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Context: Studies of high-risk families with multiple early-onset cases of breast cancer have been useful for assessing the type and spectrum of germline mutations on the BRCA1 gene, but do not provide guidance to women with modest family history profiles. Thus, studies of women from the general population are needed to determine the BRCA1 mutation frequency in women perceived to be at high risk, and to develop profiles of those most likely to be carriers.Objective: To characterize frequency and spectrum of germline BRCA1 mutations in 2 categories of women identified via population-based studies hypothesized to be at increased risk of carrying such mutations: those diagnosed as having breast cancer before age 35 years and those diagnosed before age 45 years who have first-degree breast cancer family history.Design: Study subjects were drawn from 2 population-based case-control studies of breast cancer in young women on the basis of their family history or their age of diagnosis. Cases were younger than 35 years or were younger than 45 years with first-degree family history at the time of breast cancer diagnosis and were ascertained via a population-based cancer registry, and controls (women without breast cancer) were identified via random-digit dialing.Setting: Three counties in western Washington State.Main Outcome Measure: BRCA1 germline mutations in study subjects identified in DNA from peripheral blood lymphocytes by single-strand conformation polymorphism analysis using primer pairs that span the BRCA1 coding region and intron-exon boundaries.Results: Of 193 women diagnosed as having breast cancer before age 35 years, none of whom were selected on the basis of family history status, 12 (6.2%, 95% confidence interval [CI], 3.2%-10.6%) had germline BRCA1 mutations. In 208 women diagnosed before age 45 years who had first-degree breast cancer family history, 15 (7.2%, 95% CI,4.1%-11.6%) had germline mutations in BRCA1. In both groups, there were variations in mutation frequency noted by age and by family history. Mutation frequency decreased with increasing age of diagnosis. Higher proportions of mutations were seen in cases with at least 1 relative diagnosed as having breast cancer before age 45 years, in cases with greater numbers of affected relatives, and those with ovarian cancer family history. Mutation frequency did not vary by bilateral breast cancer family history. No frameshift or nonsense mutations were observed in 71 control women with a first-degree family history, although missense changes of unknown significance were seen in cases and controls.Conclusions: Women with BRCA1 germline mutations lacked a common family history profile. Also, a large proportion of the women with a first-degree breast cancer family history and women diagnosed as having breast cancer before age 35 years did not carry germline BRCA1 mutations. Hence, while early-onset disease and a strong breast cancer family history may be useful guidelines for checking BRCA1 status, these findings on women drawn from the general population suggest that it may be difficult to develop BRCA1 mutation screening criteria among women with modest family history profiles. [ABSTRACT FROM AUTHOR]

Objective: Viral failure in people with HIV (PWH) may be influenced by multiple sociobehavioral, clinical, and context-specific factors, and supervised learning approaches may identify novel predictors. We compared the performance of two supervised learning algorithms to predict viral failure in four African countries., Design: Cohort study., Methods: The African Cohort Study is an ongoing, longitudinal cohort enrolling PWH at 12 sites in Uganda, Kenya, Tanzania, and Nigeria. Participants underwent physical examination, medical history-taking, medical record extraction, sociobehavioral interviews, and laboratory testing. In cross-sectional analyses of enrollment data, viral failure was defined as a viral load at least 1000 copies/ml among participants on antiretroviral therapy (ART) for at least 6 months. We compared the performance of lasso-type regularized regression and random forests by calculating area under the curve (AUC) and used each to identify factors associated with viral failure; 94 explanatory variables were considered., Results: Between January 2013 and December 2020, 2941 PWH were enrolled, 1602 had been on antiretroviral therapy (ART) for at least 6 months, and 1571 participants with complete case data were included. At enrollment, 190 (12.0%) had viral failure. The lasso regression model was slightly superior to the random forest in its ability to identify PWH with viral failure (AUC: 0.82 vs. 0.75). Both models identified CD4 + count, ART regimen, age, self-reported ART adherence and duration on ART as important factors associated with viral failure., Conclusion: These findings corroborate existing literature primarily based on hypothesis-testing statistical approaches and help to generate questions for future investigations that may impact viral failure., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Antibody heavy chain (HC) and light chain (LC) variable region exons are assembled by V(D)J recombination. V(D)J junctional regions encode complementarity-determining-region 3 (CDR3), an antigen-contact region immensely diversified through nontemplated nucleotide additions ("N-regions") by terminal deoxynucleotidyl transferase (TdT). HIV-1 vaccine strategies seek to elicit human HIV-1 broadly neutralizing antibodies (bnAbs), such as the potent CD4-binding site VRC01-class bnAbs. Mice with primary B cells that express receptors (BCRs) representing bnAb precursors are used as vaccination models. VRC01-class bnAbs uniformly use human HC V H 1-2 and commonly use human LCs Vκ3-20 or Vκ1-33 associated with an exceptionally short 5-amino-acid (5-aa) CDR3. Prior VRC01-class models had nonphysiological precursor levels and/or limited precursor diversity. Here, we describe VRC01-class rearranging mice that generate more physiological primary VRC01-class BCR repertoires via rearrangement of V H 1-2, as well as Vκ1-33 and/or Vκ3-20 in association with diverse CDR3s. Human-like TdT expression in mouse precursor B cells increased LC CDR3 length and diversity and also promoted the generation of shorter LC CDR3s via N-region suppression of dominant microhomology-mediated Vκ-to-Jκ joins. Priming immunization with eOD-GT8 60mer, which strongly engages VRC01 precursors, induced robust VRC01-class germinal center B cell responses. Vκ3-20-based responses were enhanced by N-region addition, which generates Vκ3-20-to-Jκ junctional sequence combinations that encode VRC01-class 5-aa CDR3s with a critical E residue. VRC01-class-rearranging models should facilitate further evaluation of VRC01-class prime and boost immunogens. These new VRC01-class mouse models establish a prototype for the generation of vaccine-testing mouse models for other HIV-1 bnAb lineages that employ different HC or LC Vs.

Prior immune responses to coronaviruses might affect human SARS-CoV-2 response. We screened 2,565 serum and plasma samples collected from 2013 through early 2020, before the COVID-19 pandemic began, from 2,250 persons in 4 countries in Africa (Kenya, Nigeria, Tanzania, and Uganda) and in Thailand, including persons living with HIV-1. We detected IgG responses to SARS-CoV-2 spike (S) subunit 2 protein in 1.8% of participants. Profiling against 23 coronavirus antigens revealed that responses to S, subunit 2, or subunit 1 proteins were significantly more frequent than responses to the receptor-binding domain, S-Trimer, or nucleocapsid proteins (p<0.0001). We observed similar responses in persons with or without HIV-1. Among all coronavirus antigens tested, SARS-CoV-2, SARS-CoV-1, and Middle East respiratory syndrome coronavirus antibody responses were much higher in participants from Africa than in participants from Thailand (p<0.01). We noted less pronounced differences for endemic coronaviruses. Serosurveys could affect vaccine and monoclonal antibody distribution across global populations.

Background: Analytic treatment interruption (ATI) studies evaluate strategies to potentially induce remission in people living with HIV-1 but are often limited in sample size. We combined data from four studies that tested three interventions (vorinostat/hydroxychloroquine/maraviroc before ATI, Ad26/MVA vaccination before ATI, and VRC01 antibody infusion during ATI)., Methods: The statistical validity of combining data from these participants was evaluated. Eleven variables, including HIV-1 viral load at diagnosis, Fiebig stage, and CD4 + T cell count were evaluated using pairwise correlations, statistical tests, and Cox survival models., Findings: Participants had homogeneous demographic and clinical characteristics. Because an antiviral effect was seen in participants who received VRC01 infusion post-ATI, these participants were excluded from the analysis, permitting a pooled analysis of 53 participants. Time to viral rebound was significantly associated with variables measured at the beginning of infection: pre-antiretroviral therapy (ART) viral load (HR = 1.34, p = 0.022), time to viral suppression post-ART initiation (HR = 1.07, p < 0.001), and area under the viral load curve (HR = 1.34, p = 0.026)., Conclusions: We show that higher viral loads in acute HIV-1 infection were associated with faster viral rebound, demonstrating that the initial stage of HIV-1 infection before ART initiation has a strong impact on viral rebound post-ATI years later., Funding: This work was supported by a cooperative agreement between the Henry M. Jackson Foundation for the Advancement of Military Medicine and the US Department of the Army (W81XWH-18-2-0040). This research was funded, in part, by the US National Institute of Allergy and Infectious Diseases (AAI20052001) and the I4C Martin Delaney Collaboratory (5UM1AI126603-05)., Competing Interests: Declaration of interests The views expressed are those of the authors and should not be construed to represent the positions of the US Army, the Department of Defense, the Department of Health and Human Services, or the Henry M. Jackson Foundation for the Advancement of Military Medicine. D.J.S. and F.L.T. are employees of Janssen Vaccines & Prevention and own stock and stock options in Johnson & Johnson. The other authors declare no competing interests. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background & Aims: The obesity nutritional treatment is structured to weight loss and diet is considered an important indicator of treatment effectiveness. The purpose of this study is to compare the diet quality among women who lost weight to women who maintained or gained weight during the nutritional treatment., Methods: This is a retrospective study that included 66 obese women in nutritional treatment for weight loss, over six months, divided in tercile according to their weight loss. The diet quality was evaluated by score, which was obtained with a food frequency questionnaire., Results: The diet quality comparison was made among the group with weight loss (GL; n = 22) and the group that maintained or gained weight during the nutritional treatment (GG; n = 22) showed that both groups had improvement in their diet quality scores from pre-treatment to post-treatment. Nevertheless, the GG had higher sugar consumption than the GL in the pre-treatment (p = 0.02) and in the post-treatment (p 0.01) periods. In the post-treatment, GL increased their scores for leafy vegetables (0.013), fruit (0.004), sweets (p 0.03), and soft drinks (p 0.02). GL improved their scores for fried food (p 0.01) and sweets (p 0.008)., Conclusion: This indicates that in the weight loss treatment special attention should be given to the incentive to the fruit and leafy vegetables consumption and, to reduce the consumption of sweets., (Copyright © 2019 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

Aim: To examine the effects of creatine (Cr) supplementation on liver fat accumulation in rats fed a choline-deficient diet., Methods: Twenty-four rats were divided into 3 groups of 8 based on 4 weeks of feeding an AIN-93 control diet (C), a choline-deficient diet (CDD) or a CDD supplemented with 2% Cr. The CDD diet was AIN-93 without choline., Results: The CDD significantly increased plasma homocysteine and TNFα concentration, as well as ALT activity. In liver, the CDD enhanced concentrations of total fat (55%), cholesterol (25%), triglycerides (87%), MDA (30%), TNFα (241%) and decreased SAM concentrations (25%) and the SAM/SAH ratio (33%). Cr supplementation prevented all these metabolic changes, except for hepatic SAM and the SAM/SAH ratio. However, no changes in PEMT gene expression or liver phosphatidylcholine levels were observed among the three experimental groups, and there were no changes in hepatic triglyceride transfer protein (MTP) mRNA level. On the contrary, Cr supplementation normalized expression of the transcription factors PPARα and PPARγ that were altered by the CDD. Further, the downstream targets and fatty acids metabolism genes, UCP2, LCAD and CPT1a, were also normalized in the Cr group as compared to CDD-fed rats., Conclusion: Cr supplementation prevented fat liver accumulation and hepatic injures in rats fed with a CDD for 4 weeks. Our results demonstrated that one-carbon metabolism may have a small role in mitigating hepatic fat accumulation by Cr supplementation. The modulation of key genes related to fatty acid oxidation pathway suggests a new mechanism by which Cr prevents liver fat accumulation., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Polygyny has been identified both as a 'benign' form of concurrency and as the cultural basis of concurrent partnerships that are considered important drivers of the HIV epidemic in sub-Saharan Africa. This paper investigates the changing cultural and economic dynamics of polygyny in concurrency in Iringa, Tanzania, a region with traditions of polygyny and high prevalence of HIV. Our analysis of focus group discussions, in-depth interviews and key informant interviews indicate that contemporary concurrent partnerships differ from regional traditions of polygyny. Whereas in the past, polygyny reflected men's and their kin group's wealth and garnered additional prestige, polygyny today is increasingly seen as a threat to health, and as leading to poverty. Nevertheless, participants evoked the social prestige of polygyny to explain men's present-day concurrency, even outside the bounds of marriage, and despite continued social prohibitions against extramarital affairs. Difficult economic conditions, combined with this prestige, made it easier for men to engage in concurrency without the considerable obligations to wives and children in polygyny. Local economic conditions also compelled women to seek concurrent partners to meet basic needs and to access consumer goods, but risked greater moral judgement than men, especially if deemed to have excessive 'desire' for money.

The leukocyte activation marker CD30 is highly expressed on the Reed Sternberg cells of Hodgkin's disease (HD). On normal tissues, CD30 has a restricted expression profile limited to activated T cells, activated B cells, and activated natural killer cells. This expression profile makes CD30 an ideal target for monoclonal antibody (mAb)-based therapies of Hodgkin's disease. CD30 mAbs have been shown to be effective in in vitro and in vivo models of hematologic malignancies such as anaplastic large cell lymphoma, yet these mAb have not been efficacious in HD models. We have found that a mAb against CD30, AC10, was able to inhibit the growth of HD cell lines in vitro. To generate a more clinically relevant molecule, the variable regions from AC10 were cloned into an expression construct containing the human gamma1 heavy chain and kappa light chain constant regions. The resulting chimeric antibody, designated SGN-30, retained the binding and in vitro growth-inhibitory activities of the parental antibody. Treatment of HD cell lines with SGN-30 in vitro resulted in growth arrest in the G(1) phase of the cell cycle and DNA fragmentation consistent with apoptosis in the HD line L540cy. Severe combined immunodeficient mouse xenograft models of disseminated HD treated with SGN-30 produced significant increases in survival. Similarly, xenograft models of localized HD demonstrated dose-dependent reduction in tumor mass in response to SGN-30 therapy. SGN-30 is being developed for the treatment of patients who have HD that is refractory to initial treatment or who have relapsed and have limited therapeutic options.

A genetic linkage map of the canine genome has been developed by typing 150 microsatellite markers using 17 three-generation pedigrees, composed of 163 F2 individuals. One hundred and thirty-nine markers were linked to at least one other marker with a lod score > or = 3.0, identifying 30 linkage groups. The largest chromosome had 9 markers spanning 106.1 cM. The average distance between markers was 14.03 cM, and the map covers an estimated 2073 cM. Eleven markers were informative on the mapping panel, but were unlinked to any other marker. These likely represent single markers located on small, distinct canine chromosomes. This map will be the initial resource for mapping canine traits of interest and serve as a foundation for development of a comprehensive canine genetic map.

The dog has served traditionally as a model for marrow and organ transplantation. A key component of any study of transplantation is histocompatibility typing of donors and recipients. Towards the development of a less expensive, more simplified typing system within canine families, a new highly polymorphic microsatellite marker for the canine Major Histocompatibility Complex class II region was isolated and characterized. In addition, we report on the application of class I and class II microsatellite-based markers for following the inheritance of the alleles within the canine analog of the human HLA loci, DLA, through multi-generation pedigree.

Five to ten percent of breast cancer in the western world may be attributed to the inheritance of highly penetrant mutations in the breast and ovarian cancer susceptibility gene, BRCA1. The biological function of BRCA1 and factors affecting expressivity, such as gene-environment and gene-gene interactions, may be more effectively studied in appropriate animal models. We report the cloning and sequencing of the canine and murine BRCA1 genes and contrast the sequences with human BRCA1. The amino terminal 120 residues of the gene are > 80% identical among the three species. The C-terminus is also highly conserved, containing an 80 amino acid stretch that is over 80% identical. Motifs of likely functional significance are maintained, including the amino terminal RING finger motif (amino acids 24-64) and the granin consensus sequence (1214-1223). The distribution of missense mutations and neutral polymorphisms identified in BRCA1-linked breast cancer suggests that disease associated missense mutations occur at highly conserved residues whereas polymorphisms are in regions of lower conservation. Among eighteen missense mutations with unknown consequences, seven occur in amino acids that are identical across species. Four of these seven (E1219D, A1708E, P1749R and M1775R) are also within conserved domains. Taken together, these data predict regions of the gene which may be critical for normal function.

We have identified and characterized a new class of polymorphic markers for the canine genome from a simple tetranucleotide repeat sequence, (GAAA)n. Genetic markers derived from this repeat are highly polymorphic compared with other canine microsatellites, yet are stable enough to be useful for following Mendelian inheritance in multigeneration pedigrees. We show further that (GAAA)n repeats are distributed throughout the canine genome and occur with sufficient frequency to be useful in the development of a framework map of the canine genome.