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Here the authors report new human fossils from Tam Pà Ling cave, Laos, consisting of a cranial and a tibial fragment, dated to 68–86 thousand years ago. This find confirms that Homo sapiens were present in Southeast Asia by this time and the shape of the fossils indicates they may have descended from non-local populations.

p53 is an important tumour suppressor gene. Two papers now show in a Kras-driven lung cancer model that p53-mediated tumour suppression is only engaged late during tumour progression, when the Kras oncogenic signal reaches a threshold sufficient to activate the ARF–p53 pathway. Therefore, p53 re-expression in p53-deficient lung tumours does not restrict early stages of tumorigenesis, but induces tumour regression of more aggressive tumours.

Florfenicol amine hijacks intrinsic resistance in Mycobacterium abscessus, highlighting that antimicrobial resistance mechanisms can be harnessed for antibiotic activation.

Bacterial secretion systems are key to pathogenesis, as they secrete the many virulence factors needed for host colonization. Bioinformatic and functional analyses have identified a transport and assembly module (TAM) in proteobacteria that may be necessary for biogenesis of the autotransporter family of virulence factors.

Adrenocortical carcinomas (ACC) are aggressive and often resistant to therapy. Here, the authors provide a single-nucleus transcriptomic atlas of ACCs and normal adrenal glands, finding ecotypes in steroid and microenvironment cells that are associated with clinical outcomes.

Understanding exciton dynamics in quantum dots is important for realizing their potential in optoelectronics. Here, the authors use femtosecond transient absorption microscopy to reveal ultrafast exciton transport, enhanced at larger interdot distance and taking place within hundreds of femtoseconds after generation.

Cancer-associated fibroblasts (CAFs) are the main component of the stroma in pancreatic cancer, but their tissue of origin remains to be defined. Here the authors perform lineage tracing and single cell RNA sequencing in mice and suggest the splanchnic mesenchyme as the tissue of origin for CAFs.

Kharas and colleagues identify the RNA-binding proteins RBMX and RBMXL1 as AML tumor promoters that alter chromatin compaction and hence cell survival via transcriptional regulation of the heterochromatin protein encoded by CBX5.

Calcium/calmodulin-dependent kinase kinase 2 (CaMKK2) is highly expressed in several cancers. Here the authors investigate the role of CaMKK2 expression in the tumour microenvironment and show that CaMKK2 expression in tumour-associated macrophages promotes tumour growth by suppressing T cell anti-tumour activity.

Autosomal dominant tubulointerstitial kidney disease (ADTKD) due to uromodulin mutations is a hereditary kidney disease causing renal fibrosis. Here, the authors show that mesencephalic astrocyte-derived neurotrophic factor can improve defective autophagy/mitophagy and decrease renal scarring in ADTKD.

Humanity’s Last Exam, a multi-modal benchmark at the frontier of human knowledge, is designed to be an expert-level closed-ended academic benchmark with broad subject coverage.

Macrophages densely populate the arterial wall, yet their origin and homeostasis are poorly understood. Robbins and colleagues show that arterial macrophages arise from CX3CR1⁺ embryonic precursors and adult bone marrow–derived monocytes that colonize the tissue immediately after birth.

Epelman and colleagues use fate mapping and single-cell transcriptomics to describe the dynamics of resident and recruited cardiac macrophages during ischemic injury.

Spatial transcriptomic studies and lineage tracing reveal that, after brain injury, transient profibrotic fibroblasts develop from existing brain fibroblasts, infiltrate lesions, regulate the local immune response and lead to beneficial scar tissue formation.

Primary prostate tumours are known to be genetically heterogeneous and clonal selection has the potential to drive metastasis. Here Hong et al. show that the acquisition of TP53 mutations is linked to clonal expansion and metastatic progression to lethality.

The eighth annual Human Genome Variation Meeting was held in September 2006 in the Hong Kong Special Administrative Region, China. The meeting highlighted recent advances in characterization of genetic variation, including genome-wide association studies and structural variation.

The role of IL-9 in the tumor microenvironment and its effects on macrophages remains unclear. Here, the authors show that IL-9 promotes the expansion of pulmonary macrophages and that targeting the IL-9R/arginase 1 axis restricts tumor growth, thus identifying this cytokine pathway as a potential therapeutic target.

Tumor microenvironment elements can influence tumor state, including in skin basal cell carcinomas. Here the authors show that spatially organized and self-propagating TREM2+ tumor associated macrophages promote Ly6D- tumor cell proliferation via secretion of oncostatin M.

A mountain-building event on the paleo-Pacific margin of Gondwana occurred 590 million years ago, based on detrital garnet geochronology of modern sands and Permo-Carboniferous glacial sediments from South Australia.

Analysis of the longest-lived mammal, the bowhead whale, reveals an improved ability to repair DNA breaks, mediated by high levels of cold-inducible RNA-binding protein.   

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.

Immune responses to pancreatic ductal adenocarcinoma can be inhibited by cancer cells. Here the authors show that high levels of progranulin in PDAC inhibits immune responses by reducing MHC class I antigen presentation through enhanced degradation of MHC class I via autophagy.

Nitric oxide delivered and released by a nanoscale carrier improves the therapeutic effectiveness of chemotherapeutics and immunotherapy by normalizing tumour vasculature.

Targeting solid tumours by chimeric antigen receptor (CAR) T cells require strategies that improve trafficking and effector function of these cells in the immunologically hostile cancer microenvironment. Here, authors show that CAR T cells engineered with incorporation of the CD28 transmembrane domain to the 4-1BB costimulatory domain and a membrane-bound form of IL-12 can achieve efficient anti-tumour activity and promote systemic disease targeting via regional T cell delivery in multi-metastatic disease models.

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.

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.

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.

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.

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.

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.

The transcription factor GATA-3 is required for the differentiation of mature CD4⁺ T cells into T_H2 cells. Wan and colleagues show that GATA-3 also controls the maintenance and proliferation of CD8⁺ T cells in the periphery.

This study identifies a novel immune checkpoint in senescent cells that is linked to the ganglioside GD3 and that contributes to the evasion of immune clearance by these cells and to aging and age-related diseases.