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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.

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.

Cells can sense mitochondrial damage through signalling via an unimported mitochondrial targeting sequence.

B cell subsets expanding during tumor progression have been associated with impaired anti-tumor responses and resistance to immunotherapy. Here the authors report that STING agonism or anti-PD-1 induce intratumoral B cell infiltration, and that depleting B-cells improves response to immunotherapies in preclinical models of hepatocellular carcinoma.

In this Review, the authors summarize epidemiological trends of type 2 diabetes in China, discuss unique risk factors contributing to diabetes risk in the Chinese population and highlight how recent advances from multi-omics studies can affect treatment of diabetes in China.

Wastewater surveillance can help in pandemic or outbreak response. Here, the authors report an unsupervised learning approach to detect emerging SARS-CoV-2 variants from rural and urban wastewater showing it achieves earlier detection than existing methods and detects new variants without clinical testing data.

Inactivating PPP2R1A mutations correlate with better survival after immune checkpoint blockade in patients with ovarian clear cell carcinoma, suggesting that targeting the phosphatase 2A (PP2A) pathway may represent an effective startegy for improving responses to immunotherapy.

Inflammatory intestinal lesions are often hypoxic, which results in the stabilization and activation of hypoxia-inducible-factors (HIF). Here authors show that in a mouse model of colitis, HIF-2α is specifically stabilized in CD4+ type 1T helper (T_H1) cells, leading to the upregulation of miR-29a expression and suppression of T_H1 cell function, which pathway is potentially targetable for therapeutic purposes.

Analyses of genome and exome sequencing data identify rare coding and structural variants associated with atrial fibrillation and highlight genetic links between atrial fibrillation and cardiomyopathies.

Here the authors identify distinct mechanisms by which domain-specific p53 mutations activate cancer cell growth via the epidermal growth factor receptor (EGFR). These mechanisms affect sensitivity to EGFR inhibitors, opening avenues for targeted therapy.

Nanotechnology offers great promise for the detection, prevention and treatment of cancer. Current limitations of this technology include the heterogeneous distribution of nanoparticles to tumors, caused in part by the physiological barriers presented by the abnormal tumor vasculature and interstitial matrix. This Review discusses these barriers and summarizes strategies that have been developed to overcome them. It additionally examines design considerations for the optimization of delivery of nanoparticles to tumors.

CD47 is a promising new target in cancer immunotherapy and recently the pro-phagocytic signal SLAMF7 has been shown to have a crucial role in phagocytosis induced by CD47-blocking antibody in hematological tumors. In this study, the authors demonstrate that SLAMF7 expressed by cancer cells is not required for phagocytosis suggesting that, in contrast to CD47 expression, SLAMF7 should not be used as selection criterion for CD47-targeted therapy.

Paul Pharoah and colleagues report the results of a large genome-wide association study of ovarian cancer. They identify new susceptibility loci for different epithelial ovarian cancer histotypes and use integrated analyses of genes and regulatory features at each locus to predict candidate susceptibility genes, including OBFC1.

Distant metastasis is a major reason for mortality in patients with prostate cancer (PC). Here, the authors show that receptor-interacting protein kinase 2 (RIPK2) stabilizes c-Myc and its targeting impairs PC metastasis development.

X-ray free electron lasers allow for studying the interaction of magnetic materials with intense X-rays beyond a linear response regime. Here, the authors demonstrate the onset of X-ray induced ultrafast demagnetization in Co/Pd multilayers via a redistribution of valence electrons on timescales shorter than 40 fs.

The Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) aims to better understand population genetics of the African diaspora. Here, it uses deeply sequenced whole-genomes to describe the impact of admixture and potential disease burden of deleterious variants.

Reducing levels of mitochondrial iron by diet or pharmacological chelation ameliorates symptoms of cigarette smoke–induced chronic obstructive pulmonary disease in mice.

Personalized medicine requires accurate and ethnicity-optimized reference genome panels. Here, the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) evaluates typical variant filters and existing genome databases against newly sequenced African-ancestry populations.

This resource describes a collection of neurons from a variety of light microscopy-based datasets, which can serve as a gold standard for testing automated tracing algorithms, as shown by comparison of the performance of 35 algorithms.

Georgia Chenevix-Trench and colleagues report meta-analyses of genome-wide association studies identifying six loci newly associated with epithelial ovarian cancer (EOC). They also test variants at the 12 known and 6 new EOC susceptibility loci for association in BRCA1 and BRCA2 mutation carriers.

Tropical teleconnections can influence polar climates through the generation of stationary Rossby waves. This Review outlines the dynamics and impacts of long-term tropical–polar connections on the Antarctic climate, which include warming trends and ice mass loss in West Antarctica.

In an inter-laboratory study, the authors compare the accuracy and performance of three optical density calibration protocols (colloidal silica, serial dilution of silica microspheres, and colony-forming unit (CFU) assay). They demonstrate that serial dilution of silica microspheres is the best of these tested protocols, allowing precise and robust calibration that is easily assessed for quality control and can also evaluate the effective linear range of an instrument.

Here Harkos et al. review the role of continuous models and discrete models in predicting and understanding therapy delivery and efficacy in solid tumours. They propose ways to integrate mechanistic and AI-based models to further improve patient outcomes.

Tumours rely on blood vessels for survival and growth. Jain and colleagues review the mechanisms by which malignant brain tumours stimulate the formation of new blood vessels, and discuss the latest methods for monitoring and treating brain tumours with anti-VEGF agents.

Cancer nanomedicines approved so far minimize toxicity, but their efficacy is often limited by physiological barriers posed by the tumour microenvironment. Here, we discuss how these barriers can be overcome through innovative nanomedicine design and through creative manipulation of the tumour microenvironment.