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A combination of real-world evidence and a reanalysis of phase 3 clinical trial data unveils KRAS codon G12 mutations as a biomarker of resistance to trifluridine/tipiracil in metastatic colorectal cancer.

Here, the authors developed a plasma cell-free RNA test for early PDAC detection in high-risk and symptomatic patients.

Aging is a risk factor for neurodegenerative diseases associated with protein aggregation. Here the authors identify age-related hyperactivation of EPS8/RAC signaling in C. elegans as a driver of pathological protein aggregation, highlighting EPS8 and its regulators as potential therapeutic targets.

Triple-negative breast cancer (TNBC) is a heterogenous disease with several molecular subtypes previously described. Here the authors perform a spatial transcriptomics analysis on a series of 92 patients, providing additional insights into the heterogeneity of TNBC, with implications for clinical outcomes and therapy.

Multiomic analysis of blast-phase myeloproliferative neoplasms identifies a chromosome 21 amplicon harboring DYRK1A as a clonal and therapeutically targetable event in around a quarter of cases.

The quark structure of the f₀(980) hadron is still unknown after 50 years of its discovery. Here, the CMS Collaboration reports a measurement of the elliptic flow of the f₀(980) state in proton-lead collisions at a nucleon-nucleon centre-of-mass energy of 8.16 TeV, providing strong evidence that the state is an ordinary meson.

People who experience optic neuritis, a cause of potentially serious sudden vision loss, have up to a 50% chance of ultimately being diagnosed with multiple sclerosis. Here, the authors find that genetic information combined with age and sex helps predict risk of future diagnosis of multiple sclerosis.

A machine learning model that uses longitudinal ctDNA metrics robustly predicts survival in two phase 3 trials of patients with metastatic NSCLC, which may improve therapy selection and risk stratification.

Two phase 2 trials, along with translational analysis of prospective cohorts and experimental analysis, indicate that immunosenescence as a mechanism of resistance to immunotherapy can be overcome with the senolytics dasatinib and quercetin in patients with head and neck squamous cell carcinoma.

Using pancreatic organoids and genetic mouse models, Antonucci et al. show that cellular stress activates an NRF2–EZH2 epigenetic axis leading to metabolic reprogramming and subsequent malignant transformation of KRAS-mutant benign lesions.

Schuermans et al. identify a causal relationship between the circulating proteins spondin-1 and atrial fibrillation and SPINT1 and coronary artery disease and show that adding proteomic data improves clinical risk factor-based cardiovascular risk prediction.

The Huntington's disease (HD) induced pluripotent stem cell (iPSC) consortium describe the combined use of differentiated patient-derived iPSCs and systems biology to discover underlying mechanisms in HD. They identify neurodevelopmental deficits in HD cells that can be corrected in cells and in vivo with a small molecule.

Assessing brain aging heterogeneity in a cohort of 49,482 individuals from 11 studies, a generative model identifies five dominant patterns of brain atrophy, with specific associations with biomedical, lifestyle and genetic factors.

Genome-wide association analyses identify new risk loci for heart failure and its subtypes, extending understanding of the underlying biological pathways and disease mechanisms.

Supervised deep learning models hold promise for the interpretation of histology images, but are limited by cost and quality of training datasets. Here, the authors develop a self-supervised deep learning method that can automatically discover features in cancer histology images that are associated with diagnosis, survival, and molecular phenotypes.

Candida auris is a fungal pathogen notorious for persistent skin colonization and transmission in healthcare settings. Here, Zhao et al. explore the mechanisms driving pathogen’s adherence to skin, involving a conserved adhesin, as well as the potential of collagen coatings as a strategy to reduce C. auris adherence to abiotic surfaces.

Circulating tumor DNA (ctDNA) allows genotyping of the tumor in multiple myeloma. Here, the authors show that minimal residual disease (MRD) by ctDNA can be detected after CAR-T therapy correlates with bone marrow-based MRD to track clonal evolution and inform treatment resistance mechanisms.

Using data from a phase 3 efficacy trial, the authors here show that post-boost Omicron BA.1 spike-specific binding and neutralizing antibodies inversely correlate with Omicron COVID-19 and booster efficacy for naive and non-naive participants, supporting the continued use of antibody as a surrogate endpoint.

The mechanisms responsible for stimulating biogeochemical activity in the hyporheic corridor (HC) are poorly understood. Here, the authors find that previously unrecognized thermodynamic mechanisms regulated by groundwater-river water mixing may strongly influence HC biogeochemical and microbial dynamics.

Brain-iron elevation is implicated in Alzheimer’s disease (AD), but the impact of the metal on disease outcomes has not been analysed in a longitudinal study. Here, the authors examine the association between the levels of ferritin, an iron storage protein, in the cerebrospinal fluid (CSF) of AD patients and show that CSF ferritin levels predict AD outcomes.

Sarcoma is a highly heterogeneous disease, which can be caused by a large variety of mutations. Here, the authors utilise multi-omics to characterise a cohort of 1,340 sarcoma tissue specimens to identify key somatic mutations and identify immune subtypes.

A global network of researchers was formed to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity; this paper reports 13 genome-wide significant loci and potentially actionable mechanisms in response to infection.

A polygenic hazard score (PHS₁) improves prostate cancer screening accuracy in European patients. Here, the authors test the performance of a version compatible with OncoArray genotypes (PHS₂) in a multi-ethnic dataset and find that it risk-stratifies men for any, aggressive, and fatal prostate cancer.

Hundreds of genetic loci associated with age at menopause, combined with experimental evidence in mice, highlight mechanisms of reproductive ageing across the lifespan.

In a large multicentric study of patients with advanced NSCLC undergoing anti-PD-1 therapy, the relative abundance of intestinal Akkermansia spp. was shown to associate with changes in the gut microbiome ecosystem and clinical outcomes.

Vitamin E metabolites are proposed to have signalling capacity, but how they may regulate immune responses is still unclear. Here the authors show that a vitamin E metabolite, α-T-13′-COOH, can inhibit 5-lipoxygenase and thereby suppress the synthesis of lipid mediators of immune activation and inflammatory responses.

Single-cell RNA-sequencing analysis of intestinal mesenchyme identified a population of fibroblasts that produce prostaglandin E₂, which, when disrupted, prevented initiation of intestinal tumours.

Mutations in RAS oncogenes and related pathways are frequent in lung cancers. Here, the authors derive a RAS gene expression signature and a machine learning classifier to predict drug response and clinical outcomes in lung adenocarcinoma and other solid tumours, with improved performance over KRAS mutations alone.

Autologous tumor lysate (ATL) dendritic cell (DC) vaccination can induce local and systemic anti-tumor immune responses in malignant glioma patients. In this randomized phase II clinical trial, the authors evaluate the effectiveness of adding the TLR agonists, poly-ICLC or resiquimod, to ATL-DC vaccination in patients with newly-diagnosed or recurrent WHO Grade III-IV malignant gliomas.

Joint analysis of new and previously published sequencing data for primary and metastatic prostate cancers identifies new candidate driver mutations and provides insights into disease progression and potential drug targets.

Whole-genome sequencing of more than 2,000 colorectal carcinoma samples provides a highly detailed view of the genomic landscape of this cancer and identifies new driver mutations.

The identification of prognostic biomarkers can help stratify cancer patients. Here, the authors apply deep RNA sequencing from primary melanomas coupled with long-term clinical outcome data from a prospective multicentre phase III trial, to develop and validate a 121 metastasis-associated gene signature identifying early-stage melanoma patients at higher risk of metastasis and worse survival.

Viral pathogen load in cancer genomes is estimated through analysis of sequencing data from 2,656 tumors across 35 cancer types using multiple pathogen-detection pipelines, identifying viruses in 382 genomic and 68 transcriptome datasets.

CREBBP mutations in B-cell acute lymphoblastic leukemia (B-ALL) are linked to poor prognosis and chemoresistance. Here, the authors show that genetic or pharmacological inactivation of CREBBP sensitizes B-ALL cells to the BCL2 inhibitor Venetoclax, inducing ferroptotic cell death and extending survival in B-ALL preclinical mouse models.

Radionuclide brachytherapy delivered via an injectable biopolymer depot conjugated with iodine-131 and combined with systemically delivered paclitaxel induced the complete regression of multiple subcutaneous and orthotopic pancreatic tumours in mice.

Here, the authors analyze 17 retinal vascular phenotypes in 72,000 subjects, finding links between retinal morphology and medical conditions including heart disease.

The tumor immune microenvironment is an important determinant of clinical outcomes and therapeutic responses in patients with triple-negative breast cancer (TNBC). Here the authors perform digital spatial profiling of tumor tissues to characterize the spatial immunobiology of treatment-naïve TNBC.

‘Engraftment of patient-derived xenografts in samples from head and neck squamous cell carcinoma is variable. Here, the authors use transcriptomic and proteomic profiling to correlate engraftment of PDX with molecular phenotype, and validate LAMC2 and TGM3 as potential biomarkers of stratification.