Broad Institute

Metabolomic profiling reveals distinct and shared biology in COPD and IPF

Chronic Obstructive Pulmonary disease (COPD) and Idiopathic Pulmonary Fibrosis (IPF) are chronic pulmonary disorders with distinct pathologies but shared risk factors. Metabolomics may provide insights into mechanisms. To identify metabolites associated with COPD and IPF, and to...

Correlation of polygenic risk score and clinical phenotype in patients with genetic generalized epilepsy

Abstract Objective The polygenic risk score (PRS) for individuals with genetic generalized epilepsy (GGE) quantifies the common risk variants in genes identified in genome‐wide association studies. We hypothesized that the phenotype of GGE patients differs based on their GGE PRS....

Acute Ethanol Exposure Inhibits GABA Uptake in Embryonic Chicken Retina

Abstract GABA is the major inhibitory amino acid in the central nervous system (CNS), and its homeostasis is crucial for inhibitory/excitatory balance. Its reuptake is mediated by GABA transporters, including type 1 (GAT-1), a high-affinity GABA plasma membrane transporter. Ethan...

Functional Multireference Alignment via Deconvolution

Abstract. This paper studies the multireference alignment (MRA) problem of estimating a signal function from shifted, noisy observations. Our functional formulation reveals a new connection between MRA and deconvolution: the signal can be estimated from second-order statistics vi...

Rare variant effect estimation and polygenic risk prediction

Abstract Due to their low frequency, estimating the effect of rare variants is challenging. Here, we propose RareEffect, a method that first estimates gene- or region-based heritability and then each variant effect size using an empirical Bayes approach. Our method uses a varianc...

The burden of low back pain in the United States, 1990 to 2021

Low back pain (LBP) is a major global health concern and remains a leading contributor to healthcare expenditure in the United States (US). Few recent studies have systematically analyzed the temporal, geographic, and demographic patterns of LBP burden and its associated risk fac...

Splicing genes as main targets of differential splicing

Abstract Splicing of transcripts via the spliceosome machinery is a complex process involving a multitude of proteins and short noncoding RNAs. In addition to full-length transcripts with all exons in the genomically encoded order, alternatively spliced transcripts can also be pr...

Platelet Reactivity and Sex Differences: Clinical Implications for Women

Platelets are central to hemostasis and thrombosis. Excessive platelet activation contributes to arterial thrombotic events, including myocardial infarction, ischemic stroke, and complications of peripheral artery disease, whereas excessive platelet inhibition increases bleeding...

Fatal Neuroinvasive Astrovirus VA1 Encephalitis in a Child With High‐Risk B‐ALL Receiving Blinatumomab

O.L. is a named inventor on patents held by Boston Children's Hospital related to vaccine adjuvants and antigens as well as human in vitro systems that model the safety and immunogenicity of vaccines and immunotherapeutics. O.L.’s laboratory receives sponsored research support fr...

Acquired resistance to the RAS(ON) multi-selective inhibitor daraxonrasib guides rational combination therapy strategies in pancreatic cancer

Abstract Daraxonrasib is an orally bioavailable RAS(ON) multi-selective tri-complex inhibitor of the oncogenic mutant and wild-type variants of N, H and KRAS. We previously reported encouraging efficacy in a phase 1/2 clinical trial evaluating daraxonrasib monotherapy at clinical...

Challenges and approaches to genetic variants of uncertain significance in clinical practice and research

Despite advances in sequencing technologies and variant interpretation frameworks, many variants identified in genetic testing, particularly missense variants, remain classified as variants of uncertain significance (VUS), posing ongoing challenges in diagnosis and clinical manag...

A compendium of next-generation patient-derived models for diverse cancers

Abstract The development of new therapeutics and the validation of pathogenetic cancer mechanisms require representative laboratory models 1,2 . However, existing collections represent only a fraction of the diversity observed in human cancer 2–4 . Recent technologies have enable...

Fecal microbiome transplant in food allergy in humans and mice identifies a role for bile acid metabolites in oral tolerance

The gut microbiome has been implicated in the pathogenesis of food allergy (FA), prompting microbiome-focused interventions. We evaluated, in a phase 1 open-label trial (NCT02960074), the safety and efficacy of oral encapsulated fecal microbiome transplantation (FMT) in 15 adults...

A dependency map enhanced with next-generation 3D cancer models

Despite advances in precision oncology, effective personalized treatments are still lacking for most patients with cancer1. The Cancer Dependency Map (DepMap) accelerates this field by systematically identifying cancer vulnerabilities in diverse preclinical models. Data from over...

A comprehensive assessment of tandem repeat genotyping methods for Nanopore long-read genomes

Tandem repeats play critical roles in human disease and phenotypic diversity but are among the most challenging classes of genomic variation to measure accurately. Long-read sequencing has the potential to accurately characterize long and complex tandem repeats. While an increasi...

High-throughput engineering of bispecific antibodies to enhance macrophage-mediated cytotoxicity of B-cell lymphoma

Abstract Macrophages are critical effectors of antibody therapies for lymphoma, but the best targets to engage their function remain unknown. Here, we develop a ‘tactical surfaceome profiling’ strategy to define a comprehensive repertoire of surface antigens on B-cell lymphoma th...