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Activity in a set of parabranchial neurons in the mouse brain is increased during chronic pain, predicts coping behaviour, and can be modulated by circuits activated by survival threats.

Integrated multi-omic analyses using samples from the TRACERx study highlight cross-talk between DNA hypermethylation and genomic lesions in non-small cell lung cancer.

Federated learning (FL) algorithms have emerged as a promising solution to train models for healthcare imaging across institutions while preserving privacy. Here, the authors describe the Federated Tumor Segmentation (FeTS) challenge for the decentralised benchmarking of FL algorithms and evaluation of Healthcare AI algorithm generalizability in real-world cancer imaging datasets.

Trans-ancestry meta-analysis of estimated glomerular filtration rate (eGFR) from 1,046,070 individuals identifies 264 associated loci, providing a resource of molecular targets for translational research of chronic kidney disease.

Inbreeding depression has been observed in many different species, but in humans a systematic analysis has been difficult so far. Here, analysing more than 1.3 million individuals, the authors show that a genomic inbreeding coefficient (FROH) is associated with disadvantageous outcomes in 32 out of 100 traits tested.

A meta-analysis of genome-wide association studies of type 2 diabetes (T2D) identifies more than 600 T2D-associated loci; integrating physiological trait and single-cell chromatin accessibility data at these loci sheds light on heterogeneity within the T2D phenotype.

Urinary albumin-to-creatinine ratio (UCAR) is associated with various clinical outcomes such as kidney disease and cardiovascular disease. Here, the authors report genome-wide meta-analysis in over 500,000 individuals and find 68 UACR loci, followed by statistical fine-mapping, gene prioritization and experimental validation in flies.

X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases such as chronic kidney disease (CKD). Here, the authors perform a sex-stratified, cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits, with results including identification of four novel loci associated with the CKD-defining trait eGFR.

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.

Stratified medicine promises to tailor treatment for individual patients, however it remains a major challenge to leverage genetic risk data to aid patient stratification. Here the authors introduce an approach to stratify individuals based on the aggregated impact of their genetic risk factor profiles on tissue-specific gene expression levels, and highlight its ability to identify biologically meaningful and clinically actionable patient subgroups, supporting the notion of different patient ‘biotypes’ characterized by partially distinct disease mechanisms.

Responses to SARS-CoV-2 vaccines in different populations are important to define efficacy. Here the authors show using a cohort in Singapore that two doses of mRNA vaccine is less effective in recipients over 60 years of age and that a further dose of vaccine can improve these antibody levels.

National implementation of a computed tomographic angiography and AI-diagnostic tool, CT-derived fractional flow reserve (FFR-CT), did not provide significant benefits in reducing mortality but led to fewer invasive coronary angiograms and downstream cardiac tests.

Genome-wide association and fine-mapping analyses in ancestrally diverse populations implicate candidate causal genes and mechanisms underlying type 2 diabetes. Trans-ancestry genetic risk scores enhance transferability across populations.

The advantage of living in cities compared with rural areas with respect to height and BMI in children and adolescents has generally become smaller globally from 1990 to 2020, except in sub-Saharan Africa.

Tailored to provide diabetes management recommendations from large training and validation datasets, an artificial intelligence system integrating language and computer vision capabilities is shown to improve self-management of patients in a prospective implementation study.

Immune lymphocyte estimation from nucleotide sequencing (ImmuneLENS) infers B cell and T cell fractions from whole-genome sequencing data. Applied to the 100,000 Genomes Project datasets, circulating T cell fraction provides sex-dependent and prognostic insights in patients.

Analyses of multiregional tumour samples from 421 patients with non-small cell lung cancer prospectively enrolled to the TRACERx study reveal determinants of tumour evolution and relationships between intratumour heterogeneity and clinical outcome.

Analyses of the TRACERx study unveil the relationship between tissue morphology, the underlying evolutionary genomic landscape, and clinical and anatomical relapse risk of lung adenocarcinomas.

Major histocompatibility complex (MHC) loss of heterozygosity, allele-specific mutation and measurement of expression and repression (MHC Hammer) detects disruption to human leukocyte antigens due to mutations, loss of heterogeneity, altered gene expression or alternative splicing. Applied to lung and breast cancer datasets, the tool shows that these aberrations are common across cancer and can have clinical implications.

Swanton and colleagues present a clonal expression signature, ORACLE, which, in combination with clinicopathological and molecular risk factors, can predict survival of patients with lung adenocarcinoma, and they prospectively validate its prognostic value.

Federated ML (FL) provides an alternative to train accurate and generalizable ML models, by only sharing numerical model updates. Here, the authors present the largest FL study to-date to generate an automatic tumor boundary detector for glioblastoma.

Measurements of subclonal expansion of ctDNA in the plasma before surgery may enable the prediction of future metastatic subclones, offering the possibility for early intervention in patients with non-small-cell lung cancer.

Combination of epidemiology, preclinical models and ultradeep DNA profiling of clinical cohorts unpicks the inflammatory mechanism by which air pollution promotes lung cancer

In this work, authors report on the PET-CT outcomes from the use of adjunctive statin therapy, rosuvastatin, in the intensive phase of tuberculosis (TB) treatment. Rosuvastatin had no impact on PET-CT changes when used as an adjunct to TB treatment. 8-weeks of TB treatment resulted in ~50% reduction in total lesion glycolysis (TLG), a metric that combines the volume of lung affected and metabolic activity.

Phosphatase of regenerating liver 3 (PRL3) is usually found intracellularly, and is over-expressed in cancer cells. Here the authors show that PRL-3 is also detectable on cell surface, and can be recognized by PRL3-zumab to recruit immune cells into tumor to promote anti-tumor immunity, thereby implicating PRL-3 as a potential tumor antigen.

The MET receptor is frequently activated in cancer. Here, the authors show that in head and neck and lung squamous carcinoma, a polymorphic MET variant enhances binding to HER2, resulting in activation of HER2 signalling and progression of the cancers.

A longitudinal evolutionary analysis of 126 lung cancer patients with metastatic disease reveals the timing of metastatic divergence, modes of dissemination and the genomic events subject to selection during the metastatic transition.

A large-scale GWAS provides insight on diabetes-dependent genetic effects on the glomerular filtration rate, a common metric to monitor kidney health in disease.

The authors defined a roadmap for investigating the genetic covariance between structural or functional brain phenotypes and risk for psychiatric disorders. Their proof-of-concept study using the largest available common variant data sets for schizophrenia and volumes of several (mainly subcortical) brain structures did not find evidence of genetic overlap.

RNA sequencing data and tumour pathology observations of non-small-cell lung cancers indicate that the immune cell microenvironment exerts strong evolutionary selection pressures that shape the immune-evasion capacity of tumours.

An avalanche photodiode is an opto-electronic amplifier that uses impact ionization to provide enhanced sensitivity at the expense of excess noise. In this manuscript, the authors demonstrate that a small amount of Bismuth (Bi) in Gallium Arsenide (GaAs) avalanche photodiodes significantly reduces this excess noise.

Openshaw and colleagues find myeloid inflammation and complement activation signatures in patients with long COVID who were previously hospitalized.

Mixed responses to targeted therapy within a patient are a clinical challenge. Here the authors show that TP53 loss-of-function cooperates with whole genome doubling which increases chromosomal instability. This leads to greater cellular diversity and multiple routes of resistance, which in turn promotes mixed responses to treatment.

Characterisation of the human antibody response to SARS-CoV-2 can help the design of serological tests and vaccines. Here, the authors identify two linear epitopes in SARS-CoV-2 spike protein that elicit neutralising antibodies in several patients and could thus be useful for serology and vaccine development.

In lung adenocarcinoma, antibodies against endogenous retroviruses promote anti-tumour activity, and expression of endogenous retroviruses can predict outcomes of immunotherapy.

Computational and machine-learning approaches that integrate genomic and transcriptomic variation from paired primary and metastatic non-small cell lung cancer samples from the TRACERx cohort reveal the role of transcriptional events in tumour evolution.

Circulating tumour DNA profiling in early-stage non-small-cell lung cancer can be used to track single-nucleotide variants in plasma to predict lung cancer relapse and identify tumour subclones involved in the metastatic process.

COVID-19 can be associated with neurological complications. Here the authors show that markers of brain injury, but not immune markers, are elevated in the blood of patients with COVID-19 both early and months after SARS-CoV-2 infection, particularly in those with brain dysfunction or neurological diagnoses.

Results of the TRACERx study shed new light into the association between body composition and body weight with survival in individuals with non-small cell lung cancer, and delineate potential biological processes and mediators contributing to the development of cancer-associated cachexia.

The authors summarize the data produced by phase III of the Encyclopedia of DNA Elements (ENCODE) project, a resource for better understanding of the human and mouse genomes.

A survey of T cell repertoire evolution in the tumors, healthy tissue and blood of patients with early-stage untreated lung cancer offers an opportunity to monitor and identify neoantigen-specific T cells for personalized immunotherapy.

COVID-19 severity is associated with cytokine levels and lymphopenia, but the role of immune cell subsets is not well understood. Here the authors immunophenotype whole blood samples from 54 COVID-19 patients and find that the immature neutrophil-to-VD2 T-cell ratio is associated with severe COVID-19.

Sexual dimorphism in genetic vulnerability to schizophrenia, systemic lupus erythematosus and Sjögren’s syndrome is linked to differential protein abundance from alleles of complement component 4.

TRACERx Lung: Intratumoral transcriptional heterogeneity, which often hinders the development of clinically useful RNA-expression-biased biomarkers for cancer, can now be overcome with an approach for the identification of clonal expression biomarkers.

In the TRACERx cohort of 171 patients with lung cancer, the ultrasensitive detection of ctDNA improves preoperative patient stratification, also in early-stage disease.

Yuan and colleagues developed an artificial intelligence-based method to derive growth patterns and morphological features from hematoxylin and eosin-stained slides of lung adenocarcinoma samples, for improved tumor grading and patient prognostication.

Wu et al. utilize multiparametric analysis of early-stage human NSCLC to characterize a population of Vδ1 T cells displaying a resident memory and effector memory phenotype, which were associated with ongoing remission.

It is shown that circularly polarized light produces enantiomeric excesses, above 30%, of twisted nanoribbons self-assembled from racemic dispersions of CdTe nanoparticles.