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An analysis of 24,202 critical cases of COVID-19 identifies potentially druggable targets in inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

High-depth sequencing of non-cancerous tissue from patients with metastatic cancer reveals single-base mutational signatures of alcohol, smoking and cancer treatments, and reveals how exogenous factors, including cancer therapies, affect somatic cell evolution.

Governments, universities and journals all have roles to play in dealing with fraud, says Emma Marris.

Hutchinson-Gilford Progeria Syndrome is characterized by premature aging with cardiovascular disease being the main cause of death. Here the authors show that inhibition of the NAT10 enzyme enhances cardiac function and fitness, and reduces age-related phenotypes in a mouse model of premature aging.

Many premalignant colorectal polyps in familial adenomatous polyposis arise polyclonally rather than from a single mutated cell, showing diverse early evolutionary trajectories that frequently occur without clonal APC or KRAS driver events.

Analysis of a newly sequenced genome of the inshore hagfish, Eptatretus burgeri, together with genomes of lampreys and jawed vertebrates, provides insights into whole-genome duplication events and their implications for vertebrate genome evolution.

Ataxia telangiectasia and Rad3-related kinase (ATR) is a rational radiosensitization target. This trial evaluates the combination of the ATR inhibitor, ceralasertib, with palliative radiotherapy in 27 patients with advanced solid tumors.

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.

St Louis wants to become a hub of agricultural biotechnology. All it needs, says Emma Marris, is more start-ups and funds.

There are worse places to do research, but for the Caribbean cruise ship Explorer of the Seas, home to two climate laboratories, it's not all smooth sailing. Emma Marris finds out why.

Developmental disorders (DDs) are more prevalent in males, thought to be due to X-linked genetic variation. Here, the authors investigate the burden of X-linked coding variants in 11,044 DD patients, showing that this contributes to ~6% of both male and female cases and therefore does not solely explain male bias in DDs.

By integrating healthcare and exome-sequencing data from parent–offspring trios of patients with developmental disorders, 28 genes that had not previously been associated with developmental disorders were identified.

‘T cell engagers promote antitumor immunity, but how macrophage modulates this activity in tumor is still unclear. Here the authors show, using biopsies from patients with uveal melanoma and single cell analyses, that a T cell engager, tebentafusp, reprograms tumor-associated macrophages and ameliorates, in synergy with IL-2, immunosuppression to cancer.

A study of SARS-CoV-2 variants examining their transmission, infectivity, and potential resistance to therapies provides insights into the biology of the Delta variant and its role in the global pandemic.

In this study, Aggarwal and colleagues perform prospective sequencing of SARS-CoV-2 isolates derived from asymptomatic student screening and symptomatic testing of students and staff at the University of Cambridge. They identify important factors that contributed to within university transmission and onward spread into the wider community.

Whole-genome sequencing analysis of individuals with primary immunodeficiency identifies new candidate disease-associated genes and shows how the interplay between genetic variants can explain the variable penetrance and complexity of the disease.

Erlich et al. show that soluble LTα and membrane-bound LTα1β2 lymphotoxins expressed by B cells play distinct roles to attenuate the pathology observed in ileitis.

Chromodomain Helicase DNA-binding (CHD) proteins have been implicated in neurodevelopmental processes. Here, the authors identify missense variants in CHD3 that disturb its chromatin remodeling activities and cause a neurodevelopmental disorder with macrocephaly and speech and language impairment.

Assessing the value of genomics is key to informing evidence-based policies; this Review outlines how current approaches to health technology assessment, implementation and data management can be adapted to suit the rapidly evolving technology and evidence base.

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.

The heterogeneity of androgen receptor (AR) gene alterations across metastases in prostate cancer remains unresolved. Here, the authors characterise AR genomic complexity across spatially separated lethal metastases from 10 prostate cancer patients and investigate how AR alterations evolve.

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.

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.

Whole-exome analysis of individuals with developmental disorders shows that de novo mutations can equally cause loss or altered protein function, but that most mutations causing altered protein function have not yet been described.

Jeppesen, Sanchez et al. identify blebbisomes as large membrane-enclosed vesicles containing organelles and secreted by cells. Blebbisomes can both secrete and internalize exosomes and microvesicles.

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.

The ATR inhibitor ceralasertib has shown clinical activity in combination with immune-checkpoint inhibitors in several cancer types. Here the authors report the anti-tumor activity and the immunomodulatory changes, dependent on up-regulation of type I interferon pathway, following intermittent ATR inhibition in preclinical cancer models.

St. Louis wants to become a hub of agricultural biotechnology. All it needs is more start-ups and funds.

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.

The APOE4 allele is a major genetic risk factor for the development of late-onset Alzheimer’s disease (AD). In this manuscript, Butovsky and colleagues suggest that APOE4 impairs the microglial response in AD by inducing TGFβ-mediated checkpoints.

But Hwang's US collaborator is chided for ‘research misbehaviour’.

Aguirre-Ghiso and colleagues report that bone-marrow-resident mesenchymal stem cells promote cancer dormancy through TGF-β family members.

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.

Fungal spores can promote immune responses of both type 2 (IL-4 / IL-5 / IL-13) and type 17 (IL-17). Here the authors characterise the subsets of cDC2 associated with type 2 and type 17 allergic responses to fungal allergens and show that Mgl2⁺ cDC2 depletion reduces type 2 but not type 17 fungal airway inflammation.

In the phase 2 HUDSON study, patients with advanced non-small-cell lung cancer received anti-PD-L1 combined with biomarker-guided therapy targeting ATR kinase, PARP, STAT3 or CD73, leading to encouraging clinical benefit in response to combination of the ATR kinase inhibitor ceralasertib with durvalumab.

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.

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.

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

Overexpression of human antigen R (HuR) correlates with high grade tumours and poor patient prognosis. Here, the authors engineer a TRIM21 biological PROTAC to demonstrate the benefit of a targeted protein degradation approach to deplete HuR, resulting in tumour growth inhibition in pre-clinical cancer models by altering the HuR-regulated proteome.

DNA-dependent protein kinase (DNA-PK) plays a major role in the DNA damage response upon double-strand break formation. Here, the authors show that the DNA-PK inhibitor AZD7648, enhances the activity of radiotherapy, chemotherapy and the PARP inhibitor olaparib in multiple mouse tumour models.

It is shown that mice deficient for β₈ integrin develop colitis, and that β₈ needs to be expressed by dendritic cells rather than T cells for colitis to develop. In addition, a decrease of T cells in the gut but not adjacent lymph nodes in diseased animals is shown. It is concluded that αVβ8-mediated integrin activation of dendritic cells is essential for prevention of colitis-inducing immune dysfunction.

Inflammatory skin diseases are frequently associated with dysregulation of cutaneous immunity. Here the authors perform human challenge with house dust mite allergen in patients with atopic dermatitis and explore the molecular network determining tolerance versus inflammation and identify a role for metallothioneins in the modulation of allergen induced inflammation.