Broad Institute

The next-generation biomarkers in early-stage triple negative breast cancer

PURPOSE OF REVIEW: Despite maximal neoadjuvant chemoimmunotherapy, nearly 40% of early-stage triple-negative breast cancer (TNBC) patients fail to achieve pathological complete response, underscoring an urgent need for biomarkers capable of guiding treatment modulation. This revi...

Mitochondria-Associated Transcription Precedes Oxidative Phosphorylation in Human Embryos

Abstract Mitochondria undergo significant structural and functional changes during human pre-implantation embryogenesis, yet the transcriptional activity of both nuclear-encoded mitochondria-associated genes and mitochondrially transcribed genes across this developmental window r...

EBV reactivation priming of the peripheral immune system in multiple sclerosis relapse

Despite decades of research, the cellular and molecular events preceding multiple sclerosis (MS) relapse remain incompletely understood. Here, in this observational study of longitudinal blood samples from patients with relapsing-remitting MS, we used single-cell RNA sequencing,...

Clinical AI and Precision Medicine: Philosophical Questions About Labels, Disease, and Evidence

Precision medicine is often framed as a move from “average-patient” care toward prevention, diagnosis, and treatment tailored to individual variability. This aspiration has been articulated in major policy and scientific calls for a new evidence-generating health system and a new...

Artificial intelligence in clinical trials—state of the evidence, gaps, and next steps

Artificial intelligence (AI) affects clinical trials in two distinct but overlapping ways: as the intervention under evaluation and as infrastructure supporting trial design, recruitment, monitoring, endpoint assessment, analysis, and reporting. In this manuscript, we define AI-a...

A HUWE1 regulatory helix gates ASCL1 degradation through its C-terminal phospho-degron in small cell lung cancer

Lineage-defining transcription factors are key oncogenic drivers but remain difficult to target pharmacologically due to the absence of ligandable pockets. The molecular rules governing substrate recognition by large HECT ubiquitin ligases also remain incompletely understood, lim...

Extensive and differential platinum chemotherapy mutagenesis in livers of children

Childhood cancer survivors often experience late adverse effects that may be linked to chemotherapy mutagenesis. We studied chemotherapy mutagenesis in normal pediatric tissues using duplex sequencing (NanoSeq) to enable the detection of mutations from single DNA molecules. We fo...

Early-Enrichment Hit Discovery via Reversible-Work c(t) Estimation in Metadynamics (CTMD)

Abstract Virtual screening for small-molecule binders is often limited by false positives from approximate scoring functions and rigid-receptor assumptions. These can be addressed downstream through accurate but expensive free-energy calculations. At the same time, recent artific...

About a Ball Removal Process on Bins

We consider a basic balls-and-bins question in which you have to distribute n balls into k bins. Then, round by round, a ball is removed from a nonempty bin chosen uniformly at random. The process ends when a single nonempty bin remains. The goal is to minimize the expected numbe...

Machine learning–driven spleen imaging and genomics uncover a splenic connection to coronary artery disease

Despite advances in managing traditional risk factors, coronary artery disease (CAD) remains the leading cause of mortality. Circulating hematopoietic cells influence risk for CAD separately from traditional risk factors, but the role of a key regulating organ, the spleen, is unk...

Accurately modeling RNase H-mediated antisense oligonucleotide efficacy.

, achieving a 5.72-fold reduction in screening effort compared to random selection. ASO Atlas provides the first systematic resource to rigorously evaluate hypotheses regarding key parameters in ASO design, including sequence composition, chemical modifications, and target region...

An Updated Evidence Assessment of the Genetic Causes of Dilated Cardiomyopathy

BACKGROUND: Evidence of the diverse genetic architecture of dilated cardiomyopathy (DCM) continues to emerge and requires reassessment of the clinical relevance of implicated disease genes. Building on the 2019-2020 Clinical Genome Resource evaluation, the DCM gene curation exper...

Integration of proteomic aging clocks in a phase 2a clinical trial supports simultaneous geroprotective assessment

Abstract Drugs for aging-related diseases may modulate aging itself, but standard clinical trial designs cannot detect such effects. Aging clocks could close this gap, but epigenetic models often yield inconsistent, hard-to-interpret results. In contrast, proteomic clocks, by tra...

Omic risk scores are associated with COPD-related traits across three cohorts

Background: Chronic obstructive pulmonary disease (COPD) exhibits marked heterogeneity in lung function decline, mortality, exacerbations, and other disease-related outcomes. Omic risk scores (ORS) estimate the cumulative contribution of omics, such as the transcriptome, proteome...

Nuclear Localization Signals Enable the Cellular Delivery of an Anti-CRISPR Protein to Control Genome Editing

ABSTRACT Precise regulation of Cas9 activity is essential to minimize off-target effects, mosaicism, chromosomal alterations, immunogenicity, and genotoxicity in genome editing. Although type II anti-CRISPR proteins (Acrs) can inhibit and regulate Cas9, their size and anionic cha...

Loss of salt iodization harmed child survival and academic achievement in Ethiopia

Abstract The introduction of salt iodization is associated with improved health and socioeconomic outcomes, but is not yet universally adopted and not always sustained. Using a quasi-experimental event study with difference-in-differences over space and time, we quantify the impa...

Robust inference and correlates from genetic associations with personality

Personality traits describe stable differences in how people think, feel and behave, and how they interact with and experience their social and physical environments1,2. Many questions remain unanswered about associations between DNA and personality traits, such as their robustne...

Development of adjuvanted HIV vaccines tailored for early life: immunologic rationale, clinical experience, and future directions

Purpose of review This review highlights the rationale for and clinical experience in advancing age-specific adjuvantation systems to develop well tolerated and effective pediatric HIV vaccines. Recent findings Due to both cellular and soluble factors, infant immunity is distinct...

Dietary protein governs the role of insulin signaling in the postprandial regulation of hepatic mTORC1

The nutrient-sensing mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway controls cellular and organismal growth and metabolism, while aberrant activation is linked to human disease, including metabolic disease. Cellular studies have established several regulator...

Deviations from genetic additivity driven by rare variants at biobank scale

Abstract Additive genetic models are the default for genome-wide association studies, but deviations from additivity are crucial for understanding disease mechanisms and therapeutic responses. Yet existing methods for testing nonadditivity are computationally infeasible for large...