Cell Reports

Immune effector cell-associated neurotoxicity syndrome (ICANS) is a common and life-threatening complication of chimeric antigen receptor (CAR) T-cell therapy, with early detection being critical for timely intervention and improved outcomes. Cytokines such as interleukin-6 (IL-6) are key mediators of the inflammatory cascade underlying ICANS pathogenesis, but prospective clinical evidence for their predictive value is limited. Here we quantify IL-6 levels in a prospective cohort of 40 CAR-T pat...

Clear cell renal cell carcinoma (ccRCC) is the leading cause of kidney cancer-related death, but how the tumor microenvironment shapes patient survival is not completely understood. Here, we describe the characterization of ccRCC tumor ecosystems from 498 patients using imaging mass cytometry with a focus on tumor, myeloid, and T cell landscapes. Data from more than 3 million single cells is analyzed using machine-learning to identify key ecosystem features that outperform basic clinical data fo...

Vaccination frequently elicits suboptimal immunogenicity in organ transplant recipients, particularly those on long-term immunosuppressive therapy, highlighting the need for improved understanding of immunosuppression mechanisms and optimized vaccination strategies. This study enrolled a cohort of 132 individuals and observed significantly lower antibody levels in kidney transplant recipients (KTRs) compared to non-transplant controls (non-KTRs). Antibody levels were inversely associated with bo...

RIG-I is a cytosolic immune receptor that provides the first line of defense by detecting viral RNA and triggering antiviral responses. Its physiological role in humans remains unclear, as no patients with complete RIG-I deficiency have yet been reported. We identified a critically ill COVID-19 patient with severe RIG-I deficiency caused by heterozygous RIG-I G731R, a novel dominant loss-of-function variant. The G731R mutation in helicase motif VI disrupts the arginine finger, impairing the ATPa...

Molecular subtyping of cancer is traditionally defined in transcriptomic space, yet routine clinical deployment is limited by the availability and cost of sequencing. Meanwhile, histopathology captures rich morphological information that is known to correlate with molecular state but lacks a principled, mechanistic bridge to gene-level representations. We propose a graph-constrained learning framework that aligns morphology-derived signals with a fixed, data-driven gene network discovered via hi...

BackgroundIn immune checkpoint inhibitor (ICI) trials, overall survival (OS) benefits are well established, yet improvements in quality of life (QoL) are often inconsistent or absent in conventional analyses. This apparent discordance raises important questions: are QoL outcomes truly unrelated to survival, and how can QoL results be better utilized and interpreted? MethodsA model-based meta-analysis (MBMA) of longitudinal EORTC QLQ-C30 global health status/quality of life data from randomized ...

Chromosome 5p15.33 harbors several independent association signals which demonstrate antagonistic pleiotropy across cancer types, with causal mechanisms largely unresolved. To identify functional variants and enhancer elements at this locus, we performed statistical fine-mapping followed by massively parallel reporter assays (MPRA) and proliferation based CRISPRi screens. This approach identified eight multi-cancer functional variants (MCFVs) across three GWAS signals. Targeting rs421629 (part o...

BackgroundThe management of residual axillary disease after neoadjuvant therapy (NAT) remains controversial, as current recommendations often treat ypN1 breast cancer as a homogeneous entity despite potential prognostic heterogeneity. Evidence supporting uniform axillary surgical strategies across different levels of residual nodal burden is limited. We investigated whether survival associations related to axillary surgical evaluation differ according to residual nodal burden in ypN1 disease, us...

Multi-cancer early detection (MCED) tests can detect several cancer types and stages. We previously developed a methylation and protein (MP V1) MCED classifier. In this study, we present a refined MP V2 classifier, developed by evaluating model architectures that improved performance in prospectively enrolled case-control cohorts under standard testing conditions. The newly developed MP V2 classifier was trained to be more generalizable and achieve increased early-stage sensitivity at a target s...

Drug-induced liver injury (DILI) is an acute inflammatory liver disease caused not only by prescription and over-the-counter medications but also by health foods and dietary supplements. Typically, DILI patients recover once the causative substance is identified and discontinued. In contrast, autoimmune hepatitis (AIH) results from the immune-mediated destruction of hepatocytes due to a breakdown of self-tolerance mechanisms. Patients presenting with acute-onset AIH often lack characteristic cli...

A recent randomized clinical trial in non-small cell lung cancer1 confirms what numerous observational studies have reported time of day (ToD) may dramatically influence treatment outcomes in cancer patients. In this recent trial median overall survival (OS) decreased from 28 months in the early ToD arm to 16.8 months in the late ToD arm. We raise the concern that clinical trial outcomes may be influenced by seemingly minor biases in treatment time across arms. We also suggest that by measuring ...

Introduction: Manual data extraction from unstructured clinical notes is labor-intensive and impractical for large-scale clinical and research operations. Existing automated approaches typically require large language models, dedicated computational infrastructure, and/or task-specific fine-tuning that depends on curated data. The objective of this study is to enable accurate extraction with smaller locally deployed models using a disease-site specific pipeline and prompt configuration that are ...

Background: Quantitative genome wide association studies (GWAS) primarily rely on additive linear models that compare average phenotypic differences between genotype groups. While effective for detecting common variants of moderate effect in large sample sizes, such approaches inherently reduce high resolution phenotypic data to summary statistics (group averages), potentially limiting the detection of subtle genotype phenotype relationships. Genomic Informational Field Theory (GIFT) is a recent...

Syphilis remains a major public health concern. However, current serologic assays are limited in their ability to distinguish active from previously treated disease. We applied tandem mass tag-based quantitative proteomics to plasma from 10 adults with active syphilis and 10 age- and gender-matched non-diseased controls. We identified 54 differentially regulated proteins (36 upregulated, 18 downregulated). Those proteins map to immune and inflammatory responses, acute-phase signaling, coagulatio...

Background: Quadriceps weakness may reduce sagittal plane shock absorption during landing, shifting load toward the frontal plane and increasing knee abduction moment (KAM), a biomechanical risk factor for anterior cruciate ligament (ACL) injuries. Purpose: The purpose of this study was to evaluate the association between isokinetic quadriceps strength and peak KAM during drop vertical jump landing in adolescent athletes. Study Design: Secondary analysis of previously collected data. Methods: He...

Acute kidney injury (AKI) and chronic kidney disease (CKD) are two interconnected clinical conditions, both defined by degree of functional impairment, but with heterogeneous clinical trajectories. Using new transcriptomic technologies, recent studies have described the cellular diversity in the healthy and injured kidney at the single cell level. Here, we used single nucleus transcriptomics to investigate the molecular diversity and commonalities in kidney biopsies from over 150 participants wi...

Biological fitness quantifies the efficiency and selective advantage of pathogens and hosts in their bilateral interaction. Key questions--such as how much more infectious an emerging variant is compared with its predecessor, or how much protection vaccination offers relative to no vaccination--require fitness to be measured systematically, in real time, and ideally beyond controlled laboratory settings. We propose an approach that infers biological fitness from mostly non-biological data on inf...

The use of semaglutide (SE), a glucagon-like peptide-1 receptor agonist (GLP-1RA) with glucose-lowering and weight-loss effects, has risen rapidly, particularly among women of reproductive age. While preclinical studies suggest benefits for ovarian function via the hypothalamic-pituitary-ovarian axis, its impact on the endometrial-embryo interface remains unclear. Here, we show that GLP-1R is dynamically expressed in fertile human endometrium, restricted to epithelial cells and markedly upregula...

Purpose: Tumor genomic testing (TGT) is standard-of-care for most patients with advanced/metastatic cancer. Despite established guidelines, patient education prior to TGT is frequently omitted. The purpose of this study was to evaluate the impact and durability of a concise 3-4 minute video for patient education prior to TGT in community versus academic sites and across cancer types. Patients and Methods: Patients undergoing standard-of-care TGT were enrolled at a tertiary academic institution ...

Importance: Lung cancer mortality in the United States has fallen substantially in recent decades, yet the relative influence of behavioral, environmental, socioeconomic, and therapeutic factors and their sex specific contributions remains unclear. Understanding these drivers is essential to sustain progress and reduce persistent disparities. Objective: To quantify how behavioral, environmental, socioeconomic, and therapeutic determinants collectively shaped US lung cancer mortality from 1994 to...