Genetic studies have identified single nucleotide polymorphisms (SNPs) associated with the risk of prostate cancer (PC). It remains unclear whether such genetic variants are associated with disease ...aggressiveness. The NCI-SPORE Genetics Working Group retrospectively collected clinicopathologic information and genotype data for 36 SNPs which at the time had been validated to be associated with PC risk from 25,674 cases with PC. Cases were grouped according to race, Gleason score (Gleason ≤6, 7, ≥8) and aggressiveness (non-aggressive, intermediate, and aggressive disease). Statistical analyses were used to compare the frequency of the SNPs between different disease cohorts. After adjusting for multiple testing, only PC-risk SNP rs2735839 (G) was significantly and inversely associated with aggressive (OR = 0.77; 95 % CI 0.69–0.87) and high-grade disease (OR = 0.77; 95 % CI 0.68–0.86) in European men. Similar associations with aggressive (OR = 0.72; 95 % CI 0.58–0.89) and high-grade disease (OR = 0.69; 95 % CI 0.54–0.87) were documented in African-American subjects. The G allele of rs2735839 was associated with disease aggressiveness even at low PSA levels (<4.0 ng/mL) in both European and African-American men. Our results provide further support that a PC-risk SNP rs2735839 near the KLK3 gene on chromosome 19q13 may be associated with aggressive and high-grade PC. Future prospectively designed, case-case GWAS are needed to identify additional SNPs associated with PC aggressiveness.
Poor nutrition plays a fundamental role in the development of insulin resistance, an underlying characteristic of type 2 diabetes. We have previously shown that high-fat diet-induced insulin ...resistance in rats can be ameliorated by a single glucose meal, but the mechanisms for this observation remain unresolved. To determine if this phenomenon is mediated by gut or hepatoportal factors, male Wistar rats were fed a high-fat diet for 3 weeks before receiving one of five interventions: high-fat meal, glucose gavage, high-glucose meal, systemic glucose infusion or portal glucose infusion. Insulin sensitivity was assessed the following day in conscious animals by a hyperinsulinaemic-euglycaemic clamp. An oral glucose load consistently improved insulin sensitivity in high-fat-fed rats, establishing the reproducibility of this model. A systemic infusion of a glucose load did not affect insulin sensitivity, indicating that the physiological response to oral glucose was not due solely to increased glucose turnover or withdrawal of dietary lipid. A portal infusion of glucose produced the largest improvement in insulin sensitivity, implicating a role for the hepatoportal region rather than the gastrointestinal tract in mediating the effect of glucose to improve lipid-induced insulin resistance. These results further deepen our understanding of the mechanism of glucose-mediated regulation of insulin sensitivity and provide new insight into the role of nutrition in whole body metabolism.
Abstract BACKGROUND Children and young adults diagnosed with high-grade glioma (HGG) face extremely poor prognoses. Despite multiple clinical trials testing new treatments in this population, a ...survival advantage has yet to be achieved. Herein we assessed, in a single-arm, multi-center pilot trial, the feasibility of molecular profiling of primary HGG tumor tissue to create an individualized treatment plan with up to four FDA approved medications. METHODS Patients aged <21 years with newly diagnosed, localized, hemispheric HGG (Stratum A) or midline HGG (non-DIPG; Stratum B) were eligible. Tumor tissue underwent comprehensive molecular profiling (targeted gene panel, whole exome, and whole transcriptome sequencing). Based on detailed review of the molecular data by a dedicated tumor board, an individualized treatment plan that combined up to four FDA approved drugs was recommended. Circulating tumor DNA (ctDNA), imaging, and quality of life (QOL) measures were collected at multiple timepoints. RESULTS Fifty-five patients enrolled between 2018 and 2023 (median age 11 years range 2-20, n=31 female, n=29 Stratum A). The most common integrated diagnoses included H3K27-altered diffuse midline glioma (n=17), H3/IDH-wildtype diffuse pediatric-type HGG (n=16), and H3G34-mutant diffuse hemispheric glioma (n=12). Median overall survival (OS) from the time of study enrollment was 26.5 months in Stratum A (lower 95% CI: 18.7) and 21.7 months in Stratum B (lower 95% CI: 16.8), with a median follow-up of 35.4 months for all patients (lower 95% CI: 32.5). The most common grade 3 or 4 treatment-related adverse events were decreased neutrophils (n=28), decreased platelets (n=22), and decreased white blood cells (n=16). As of December 2023, seven patients remain on therapy. Central imaging, ctDNA, and QOL analyses are underway. CONCLUSIONS A personalized treatment recommendation for children and young adults with HGG based on comprehensive transcriptomic and genomic analysis is feasible. Current survival data are encouraging, and molecular subgroup analyses are ongoing.
Clinically ascertained variants are under-utilized in neurodevelopmental disorder research. We established the Brain Gene Registry (BGR) to coregister clinically identified variants in putative brain ...genes with participant phenotypes. Here, we report 179 genetic variants in the first 179 BGR registrants and analyze the proportion that were novel to ClinVar at the time of entry and those that were absent in other disease databases.
From 10 academically affiliated institutions, 179 individuals with 179 variants were enrolled into the BGR. Variants were cross-referenced for previous presence in ClinVar and for presence in 6 other genetic databases.
Of 179 variants in 76 genes, 76 (42.5%) were novel to ClinVar, and 62 (34.6%) were absent from all databases analyzed. Of the 103 variants present in ClinVar, 37 (35.9%) were uncertain (ClinVar aggregate classification of variant of uncertain significance or conflicting classifications). For 5 variants, the aggregate ClinVar classification was inconsistent with the interpretation from the BGR site-provided classification.
A significant proportion of clinical variants that are novel or uncertain are not shared, limiting the evidence base for new gene-disease relationships. Registration of paired clinical genetic test results with phenotype has the potential to advance knowledge of the relationships between genes and neurodevelopmental disorders.
The HIV epidemic disproportionately impacts transgender women in the United States. Cohort studies identify unique risks for affected populations, but use of facility-based methods may bias findings ...towards individuals living in research catchment areas, more engaged in health services, or, in the case of transgender populations, those who are open about their transgender identity. Digital clinical trials and other online research methods are increasingly common, providing opportunity to reach those not commonly engaged in research. Simultaneously, there is a need to understand potential biases associated with digital research, how these methods perform, and whether they are accepted across populations.
This study aims to assess the feasibility of developing and implementing an online cohort of transgender women to assess risks for HIV acquisition and other health experiences. Further, this study aims to evaluate how an online cohort compares to a site-based, technology-enhanced cohort for epidemiologic research. The overarching goal is to estimate incidence of HIV and other health outcomes among transgender women in eastern and southern United States.
This substudy is part of a larger multisite prospective cohort (LITE) conducted among transgender women, which also includes a site-based, technology-enhanced cohort in 6 eastern and southern US cities. The online cohort was launched to enroll and follow participants across 72 cities in the same region and with similar demographic characteristics as the site-based cohort. Participants are followed for 24 months. Adult transgender women are recruited via convenience sampling (eg, peer referrals, social media, and dating apps). Participants reporting negative or unknown HIV status are enrolled in a baseline study visit, complete a sociobehavioral survey, and provide oral fluid specimens to test for HIV. Participants not living with HIV (lab-confirmed) at baseline are offered enrollment into the cohort; follow-up assessments occur every 6 months.
Enrollment into the online cohort launched in January 2019. Active recruitment stopped in May 2019, and enrollment officially closed in August 2020. A total of 580 participants enrolled into and are followed in the cohort. A recruitment-enrollment cascade was observed across screening, consent, and completion of study activities. Implementation experiences with HIV test kits highlight the need for heavy staff engagement to support participant engagement, visit completion, and retention, even with automated digital procedures.
This study is responsive to increasing research interest in digital observational and intervention research, particularly for populations who are most affected by the HIV epidemic and for those who may otherwise not participate in person. The progression across stages of the recruitment-enrollment cascade provides useful insight for implementation of cohort studies in the online environment.
DERR1-10.2196/29152.
Policy protections for transgender adults in the United States are consistently associated with positive health outcomes. However, studies over-represent non-Latinx White transgender people and ...obscure variation in policies' intended goals. This study examined racial differences in the relationship between transgender-related policies and transgender women's self-rated health. Guided by Critical Race Theory, we hypothesized that policies conferring access to resources (e.g., healthcare) would be associated with better self-rated health among all participants while policies signifying equality (e.g., nondiscrimination laws) would be associated with better self-rated health only for White participants.
Using cross-sectional data collected between March 2018-December 2020 from 1566 transgender women, we analyzed 7 state-level 'access policies,' 5 'equality policies,' and sum indices of each. Participants represented 29 states, and 54.7% were categorized as people of color. We fit a series of multilevel ordinal regression models predicting self-rated health by each policy. Multivariate models were adjusted for relevant covariates at the individual- and state-level. We then tested moderation by race/ethnicity using interaction terms and generated stratified predicted probability plots.
In bivariate models, 4 access policies, 2 equality policies, and both indices were associated with better self-rated health, but associations did not persist in adjusted models. Results from the multivariable models including interaction terms indicated that policies concerning private insurance coverage of gender-affirming care, private insurance nondiscrimination, credit nondiscrimination, and both indices were statistically significantly associated with better self-rated health for White participants and worse self-rated health for participants of color.
The policies included in this analysis do not mitigate racism's effects on access to resources, indicating they may be less impactful for transgender women of color than White transgender women. Future research and policy advocacy efforts promoting transgender women's health must center racial equity as well as transgender people of color's priorities.
5q31.3 microdeletion syndrome is characterized by neonatal hypotonia, encephalopathy with or without epilepsy, and severe developmental delay, and the minimal critical deletion interval harbors three ...genes. We describe 11 individuals with clinical features of 5q31.3 microdeletion syndrome and de novo mutations in PURA, encoding transcriptional activator protein Pur-α, within the critical region. These data implicate causative PURA mutations responsible for the severe neurological phenotypes observed in this syndrome.
WDR44 prevents ciliogenesis initiation by regulating RAB11-dependent vesicle trafficking. Here, we describe male patients with missense and nonsense variants within the WD40 repeats (WDR) of WDR44, ...an X-linked gene product, who display ciliopathy-related developmental phenotypes that we can model in zebrafish. The patient phenotypic spectrum includes developmental delay/intellectual disability, hypotonia, distinct craniofacial features and variable presence of brain, renal, cardiac and musculoskeletal abnormalities. We demonstrate that WDR44 variants associated with more severe disease impair ciliogenesis initiation and ciliary signaling. Because WDR44 negatively regulates ciliogenesis, it was surprising that pathogenic missense variants showed reduced abundance, which we link to misfolding of WDR autonomous repeats and degradation by the proteasome. We discover that disease severity correlates with increased RAB11 binding, which we propose drives ciliogenesis initiation dysregulation. Finally, we discover interdomain interactions between the WDR and NH
-terminal region that contains the RAB11 binding domain (RBD) and show patient variants disrupt this association. This study provides new insights into WDR44 WDR structure and characterizes a new syndrome that could result from impaired ciliogenesis.
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