 35-49 years (unweighted n = 1,681). Using data from the Third National Health and Nutrition Examination Survey (1988-1994), we conducted Poisson regression to estimate adjusted relative risks and 95% confidence intervals. Because the best approach to correcting for urinary dilution in spot samples with creatinine remains controversial, we employed 3 approaches: standardization, covariate adjustment, and covariate-adjusted standardization. Our data suggested a modest association with standardization (highest quartile vs. lowest: relative risk (RR) = 1.3, 95% confidence interval (CI): 0.8, 1.9; P for trend = 0.06) and covariate-adjusted standardization (highest quartile vs. lowest: RR = 1.3, 95% CI: 0.9, 1.9; P for trend = 0.05) and a stronger association with covariate adjustment (highest quartile vs. lowest: RR = 1.8, 95% CI: 1.2, 2.9; P for trend = 0.01). The stronger association with covariate adjustment may reflect bias from conditioning on urinary creatinine, a collider in the hypothesized causal pathway. We conclude that cadmium may contribute to ovarian aging in women and that careful consideration of the creatinine adjustment approach is needed to minimize bias.
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http://dx.doi.org/10.1093/aje/kwaa037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946799PMC
January 2021

Long-Term Follow-Up and Treatment of a Female With Complete Estrogen Insensitivity.

J Clin Endocrinol Metab 2020 05;105(5)

Medical College of Georgia at Augusta University, Section of Reproductive Endocrinology, Infertility, & Genetics, Augusta, Georgia.

Context: We previously reported the first female with a causative ESR1 gene variant, who exhibited absent puberty and high estrogens. At age 15 years, she presented with lower abdominal pain, absent breast development, primary amenorrhea, and multicystic ovaries. The natural history of complete estrogen insensitivity (CEI) in women is unknown.

Objective: The purpose of this report is to present the neuroendocrine phenotype of CEI, identify potential ligands, and determine the effect of targeted treatment.

Design: We have characterized gonadotropin pulsatility and followed this patient's endocrine profile and bone density over 8 years. Seventy-five different compounds were tested for transactivation of the variant receptor. A personalized medicine approach was tailored to our patient.

Setting: Academic medical center.

Patient Or Other Participants: A 24-year-old adopted white female with CEI.

Intervention(s): The patient was treated with diethylstilbestrol (DES) for approximately 2.5 years.

Main Outcome Measure(s): Induction of secondary sexual characteristics.

Results: Luteinizing hormone (LH) pulse studies demonstrated normal pulsatile LH secretion, elevated mean LH, and mildly elevated mean follicle-stimulating hormone (FSH) in the presence of markedly increased estrogens. DES transactivated the variant ESR1 in vitro. However, DES treatment did not induce secondary sexual characteristics in our patient.

Conclusions: Treatment with DES was not successful in our patient. She remains hypoestrogenic despite the presence of ovarian cysts with a hypoestrogenic vaginal smear, absent breast development, and low bone mineral mass. Findings suggest additional receptor mechanistic actions are required to elicit clinical hormone responses.
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http://dx.doi.org/10.1210/clinem/dgaa106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108680PMC
May 2020

Insight Into the Ontogeny of GnRH Neurons From Patients Born Without a Nose.

J Clin Endocrinol Metab 2020 05;105(5)

Service de Génétique Clinique, CHU Robert Debré, Paris, France.

Context: The reproductive axis is controlled by a network of gonadotropin-releasing hormone (GnRH) neurons born in the primitive nose that migrate to the hypothalamus alongside axons of the olfactory system. The observation that congenital anosmia (inability to smell) is often associated with GnRH deficiency in humans led to the prevailing view that GnRH neurons depend on olfactory structures to reach the brain, but this hypothesis has not been confirmed.

Objective: The objective of this work is to determine the potential for normal reproductive function in the setting of completely absent internal and external olfactory structures.

Methods: We conducted comprehensive phenotyping studies in 11 patients with congenital arhinia. These studies were augmented by review of medical records and study questionnaires in another 40 international patients.

Results: All male patients demonstrated clinical and/or biochemical signs of GnRH deficiency, and the 5 men studied in person had no luteinizing hormone (LH) pulses, suggesting absent GnRH activity. The 6 women studied in person also had apulsatile LH profiles, yet 3 had spontaneous breast development and 2 women (studied from afar) had normal breast development and menstrual cycles, suggesting a fully intact reproductive axis. Administration of pulsatile GnRH to 2 GnRH-deficient patients revealed normal pituitary responsiveness but gonadal failure in the male patient.

Conclusions: Patients with arhinia teach us that the GnRH neuron, a key gatekeeper of the reproductive axis, is associated with but may not depend on olfactory structures for normal migration and function, and more broadly, illustrate the power of extreme human phenotypes in answering fundamental questions about human embryology.
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http://dx.doi.org/10.1210/clinem/dgaa065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108682PMC
May 2020

Impact of Estradiol Variability and Progesterone on Mood in Perimenopausal Women With Depressive Symptoms.

J Clin Endocrinol Metab 2020 03;105(3)

Division of Intramural Science, National Institute of Environmental Health Sciences, NIH.

Context: Women are at increased risk for depressive symptoms during the menopause transition. Changes in estradiol secretion and presence of vasomotor symptoms (VMS) contribute to perimenopausal depressive symptoms, but links with progesterone have not been investigated.

Objective: To determine whether estradiol variability, ovulatory levels of progesterone, and VMS burden are independently associated with perimenopausal depressive symptomatology.

Design And Intervention: Depressive symptoms, serum levels of estradiol and progesterone, and VMS frequency were assessed weekly in an 8-week observational study. Association of mood with estradiol variability, ovulatory levels of progesterone, and VMS frequency were estimated using generalized estimating equation models.

Setting: Academic medical center.

Patients: Fifty unmedicated perimenopausal women with mild-to-moderate depressive symptoms (mean Montgomery-Åsberg Depression Rating Scale [MADRS] score 15.5 ± 5.3).

Main Outcome Measure: Depressive symptoms (MADRS score).

Results: During the study, 90.0% of participants had varying estradiol levels, 51.1% had ovulatory progesterone levels, and 90% had VMS. Greater estradiol variability and absence of progesterone levels consistent with ovulation, but not VMS frequency, are associated with higher levels of depressive symptoms (β = 0.11 [95% confidence interval (95% CI), 0.04 to 0.18; P = 0.001]; β = -2.62 [95% CI, -4.52 to -0.71; P = 0.007], respectively), after accounting for higher body mass index, lifetime history of depression, and stressful life events.

Conclusions: Increasing dysregulation of ovarian hormones, but not VMS, associates with more depressive symptom burden during perimenopause. These results suggest that perimenopausal mood instability is driven by the underlying hormonal dysregulation of the menopause transition involving changes in both estradiol and progesterone.
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http://dx.doi.org/10.1210/clinem/dgz181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7075107PMC
March 2020

The Distinguished Legacy of Linda S. Birnbaum, an Environmental Health Champion.

Environ Health Perspect 2019 10 22;127(10):101001. Epub 2019 Oct 22.

Division of Intramural Research, NIEHS, NIH, DHHS, Research Triangle Park, North Carolina, USA.

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http://dx.doi.org/10.1289/EHP6332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6910772PMC
October 2019

Alteration of splicing factors' expression during liver disease progression: impact on hepatocellular carcinoma outcome.

Hepatol Int 2019 Jul 28;13(4):454-467. Epub 2019 May 28.

INSERM U1135, Centre d'immunologie et de maladie infectieuse, 91 boulevard de l'Hôpital, 75013, Paris, France.

Purpose: Trans-acting splicing factors (SF) shape the eukaryotic transcriptome by regulating alternative splicing (AS). This process is recurrently modulated in liver cancer suggesting its direct contribution to the course of liver disease. The aim of our study was to investigate the relationship between the regulation of SFs expression and liver damage.

Methods: The expression profile of 10 liver-specific SF and the AS events of 7 genes associated with liver disorders was assessed by western-blotting in 6 murine models representing different stages of liver damage, from inflammation to hepatocellular carcinoma (HCC). Relevant SFs (PSF, SRSF3, and SRSF6) and target genes (INSR, SRSF3, and SLK) modulated in mice were investigated in a cohort of 179 HCC patients.

Results: Each murine model of liver disease was characterized by a unique SF expression profile. Changes in the SF profile did not affect AS events of the selected genes despite the presence of corresponding splicing sites. In human HCC expression of SFs, including the tumor-suppressor SRSF3, and AS regulation of genes studied were frequently upregulated in tumor versus non-tumor tissues. Risk of tumor recurrence positively correlated with AS isoform of the INSR gene. In contrast, increased levels of SFs expression correlated with an extended overall survival of patients.

Conclusions: Dysregulation of SF expression is an early event occurring during liver injury and not just at the stage of HCC. Besides impacting on AS regulation, overexpression of SF may contribute to preserving hepatocyte homeostasis during liver pathogenesis.
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http://dx.doi.org/10.1007/s12072-019-09950-7DOI Listing
July 2019

Hypothalamic Reproductive Endocrine Pulse Generator Activity Independent of Neurokinin B and Dynorphin Signaling.

J Clin Endocrinol Metab 2019 10;104(10):4304-4318

Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts.

Context: Kisspeptin-neurokinin B (NKB)-dynorphin neurons are critical regulators of the hypothalamic-pituitary-gonadal axis. NKB and dynorphin are hypothesized to influence the frequency of GnRH pulses, whereas kisspeptin is hypothesized to be a generator of the GnRH pulse. How these neuropeptides interact remains unclear.

Objective: To probe the role of NKB in GnRH pulse generation and to determine the interactions between NKB, kisspeptin, and dynorphin in humans and mice with a complete absence of NKB.

Design: Case/control.

Setting: Academic medical center.

Participants: Members of a consanguineous family bearing biallelic loss-of-function mutations in the gene encoding NKB and NKB-deficient mice.

Interventions: Frequent blood sampling to characterize neuroendocrine profile and administration of kisspeptin, GnRH, and naloxone, a nonspecific opioid receptor antagonist used to block dynorphin.

Main Outcome Measures: LH pulse characteristics.

Results: Humans lacking NKB demonstrate slow LH pulse frequency, which can be increased by opioid antagonism. Mice lacking NKB also demonstrate impaired LH secretion, which can be augmented with an identical pharmacologic manipulation. Both mice and humans with NKB deficiency respond to exogenous kisspeptin.

Conclusion: The preservation of LH pulses in the absence of NKB and dynorphin signaling suggests that both peptides are dispensable for GnRH pulse generation and kisspeptin responsiveness. However, NKB and dynorphin appear to have opposing roles in the modulation of GnRH pulse frequency.
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http://dx.doi.org/10.1210/jc.2019-00146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736049PMC
October 2019

Resting-state functional connectivity, cortical GABA, and neuroactive steroids in peripartum and peripartum depressed women: a functional magnetic resonance imaging and spectroscopy study.

Neuropsychopharmacology 2019 02 17;44(3):546-554. Epub 2018 Oct 17.

Center for Comparative Neuroimaging, University of Massachusetts Medical School, Worcester, MA, USA.

Postpartum depression (PPD) is associated with abnormalities in resting-state functional connectivity (RSFC) but the underlying neurochemistry is unclear. We hypothesized that peripartum GABAergic neuroactive steroids (NAS) are related to cortical GABA concentrations and RSFC in PPD as compared to healthy comparison women (HCW). To test this, we measured RSFC with fMRI and GABA+/Creatine (Cr) concentrations with proton magnetic resonance spectroscopy (H MRS) in the pregenual anterior cingulate (pgACC) and occipital cortices (OCC) and quantified peripartum plasma NAS. We examined between-group differences in RSFC and the relationship between cortical GABA+/Cr concentrations with RSFC. We investigated the relationship between NAS, RSFC and cortical GABA+/Cr concentrations. Within the default mode network (DMN) an area of the dorsomedial prefrontal cortex (DMPFC) had greater connectivity with the rest of the DMN in PPD (peak voxel: MNI coordinates (2, 58, 32), p = 0.002) and was correlated to depression scores (peak HAM-D17 voxel: MNI coordinates (0, 60, 34), p = 0.008). pgACC GABA+/Cr correlated positively with DMPFC RSFC in a region spanning the right anterior/posterior insula and right temporal pole (r = +0.661, p = 0.000). OCC GABA+/Cr correlated positively with regions spanning both amygdalae (right amygdala: r = +0.522, p = 0.000; left amygdala: r = +0.651, p = 0.000) as well as superior parietal areas. Plasma allopregnanolone was higher in PPD (p = 0.03) and positively correlated with intra DMPFC connectivity (r = +0.548, p = 0.000) but not GABA+/Cr. These results provide initial evidence that PPD is associated with altered DMN connectivity; cortical GABA+/Cr concentrations are associated with postpartum RSFC and allopregnanolone is associated with postpartum intra-DMPFC connectivity.
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http://dx.doi.org/10.1038/s41386-018-0242-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333815PMC
February 2019

Healthy Post-Menarchal Adolescent Girls Demonstrate Multi-Level Reproductive Axis Immaturity.

J Clin Endocrinol Metab 2019 02;104(2):613-623

Clinical Research Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina.

Context: Menstrual irregularity after menarche has been attributed to immature estrogen positive feedback activity (E+FB) but data are conflicting.

Objective: To determine the hypothalamic-pituitary-ovarian contributions to menstrual irregularity in adolescents.

Methods: Twenty-three healthy girls [aged 12.8 to 17.6 years; 0.4 to 3.5 years postmenarche; body mass index (BMI) percentile, 41.0 to 99.3] underwent serial hormone measurements and pelvic ultrasounds during two consecutive menstrual cycles. Hormones and follicle growth were compared with 65 adult historic controls with ovulatory cycles (OVs).

Results: Girls had anovulatory cycles (ANOVs; 30%), OVs with a short luteal phase (short OVs; 22%), or OVs with normal luteal phase (normal OVs; 48%) without differences in cycle length, chronologic or gynecologic age, or BMI. Adolescents showed a spectrum of E+FB [midcycle LH adjusted for preovulatory estradiol (E2)]; only normal OV girls were comparable to adults. All OV girls had lower E2, progesterone, and gonadotropins during the luteal phase and luteal-follicular transition compared with adults. Normal OV girls also had lower follicular phase LH and FSH levels, a longer follicular phase, a slower dominant follicle growth rate, and smaller estimated preovulatory follicle size than adults. Follicular phase E2 and inhibin B levels were lower in normal OV girls than in adults even after adjusting for differences in FSH and follicle size.

Conclusions: Early postmenarchal girls with normal OVs demonstrate mature E+FB but continue to have lower gonadotropin levels, diminished ovarian responsiveness, and decreased corpus luteum sex steroid synthesis compared with adults, indicating that reproductive axis maturity requires coordinated development of all components of the hypothalamic-pituitary-ovarian axis.
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http://dx.doi.org/10.1210/jc.2018-00595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325170PMC
February 2019

NIEHS: Making a Mark on Translational Research Science.

Environ Health Perspect 2018 08 2;126(8):081001. Epub 2018 Aug 2.

Office of the Director, National Institute of Environmental Health Sciences, Durham, North Carolina, USA.

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http://dx.doi.org/10.1289/EHP4075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6108839PMC
August 2018

Expanding the Concept of Translational Research: Making a Place for Environmental Health Sciences.

Environ Health Perspect 2018 07 16;126(7):074501. Epub 2018 Jul 16.

Division of Extramural Research and Training, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Department of Health and Human Services (DHHS), Durham, North Carolina, USA.

Summary: The National Institute of Environmental Health Sciences (NIEHS) introduces a new translational research framework that builds upon previous biomedical models to create a more comprehensive and integrated environmental health paradigm. The framework was developed as a graphical construct that illustrates the complexity of designing, implementing, and tracking translational research in environmental health. We conceptualize translational research as a series of concentric rings and nodes, defining "translation" as movement either from one ring to another or between nodes on a ring. A "Fundamental Questions" ring expands upon the research described in other frameworks as "basic" to include three interrelated concepts critical to basic science research: research questions, experimental settings, and organisms. This feature enables us to capture more granularity and thus facilitates an approach for categorizing translational research and its growth over time. We anticipate that the framework will help researchers develop compelling long-term translational research stories and accelerate public health impacts by clearly mapping out opportunities for collaborations. By using this paradigm, researchers everywhere will be better positioned to design research programs, identify research partners based on cross-disciplinary research needs, identify stakeholders who are likely to use the research for environmental decision-making and intervention, and track progress toward common goals. https://doi.org/10.1289/EHP3657.
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http://dx.doi.org/10.1289/EHP3657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6108854PMC
July 2018

Smc5/6 Antagonism by HBx Is an Evolutionarily Conserved Function of Hepatitis B Virus Infection in Mammals.

J Virol 2018 08 31;92(16). Epub 2018 Jul 31.

CIRI-International Center for Infectiology Research, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, Université Lyon, Lyon, France

Chronic infection with hepatitis B virus (HBV) is a major cause of liver disease and cancer in humans. HBVs (family ) have been associated with mammals for millions of years. Recently, the Smc5/6 complex, known for its essential housekeeping functions in genome maintenance, was identified as an antiviral restriction factor of human HBV. The virus has, however, evolved to counteract this defense mechanism by degrading the complex via its regulatory HBx protein. Whether the antiviral activity of the Smc5/6 complex against hepadnaviruses is an important and evolutionarily conserved function is unknown. In this study, we used an evolutionary and functional approach to address this question. We first performed phylogenetic and positive selection analyses of the Smc5/6 complex subunits and found that they have been conserved in primates and mammals. Yet, Smc6 showed marks of adaptive evolution, potentially reminiscent of a virus-host "arms race." We then functionally tested the HBx proteins from six divergent hepadnaviruses naturally infecting primates, rodents, and bats. We demonstrate that despite little sequence homology, these HBx proteins efficiently degraded mammalian Smc5/6 complexes, independently of the host species and of the sites under positive selection. Importantly, all HBx proteins also rescued the replication of an HBx-deficient HBV in primary human hepatocytes. These findings point to an evolutionarily conserved requirement for Smc5/6 inactivation by HBx, showing that Smc5/6 antiviral activity has been an important defense mechanism against hepadnaviruses in mammals. It will be interesting to investigate whether Smc5/6 may further be a restriction factor of other, yet-unidentified viruses that may have driven some of its adaptation. Infection with hepatitis B virus (HBV) led to 887,000 human deaths in 2015. HBV has been coevolving with mammals for millions of years. Recently, the Smc5/6 complex, which has essential housekeeping functions, was identified as a restriction factor of human HBV antagonized by the regulatory HBx protein. Here we address whether the antiviral activity of Smc5/6 is an important evolutionarily conserved function. We found that all six subunits of Smc5/6 have been conserved in primates, with only Smc6 showing signatures of an "evolutionary arms race." Using evolution-guided functional analyses that included infections of primary human hepatocytes, we demonstrated that HBx proteins from very divergent mammalian HBVs could all efficiently antagonize Smc5/6, independently of the host species and sites under positive selection. These findings show that Smc5/6 antiviral activity against HBV is an important function in mammals. They also raise the intriguing possibility that Smc5/6 may restrict other, yet-unidentified viruses.
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http://dx.doi.org/10.1128/JVI.00769-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6069175PMC
August 2018

Morphology and genomic hallmarks of breast tumours developed by ATM deleterious variant carriers.

Breast Cancer Res 2018 04 17;20(1):28. Epub 2018 Apr 17.

Laboratoire de Diagnostic Génétique, UF1422 Oncogénétique Moléculaire, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.

Background: The ataxia telangiectasia mutated (ATM) gene is a moderate-risk breast cancer susceptibility gene; germline loss-of-function variants are found in up to 3% of hereditary breast and ovarian cancer (HBOC) families who undergo genetic testing. So far, no clear histopathological and molecular features of breast tumours occurring in ATM deleterious variant carriers have been described, but identification of an ATM-associated tumour signature may help in patient management.

Methods: To characterise hallmarks of ATM-associated tumours, we performed systematic pathology review of tumours from 21 participants from ataxia-telangiectasia families and 18 participants from HBOC families, as well as copy number profiling on a subset of 23 tumours. Morphology of ATM-associated tumours was compared with that of 599 patients with no BRCA1 and BRCA2 mutations from a hospital-based series, as well as with data from The Cancer Genome Atlas. Absolute copy number and loss of heterozygosity (LOH) profiles were obtained from the OncoScan SNP array. In addition, we performed whole-genome sequencing on four tumours from ATM loss-of-function variant carriers with available frozen material.

Results: We found that ATM-associated tumours belong mostly to the luminal B subtype, are tetraploid and show LOH at the ATM locus at 11q22-23. Unlike tumours in which BRCA1 or BRCA2 is inactivated, tumours arising in ATM deleterious variant carriers are not associated with increased large-scale genomic instability as measured by the large-scale state transitions signature. Losses at 13q14.11-q14.3, 17p13.2-p12, 21p11.2-p11.1 and 22q11.23 were observed. Somatic alterations at these loci may therefore represent biomarkers for ATM testing and harbour driver mutations in potentially 'druggable' genes that would allow patients to be directed towards tailored therapeutic strategies.

Conclusions: Although ATM is involved in the DNA damage response, ATM-associated tumours are distinct from BRCA1-associated tumours in terms of morphological characteristics and genomic alterations, and they are also distinguishable from sporadic breast tumours, thus opening up the possibility to identify ATM variant carriers outside the ataxia-telangiectasia disorder and direct them towards effective cancer risk management and therapeutic strategies.
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http://dx.doi.org/10.1186/s13058-018-0951-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5905168PMC
April 2018

White matter integrity in medication-free women with peripartum depression: a tract-based spatial statistics study.

Neuropsychopharmacology 2018 06 5;43(7):1573-1580. Epub 2018 Feb 5.

Center for Psychopharmacologic Research & Treatment, University of Massachusetts Medical School, Worcester, MA, 01655, USA.

Diffusion tensor imaging (DTI) studies in depression show decreased structural connectivity in the left anterior limb of the internal capsule and the genu of the corpus callosum but no such studies exist in peripartum depression (PPD), which affects 1 in 8 women. We analyzed fractional anisotropy (FA) as a measure of white matter integrity of these two tracts using tract-based spatial statistics (TBSS). We then conducted an exploratory whole-brain analysis to identify additional regions implicated in PPD. Seventy-five pregnant, medication-free women were evaluated with the Edinburgh Postnatal Depression Scale (EPDS) and Structured Clinical Interview (SCID) for DSM-IV-TR in pregnancy and in the postpartum. Structural MRI and DTI sequences were acquired in forty-four women within 2-8 weeks postpartum. TBSS data were analyzed between healthy comparison postpartum women (HCW) and women who developed PPD to determine differences in white matter integrity within the left anterior limb of the internal capsule and the genu of the corpus callosum, then analyzed across participants to explore correlation between FA and the EPDS score. An exploratory whole-brain analysis was also conducted to identify other potential regions showing differences in white matter integrity between groups, as well as correlation between EPDS and FA across groups. All results were corrected for multiple comparisons and analyses conducted using FSL, p < 0.05, K > 10. In comparison to HCW, women with PPD had significantly lower FA in left anterior limb of the internal capsule (p = 0.010). FA was negatively correlated with EPDS scores in the left anterior limb of the internal capsule (p = 0.019). In the whole-brain analysis, FA in the right retrolenticular internal capsule (p = 0.03) and two clusters within the body of the corpus callosum (p = 0.044, p = 0.050) were negatively correlated with EPDS; there were no between-group differences in FA. Reduced FA in the left anterior limb of the internal capsule suggests disruption of fronto-subcortical circuits in PPD. A negative correlation between FA within the body of the corpus callosum and EPDS total score could additionally reflect disrupted interhemispheric structural connectivity in women with depressive symptoms.
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http://dx.doi.org/10.1038/s41386-018-0023-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983547PMC
June 2018

PARP2 controls double-strand break repair pathway choice by limiting 53BP1 accumulation at DNA damage sites and promoting end-resection.

Nucleic Acids Res 2017 Dec;45(21):12325-12339

Institut Curie, PSL Research University, UMR 3348, 91405 Orsay, France.

Double strand breaks (DSBs) are one of the most toxic lesions to cells. DSB repair by the canonical non-homologous end-joining (C-EJ) pathway involves minor, if any, processing of the broken DNA-ends, whereas the initiation of DNA resection channels the broken-ends toward DNA repair pathways using various lengths of homology. Mechanisms that control the resection initiation are thus central to the regulation to the choice of DSB repair pathway. Therefore, understanding the mechanisms which regulate the initiation of DNA end-resection is of prime importance. Our findings reveal that poly(ADP-ribose) polymerase 2 (PARP2) is involved in DSBR pathway choice independently of its PAR synthesis activity. We show that PARP2 favors repair by homologous recombination (HR), single strand annealing (SSA) and alternative-end joining (A-EJ) rather than the C-EJ pathway and increases the deletion sizes at A-EJ junctions. We demonstrate that PARP2 specifically limits the accumulation of the resection barrier factor 53BP1 at DNA damage sites, allowing efficient CtIP-dependent DNA end-resection. Collectively, we have identified a new PARP2 function, independent of its PAR synthesis activity, which directs DSBs toward resection-dependent repair pathways.
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http://dx.doi.org/10.1093/nar/gkx881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5716083PMC
December 2017
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