Prioritization of causal genes from genome-wide association studies by Bayesian data integration across loci.

Motivation: Genome-wide association studies (GWAS) have identified genetic variants, usually single-nucleotide polymorphisms (SNPs), associated with human traits, including disease and disease risk. These variants (or causal variants in linkage disequilibrium with them) usually affect the regulation or function of a nearby gene. A GWAS locus can span many genes, however, and prioritizing which gene or genes in a locus are most likely to be causal remains a challenge.

The RNA-binding protein HuR impairs adipose tissue anabolism in pancreatic cancer cachexia.

Background: Cachexia is defined by chronic loss of fat and muscle, is a frequent complication of pancreatic ductal adenocarcinoma (PDAC), and negatively impacts patient outcomes. Nutritional supplementation cannot fully reverse tissue wasting, and the mechanisms underlying this phenotype are unclear. This work aims to define the relative contributions of catabolism and anabolism to adipose wasting in PDAC-bearing mice.

Bispecific antibody targeting of lipid nanoparticles.

Lipid nanoparticles (LNP) are the most clinically advanced non-viral gene delivery system. While progress has been made for enhancing delivery, cell specific targeting remains a challenge. Targeting moieties such as antibodies can be chemically-conjugated to LNPs however, this approach is complex and has challenges for scaling up.

Dendritic cells type 1 control the formation, maintenance, and function of tertiary lymphoid structures in cancer.

Tertiary lymphoid structures (TLS) are organized immune cell aggregates that arise in chronic inflammatory conditions. In cancer, TLS are associated with better prognosis and enhanced response to immunotherapy, making these structures attractive therapeutic targets. However, the mechanisms regulating TLS formation and maintenance in cancer are incompletely understood.

The expected polygenic risk score (ePRS) framework: an equitable metric for quantifying polygenetic risk via modeling of ancestral makeup.

Polygenic risk scores (PRSs) depend on genetic ancestry due to differences in allele frequencies between ancestral populations. This leads to implementation challenges in diverse populations. We propose a framework to calibrate PRS based on ancestral makeup.

Participant perspectives related to individual chemical exposure report-back approaches in three environmental health studies.

Returning results to participants of environmental exposure studies has become more common in recent years. Despite evidence of benefits for study participants, there are challenges in communicating results to people with limited resources or capacity to mitigate chemical exposures. We interviewed N = 54 participants and compared exposure report-back conducted in 2010-2013 across three susceptible study populations: 1) low-income pregnant individuals in the Chemicals in Our Bodies (CIOB) study; 2) the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) cohort; and 3) early childhood educators (ECE).

Challenges and Opportunities in Targeting the Complex Pancreatic Tumor Microenvironment.

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths with a 5-year survival rate of 13%. Surgical resection remains the only curative option as systemic therapies offer limited benefit. Poor response to chemotherapy and immunotherapy is due, in part, to the dense stroma and heterogeneous tumor microenvironment (TME).

Genomic Landscape of Thrombosis Recurrence Risk Across Venous Thromboembolism Subtypes.

Venous thromboembolism (VT) is a frequent (annual incidence of 1 to 2 per 1,000) and potentially life-threatening (case-fatality rate up to 10%) disease. VT is associated with serious short-term and long-term complications including a recurrence rate of approximately 20% within five years. Anticoagulant therapy, the mainstay of VT treatment, drastically reduces the risk of early VT recurrence, but it exposes patients to a substantial risk of bleeding.

Utility of Abdominal Cross-Sectional Imaging in Motor Vehicle Accidents in an Inner City Trauma Center: A Retrospective Cohort Study.

Background The use of computed tomography (CT) of the abdomen and pelvis following motor vehicle collisions (MVCs) as standard diagnostic evaluation is widely accepted. However, the incidence of positive findings is low, and it is unknown which features increase the risk of having abdominal injuries. Objectives The aim of this study is to identify risk factors on presentation that are associated with positive CT findings.

Dexamethasone is associated with reduced frequency and intensity of cytokine release syndrome compared with alternative corticosteroid regimens as premedication for glofitamab in patients with relapsed / refractory large B-cell lymphoma.

Not available.

The polymeric fluoropyrimidine CF10 overcomes limitations of 5-FU in pancreatic ductal adenocarcinoma cells through increased replication stress.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease soon to become the second leading cause of cancer deaths in the US. Beside surgery, current therapies have narrow clinical benefits with systemic toxicities. FOLFIRINOX is the current standard of care, one component of which is 5- Fluorouracil (5-FU), which causes serious gastrointestinal and hematopoietic toxicities and is vulnerable to resistance mechanisms.

Quantifying Medical Waste at a Veterans Affairs Operating Room.

Medical waste is an environmental, financial, and administrative burden to the health care system. Attempts to decrease waste should begin by quantifying the amount of waste at an individual facility. This study attempts to quantify the amount of medical waste associated with operative cases at an urban Veterans Affairs Medical Center (VAMC).

CASPER: A Phase I trial combining calaspargase pegol-mnkl and cobimetinib in pancreatic cancer.

Asparagine synthetase (ASNS) catalyzes the biosynthesis of asparagine from aspartate and glutamine. Cells lacking ASNS, however, are auxotrophic for asparagine. Use of L-asparaginase to promote asparagine starvation in solid tumors with low ASNS levels, such as pancreatic ductal adenocarcinoma (PDAC), is a rationale treatment strategy.

The Pivotal Role of Germline BRCA2 Pathogenic Variants in "Apparently Sporadic" Pancreatic Cancer.

In 1996, Goggins and colleagues demonstrated the importance of germline BRCA2 pathogenic variants in the development of apparently sporadic pancreatic ductal adenocarcinoma (PDAC). Previously, the group identified homozygous deletion of the 13q region in PDACs, enabling the identification of the BRCA2 gene. This 1996 article first revealed loss of BRCA2, both germline and somatic, as a key driver of PDAC at a time when there was still doubt if PDAC even had an inherited component.

Single-Ancestry versus Multi-Ancestry Polygenic Risk Scores for CKD in Black American Populations.

Key Points: The predictive performance of an African ancestry–specific polygenic risk score (PRS) was comparable to a European ancestry–derived PRS for kidney traits. However, multi-ancestry PRSs outperform single-ancestry PRSs in Black American populations. Predictive accuracy of PRSs for CKD was improved with the use of race-free eGFR.

A Large-Scale Genome-Wide Study of Gene-Sleep Duration Interactions for Blood Pressure in 811,405 Individuals from Diverse Populations.

Although both short and long sleep duration are associated with elevated hypertension risk, our understanding of their interplay with biological pathways governing blood pressure remains limited. To address this, we carried out genome-wide cross-population gene-by-short-sleep and long-sleep duration interaction analyses for three blood pressure traits (systolic, diastolic, and pulse pressure) in 811,405 individuals from diverse population groups. We discover 22 novel gene-sleep duration interaction loci for blood pressure, mapped to 23 genes.

Epigenome-wide DNA Methylation Association Study of CHIP Provides Insight into Perturbed Gene Regulation.

With age, hematopoietic stem cells can acquire somatic mutations in leukemogenic genes that confer a proliferative advantage in a phenomenon termed "clonal hematopoiesis of indeterminate potential" (CHIP). How these mutations confer a proliferative advantage and result in increased risk for numerous age-related diseases remains poorly understood. We conducted a multiracial meta-analysis of epigenome-wide association studies (EWAS) of CHIP and its subtypes in four cohorts (N=8196) to elucidate the molecular mechanisms underlying CHIP and illuminate how these changes influence cardiovascular disease risk.