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Results of the phase 2 POLAR trial show that biomarker-guided treatment in patients with metastatic pancreatic cancer based on homologous repair deficiency leads to encouraging clinical response rates in immune cell-infiltrated tumors.

Ciro Romano, Jack I. Mansell, and David J. Procter have explored the versatility and selectivity of samarium diiodide, and its use as a radical relay catalyst.

The gbu gene cluster, present in the human gut microbiota member Emergencia timonensis, converts γ-butyrobetaine (γBB) to trimethylamine in the conversion of dietary l-carnitine, which is found in red meat, to the proatherosclerotic metabolite trimethylamine-N-oxide. Individuals with high plasma γBB levels had increased risk of cardiovascular events.

1,2-Diols and 1,2-amino alcohols are widely found in bioactive compounds. Now it has been shown that alcohols can be converted, via alkoxy sulfonium salts, to alkoxy radicals that add to alkenes to give 1,2-diol and 1,2-amino-alcohol derivatives. The photocatalytic method can be run on a kilogram scale using a photoflow system.

The mechanisms underlying gut microbial metabolite (GMM) contribution towards alcohol-mediated cardiovascular disease (CVD) are unknown. Herein, the authors reveal that alcohol-induced microbial reorganization and resultant elevation in GMM phenylacetylglutamine, directly contributes to CVD.

Benzothiophenes are common motifs in bioactive compounds, but selective functionalization at C3 is challenging. Here the authors report a method starting from benzothiophene S-oxides via an interrupted Pummerer reaction, giving access to a range of C3-alkylated and -arylated products.

Diversity-oriented synthesis is a valuable strategy to construct complex molecules of medicinal interest. Here, the authors show a folding cascade strategy to convert linear substrates into polycyclic compounds with multiple stereocentres by combining the reductive chemistry of SmI₂ with 1,5-hydrogen atom transfer.

Substituted bicyclo[2.1.1]hexanes (BCHs) are emerging bicyclic hydrocarbon bioisosteres for ortho- and meta-substituted benzenes, but are difficult to access. Now a SmI₂-catalysed intermolecular coupling of bicyclo[1.1.0]butyl ketones and alkenes provides a general approach to access substituted BCHs, thus promoting their widespread use in medicinal chemistry and crop science.

Forming carbon–carbon bonds at the expense of two C–H bonds is difficult, but attractive, as it reduces the number of chemical steps during synthesis by avoiding prefunctionalization. Here such a method is reported, involving an interrupted Pummerer reaction and a photoredox-catalysed coupling.

Samarium iodide is a remarkably useful and mild reductant in organic synthesis, but its use can be problematic due to the need for (super)stoichiometric loadings. Now a method that employs samarium iodide as a catalyst—without the need for a stoichiometric co-reductant—is reported. Loadings as low as 5% are shown to catalyse radical cyclization cascades.

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.

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

Our improved understanding of how to tame aryl radicals means they are now used in many transformations to access high-value products. This Review provides a summary of contemporary approaches towards the photogeneration of aryl radicals and their use in metal-free cross-coupling reactions.

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.

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 environmental microbiota can have important implications for our well-being. Here, the authors describe the composition of microbiomes from diverse buildings, including samples from clinical environments, and show that cleaner environments are associated with a loss of microbial diversity and an increase in genes associated with antibiotic resistance.

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 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.

Methods and tools for visualizing biological data have improved considerably over the last decades, but they are still inadequate for some high-throughput data sets. For most users, a key challenge is to benefit from the deluge of data without being overwhelmed by it. This challenge is still largely unfulfilled and will require the development of truly integrated and highly useable tools.

Photoactivation of EDA complexes was previously limited to electronically biased partners to secure productive charge-transfer interactions. Now, the participation of triarylsulfonium salts—formed by selective C–H sulfenylation—in photoactive EDA complexes with catalytic triarylamine donors provides a site-selective and metal-free strategy for the generation of aryl radicals and the formal C–H functionalization of native arenes.

Patient-derived xenografts are important tools for cancer drug development. Here, the authors develop models from 22 non-small cell lung cancer patients. They show genomic differences between models created from different spatial regions of tumours and a bottleneck on model establishment.

Although samarium-mediated cyclizations have the potential to generate significant molecular complexity, historically it has not proven possible to exert enantiocontrol through the use of a chiral ligand in complex product synthesis. Now, an enantioselective SmI₂-mediated radical cyclization has been developed using a chiral aminodiol ligand. Desymmetrizing 5-exo ketyl-alkene cyclizations and cyclization cascades of unsaturated ketoesters deliver complex products and typically proceed with high enantioselectivity and diastereoselectivity.

Fernando Rivadeneira and colleagues in the Genetic Factors for Osteoporosis Consortium report a large-scale meta-analysis identifying new loci associated with bone mineral density (BMD) and risk of fracture. Thirty-two new loci are found to be associated with BMD, and 6 loci confer higher risk for low-trauma bone fracture.

This Review considers cascade reactions initiated by single electron transfer. Open-shell intermediates are highly reactive but undergo reactions with high selectivity. They are thus ideal intermediates in cascade reactions that generate complex, high-value products from simple starting materials

There is lack of therapies targeting the PAX3-FOXO1 fusion oncogene in fusion-positive rhabdomyosarcoma (FP-RMS). Here, the authors identify and characterise an inhibitor with highest inhibition of histone lysine demethylase 3B that suppresses PAX3-FOXO1 activity in FP-RMS.

Entanglement was observed in top–antitop quark events by the ATLAS experiment produced at the Large Hadron Collider at CERN using a proton–proton collision dataset with a centre-of-mass energy of √s  = 13 TeV and an integrated luminosity of 140 fb⁻¹.

COVID-19-related travel restrictions were imposed in China around the same time as major annual holiday migrations, with unknown combined impacts on mobility patterns. Here, the authors show that restructuring of the travel network in response to restrictions was temporary, whilst holiday-related travel increased pressure on healthcare services with lower capacity.

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.

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.

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.

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

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.

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.

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.

The Human Microbiome Project Consortium has established a population-scale framework to study a variety of microbial communities that exist throughout the human body, enabling the generation of a range of quality-controlled data as well as community resources.

Vaccination is effective in protecting from COVID-19. Here the authors report immune responses and breakthrough infections in twice-vaccinated patients receiving anti-TNF treatments for inflammatory bowel disease, and find dampened vaccine responses that implicate the need of adapted vaccination schedules for these patients.

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.

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.

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.

Lukacs et al. identify mutations in the PIEZO1gene in patients with congenital lymphatic dysplasia. The study also characterizes the functional consequence of the disease-associated Piezo1 mutant proteins and show attenuated ion channel function in cellular context.

The Human Microbiome Project Consortium reports the first results of their analysis of microbial communities from distinct, clinically relevant body habitats in a human cohort; the insights into the microbial communities of a healthy population lay foundations for future exploration of the epidemiology, ecology and translational applications of the human microbiome.

Many countries have closed schools as part of their COVID-19 response. Here, the authors model SARS-CoV-2 transmission on a network of schools and households in England, and find that risk of transmission between schools is lower if primary schools are open than if secondary schools are open.

Here, the authors simulate COVID-19 outbreaks on an empirical contact network derived from digital contact data collected on cruise ships. They model impacts of different control measures and find that combinations of measures, particularly vaccination and rapid antigen testing, are important for mitigating outbreaks.

Mechanism-based small-molecule inhibitors targeting a gut microbial enzyme lower circulating levels of the prothrombotic metabolite trimethylamine-N-oxide and suppress diet-induced thrombosis in mice.

Phytate metabolism and production of inositol trisphosphate by commensal bacteria activates epithelial histone deacetylase 3 and promotes intestinal repair.

This mathematical modelling study projects the dynamics of SARS-CoV-2 in England until the end of 2022 assuming that the Omicron BA.2 sublineage remains dominant. They show that booster vaccination was highly effective in mitigating severe outcomes and that future dynamics will depend greatly on assumptions about waning immunity.