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The MOUNTAINEER phase 2 trial demonstrated the efficacy and safety of tucatinib (HER2-targeted TKI) and trastuzumab (anti-HER2 antibody) in patients with HER2 + , RAS wildtype unresectable or metastatic colorectal cancer that had progressed on chemotherapy, resulting in the approval of the regimen. Here, the authors report the updated analysis of the MOUNTAINEER trial.

Here, the authors show that pre-infection gastrointestinal microbial composition predicts parasite levels in rhesus macaques infected with P. fragile and humans infected with P. falciparum in a controlled human malaria infection (CHMI) study.

Somatic instability plays a role in Huntington’s disease. Here, the authors show that lowering HTT levels by transcriptional repression suppresses somatic instability. This can also be done without affecting HTT levels by direct CAG repeat binding.

Neuroinflammation following intracortical microelectrode implantation impairs long-term brain-machine interface performance. Here, the authors developed a nanoparticle-based therapy that improves local hemostasis and delivers dexamethasone, reducing inflammation.

The 3CL protease of SARS-CoV-2 is inhibited by PF-00835231 in vitro. Here, the authors show that the prodrug PF-07304814 has broad spectrum activity, inhibiting SARS-CoV and SARS-CoV-2 in mice and its ADME and safety profile support clinical development.

Oncolytic viruses (OVs) represent a treatment option for patients with cancer. Here the authors propose a tumour-agnostic dual-virus strategy for cancer therapy by generating a vesicular stomatitis virus encoding a truncated version of HER2, combined with a vaccinia virus as a delivery platform for a HER2-targeted T-cell engager.

The flagship paper of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium describes the generation of the integrative analyses of 2,658 cancer whole genomes and their matching normal tissues across 38 tumour types, the structures for international data sharing and standardized analyses, and the main scientific findings from across the consortium studies.

Semiconductor-based, non-optical DNA sequencing technologies such as Ion Torrent sequencing offer speed and cost advantages compared with alternative techniques. Cheng et al. demonstrate a protocol allowing the use of Ion Torrent technology to sequence DNA from chromatin immunoprecipitation experiments.

Diabetes results in part from a deficiency of functional pancreatic beta cells. Here, the authors study the genomic and epigenetic landscapes of human insulinomas to gain insight into possible pathways for therapeutic beta cell regeneration, highlighting epigenetic genes and pathways.

Epilepsy is a chronic, heterogeneous disease with an urgent need for novel therapies. Here, the authors show a systematic comparison of the global molecular signature of refractory epilepsies elucidating the key mechanisms of the disease pathology.

There’s an emerging body of evidence to show how biological sex impacts cancer incidence, treatment and underlying biology. Here, using a large pan-cancer dataset, the authors further highlight how sex differences shape the cancer genome.

Analyses of 2,658 whole genomes across 38 types of cancer identify the contribution of non-coding point mutations and structural variants to driving cancer.

In somatic cells the mechanisms maintaining the chromosome ends are normally inactivated; however, cancer cells can re-activate these pathways to support continuous growth. Here, the authors characterize the telomeric landscapes across tumour types and identify genomic alterations associated with different telomere maintenance mechanisms.

With the generation of large pan-cancer whole-exome and whole-genome sequencing projects, a question remains about how comparable these datasets are. Here, using The Cancer Genome Atlas samples analysed as part of the Pan-Cancer Analysis of Whole Genomes project, the authors explore the concordance of mutations called by whole exome sequencing and whole genome sequencing techniques.

Whole-genome sequencing data from more than 2,500 cancers of 38 tumour types reveal 16 signatures that can be used to classify somatic structural variants, highlighting the diversity of genomic rearrangements in cancer.

A pan-cancer genomic analysis reports the effects of structural variations on chromatin domains (TADs). Most TAD disruptions do not result in appreciable changes in expression of nearby genes.

An analysis of 2,954 genomes from 38 cancer subtypes identified 19,166 retrotransposition events in 35% of samples. Aberrant LINE-1 retrotranspositions can lead to the deletion of tumor-suppressor genes as well as the amplification of oncogenes.

Some cancer patients first present with metastases where the location of the primary is unidentified; these are difficult to treat. In this study, using machine learning, the authors develop a method to determine the tissue of origin of a cancer based on whole sequencing data.

In this study the authors consider the structural variants (SVs) present within cancer cases of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. They report hundreds of genes, including known cancer-associated genes for which the nearby presence of a SV breakpoint is associated with altered expression.

White-tailed deer are an important reservoir of SARS-CoV-2 in the USA and continued monitoring of the virus in deer populations is needed. In this genomic epidemiology study from Ohio, the authors show that the virus has been introduced multiple times to deer from humans, and that it has evolved faster in deer.

Vaccination efficiency in HIV infection is hampered by the low immunogenicity of HIV-1 Env glycoprotein (Env). Here authors optimise the neutralising antibody response to Env by stabilizing the Env trimers in the context of expressing them in a Newcastle Disease Virus-like particle and providing conditions that mimics replicating virus infection.

Tumor draining lymph nodes are essential for immunotherapy efficacy in head and neck squamous cell carcinoma (HNSCC). Here, the authors show that sequential tumor-directed radiotherapy and PD-1 inhibition and migratory CCR7+ dendritic cells are required for complete and durable tumor responses in HNSCC.

Researchers show inhibiting immune cell steroidogenesis enhances anti-tumour immunity in triple-negative breast cancer. Posaconazole showed promise in a humanised mouse model.

Understanding deregulation of biological pathways in cancer can provide insight into disease etiology and potential therapies. Here, as part of the PanCancer Analysis of Whole Genomes (PCAWG) consortium, the authors present pathway and network analysis of 2583 whole cancer genomes from 27 tumour types.

Integrative analyses of transcriptome and whole-genome sequencing data for 1,188 tumours across 27 types of cancer are used to provide a comprehensive catalogue of RNA-level alterations in cancer.

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.

Analysis of cancer genome sequencing data has enabled the discovery of driver mutations. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium the authors present DriverPower, a software package that identifies coding and non-coding driver mutations within cancer whole genomes via consideration of mutational burden and functional impact evidence.

Whole-genome sequencing data for 2,778 cancer samples from 2,658 unique donors across 38 cancer types is used to reconstruct the evolutionary history of cancer, revealing that driver mutations can precede diagnosis by several years to decades.

The authors present SVclone, a computational method for inferring the cancer cell fraction of structural variants from whole-genome sequencing data.

Many tumours exhibit hypoxia (low oxygen) and hypoxic tumours often respond poorly to therapy. Here, the authors quantify hypoxia in 1188 tumours from 27 cancer types, showing elevated hypoxia links to increased mutational load, directing evolutionary trajectories.

Multi-omics datasets pose major challenges to data interpretation and hypothesis generation owing to their high-dimensional molecular profiles. Here, the authors develop ActivePathways method, which uses data fusion techniques for integrative pathway analysis of multi-omics data and candidate gene discovery.

The characterization of 4,645 whole-genome and 19,184 exome sequences, covering most types of cancer, identifies 81 single-base substitution, doublet-base substitution and small-insertion-and-deletion mutational signatures, providing a systematic overview of the mutational processes that contribute to cancer development.

Cancers evolve as they progress under differing selective pressures. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, the authors present the method TrackSig the estimates evolutionary trajectories of somatic mutational processes from single bulk tumour data.

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

Composition and function of immune populations at barrier surfaces is crucial for response to infection. Here, the authors identify a population of dendritic cells in human epidermis, abundant in anogenital epithelia and distinct from Langerhans cells by surface phenotype and by high capacity for HIV infection and transmission.

Clinical evidence suggests that debulking surgery in patients with metastatic disease could enhance response to immune checkpoint therapy. Here the authors report the results of a clinical trial of immune checkpoint inhibitors plus debulking surgery in patients with metastatic renal cell carcinoma.

Phylogenomic analysis of 7,923 angiosperm species using a standardized set of 353 nuclear genes produced an angiosperm tree of life dated with 200 fossil calibrations, providing key insights into evolutionary relationships and diversification.

Ibogaine is a natural substance that interrupts opioid addiction but has cardiac risks. This article introduces novel ibogaine analogs that show reduced cardiac risk and enhanced neuroplasticity and therapeutic-like effects in models of opioid use disorder.

Preeclampsia, a hypertension condition with no approved therapies, is treated in monkeys by gene silencing in the placenta.

ß-Sheet-rich aggregates of α-synuclein (αS) characterize Parkinson's disease (PD) and recent work suggests that αS exists as α-helix-rich tetramers and related low-nmultimers in normal cells. Here the authors show that αS mutations associated with familial PD decrease the intraneuronal tetramer:monomer ratio and are correlated with neurotoxicity.

7DW8-5 is a glycolipid that binds CD1d and stimulates invariant natural killer T (iNKT) cells. Here the authors show that 7DW8-5, when administered intranasally, provides prophylactic anti-viral effects against influenza, RSV, and SARS-CoV-2 in mice or hamsters, and that this effect is mediated by iNKT cells and IFN-γ.

The authors use fMRI in rats to show that covert sensory input influences the dynamics of resting state brain activity. This indicates a mechanism by which the environment shapes neural function even in the absence of explicit stimuli or tasks.

Fentanyl continues to drive the opioid crisis by contributing to >70,000 deaths per year in the US. Here, the authors investigate a candidate medication for fentanyl overdose prevention (monoclonal antibody CSX-1004) demonstrating its mitigation of fentanyl’s effects in preclinical animal models.

Stabilized, native-like trimers of the HIV envelope protein, such as SOSIP trimers, are potential antigens for an HIV vaccine. Here, the authors generate a SOSIP trimer based on the consensus sequence of group M isolates, determine its structure and exposure of common epitopes, and show immunogenicity in rabbits and non-human primates.

Microtubule-destabilizing drugs and oncolytic viruses are two unrelated approaches to battle cancer. Here the authors show that microtubule-destabilizing drugs potentiate the efficiency of oncolytic rhabdoviruses by altering the cytokine production and response of the tumour cells.