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While CDK4/6 inhibitors (CDK4/6i) are often initially successful in many breast cancer subtypes, often resistance develops and other subtypes like triple-negative breast cancer (TNBC) fail to respond. Here, the authors demonstrate that the CDK2 inhibitor BLU-222, alone or with CDK4/6i, restores cell-cycle control via p21/p27 induction overcoming resistance in preclinical models of breast cancer, including TNBC.

In the context of ongoing A(H5N1) outbreak events, in this study, the authors use a ferret transmission model to show that genotype B3.13 viruses are shed into the air at higher levels than other A(H5N1) strains, highlighting the need for continued surveillance and aerobiological analyses.

Researchers used explainable AI to analyze pancreas tissue from living donors, revealing that changes in fat cell clusters, nerve structures, and islet proximity to fat cells distinguish people with type 2 diabetes from those without the condition.

Targeting FSP1 in lymph nodes has considerable potential for blocking melanoma progression.

Determinants of WEE1 inhibitor sensitivity in cancer cells are largely undefined. Here, the authors show that WEE1 inhibitors beyond their cell cycle perturbing effects also lead to paradoxical activation of the integrated stress response kinase GCN2.

Targeted inhibition of the ERK-MAPK pathway is challenged by the development of resistance and toxicity. Here, the authors show that SHOC2 genetic inhibition impairs lung tumour development and improves MEK inhibitor efficacy in RAS- and EGFR-mutant cells.

This study demonstrates the capability of deep learning protein design models in generating functionally validated β-strand pairing interfaces, expanding the structural diversity of de novo binding proteins and accessible target surfaces.

How the complex interplay between multiple nutrients within the microenvironment dictates potential sites of metastatic cancer growth is explored.

Large-effect variants in autism remain elusive. Here, the authors use long-read sequencing to assemble phased genomes for 189 individuals, identifying pathogenic variants in TBL1XR1, MECP2, and SYNGAP1, plus nine candidate structural variants missed by short-read methods.

JWST’s COSMOS-Web survey is used to create an ultra-high-detail dark matter map, revealing hidden filaments, clusters and distant structures. By tracing features out to z = 2, this map shows how dark and luminous matter build the cosmic web across cosmic time.

Using a statistical model that incorporates transmission intensity and stratum-specific rates of severe outcomes, either associated with disease or vaccination, a framework is proposed to compare the risks and benefits of deploying new vaccines, using early epidemiological data.

RaST activates complementary apoptotic, necroptotic, and immune pathways to eliminate tumors, prevent metastasis, and achieve long term cancer remission.

Familial Mediterranean fever is an autoinflammatory disease caused by gain-of-function mutations in the pyrin inflammasome. Kastner and colleagues show that mutant pyrin better resists suppression by the plague bacterium Yersinia pestis and may have been positively selected in human Middle Eastern populations.

Induction of cardiac contractility, although desirable for restoring heart function, often has long-term detrimental effects. From studies on RKIP, an upstream regulator of β-adrenergic receptor signaling, Schmid et al. show that cardiac contractility in mice can be increased in a well-tolerated manner through the balanced activation of the β1 and β2 subtypes of the adrenergic receptor.

Arrestins terminate signaling from GPCRs, but several lines of evidence suggest that they are also able to transduce signals independently of G proteins. Here, the authors systematically ablate G proteins in cell lines, and show that arrestins are unable to act as genuine signal initiators.

Despite improving therapeutic options, the prognosis for patients with metastatic castration-resistance prostate cancer (mCRPC) remains poor. Here, the authors identify MCL1 copy number alterations as a prognostic and predictive biomarker, demonstrating its therapeutic potential as a drug target, either alone or in combination, in patients with mCRPC.

Joller and colleagues show that the co-inhibitory receptor TIGIT induces the expression of the tissue growth factor amphiregulin (Areg) in regulatory T cells and contributes to tissue repair in response to viral infection.

Seagrass meadows store 24–40 million tons of carbon and fix 83–137 million tons of carbon annually in their biomass, ranking among the most productive ecosystems on Earth. Seagrass conservation can contribute to climate change mitigation.

Understanding how SARS-CoV-2 gains initial entry into the human body is a key step towards the development of prophylaxes and therapeutics for COVID-19. Here, the authors show that ACE2, the receptor for SARS-CoV-2, is abundantly expressed in the motile cilia of the human nasal and respiratory tract and is not affected by the use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers.

Coufal and colleagues generated microglia from human iPS cells to examine mechanistic roles of the transcription factor MEF2C and how these roles might relate to the autism phenotype seen following the loss of MEF2C in human microglia.

The Wilms’ tumour suppressor Wt1 is highly expressed in vessels and stromal cells of human tumours, but not in adjacent healthy tissue. Here the authors show that Wt1 regulates Pecam-1 and c-kitand that deletion of Wt1 in endothelial, haematopoietic and myeloid suppressor cells leads to tumour regression.

Here the authors show that lowering IGF-1R levels in endothelial cells improves insulin sensitivity, boosts energy use, and supports beneficial changes in adipose tissue, offering insights into potential treatments for obesity-related metabolic disorders.

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.

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.

Spatial transcriptomic analysis of cells in intestinal fistulae of patients with Crohn’s disease reveals the existence of specialized fistula-associated cell states with distinct signalling profiles and extracellular matrix architecture.

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.

Pathological cardiac fibrosis is a hallmark of diseases leading to heart failure. Here, the authors used systems genetics to identify a pro-fibrotic gene network regulated by WWP2, a E3 ubiquitin ligase, which orchestrates the nucleocytoplasmic shuttling and transcriptional activity of SMAD2 in the diseased heart.

Rutz and colleagues report STK40, a non-catalytic member of the Tribbles pseudokinase family, negatively regulates c-Jun activity during proliferative T cell responses and exhaustion.

Peptidylarginine deiminase 4 (PADI4) is a transcriptional co-regulator that converts arginine residues at histone tails to citrulline. The authors show that PADI4 interacts with the central haematopoietic transcription factor TAL1 to regulate gene expression in an erythroleukemia cell line.

The MAGIC investigators report results of a large genome-wide association study meta-analysis to identify common variants influencing fasting glucose homeostasis. They further show that several of the newly discovered loci influencing glycemic traits are also associated with risk of type 2 diabetes.

TP53 alteration and TMPRSS2-ERG fusion are often found together in prostate cancer. Here, the authors show that gain-of-function mutant p53 collaborates with ERG proto-oncogene to drive prostate cancer tumourigenesis by activating beta-catenin expression and afterwards pyrimidine synthesis.

Genetic variants at multiple loci of chr5p15.33 have been associated with susceptibility to numerous cancers. Here the authors show that the association of one of these loci may be explained by a variant, rs36115365, influencing telomerase reverse transcriptase (TERT) expression via ZNF148.

A cell-sorting method leveraging leucine zippers allows for the generation of T cells displaying multiple chimaeric antigen receptors as well as receptors converting inhibitory signals into stimulatory signals.

Nicole Soranzo and colleagues report a meta-analysis of genome-wide association datasets identifying 22 associations to 8 clinically relevant hematological traits. They also identify a long-range haplotype at 12q24 that includes variants associated with platelet counts as well as coronary artery disease and shows evidence of a selective sweep in Europeans.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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