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Analysis of a placebo-controlled trial of a BCMA-targeting CAR-T cell therapy in patients with myasthenia gravis shows that CAR-T cell infusion selectively remodels the systemic immune environment, with elimination of BCMA-high plasma cells and activated plasmacytoid dendritic cells and changes in the autoreactive B cell repertoire.

Global Burden of Disease estimates show that between 1990 and 2023, the prevalence and burden of drug use disorders, inclusive of amphetamine, cannabis, cocaine and opioid use, have been increasing in high-income countries, particularly in the USA.

Structures of two short-lived intermediates during the photocycle of the photoactive yellow protein (PYP) have been determined using X-ray crystallography. These structures demonstrate the power of cryo-trapping and the Laue method in trapping transient intermediates.

HER2-low breast cancer has recently emerged as a targetable subset of breast tumors, for which the molecular landscape remains incompletely understood. Here, the authors use genomic data from 1039 patients to unveil and compare the genomic landscape of HER2-low and HER2-0 breast cancer.

Telomere shortening is a hallmark of several disorders and aging. Here, the authors uncover that RIOK2 maintains telomerase activity, thereby preventing telomere shortening. Thus, increasing RIOK2 levels may help rescue telomere biology disorders.

Microscopy artifacts and tissue imperfections interfere with single-cell analysis. CyLinter software offers quality control for high-plex tissue profiling by removing artifactual cells, thereby facilitating accuracy of biological interpretation.

It remains unclear whether machine learning methods can accurately identify cancer driver alterations. Here, the authors compare machine learning-based approaches to other computational methods to determine their utility for annotating variants of unknown significance and identifying driver alterations in real-world cancer patient data, demonstrating superior performance.

Healthcare emissions negatively affect the environment and health, posing ethical questions between health and environmental impacts. A focus group study in US health systems revealed a willingness to make environmentally informed health decisions and identified barriers to making such decisions.

It is nearly 10 years since the first attempts were made to grow better protein crystals in the low gravity environment of space. Can the enormous cost of these experiments be justified by the results?

The combination of massively parallel mutation enrichment and duplex sequencing allows for the tracking of up to 10,000 low-frequency mutations with up to 100-fold fewer reads per locus than conventional duplex sequencing.

Ghosh et al. report findings showing that the atypical kinase RIOK2 functions as a winged helix-turn-helix domain containing transcription factor that regulates the differentiation of human hematopoietic stem and progenitor cells toward erythroid, myeloid and megakaryocytic lineages. RIOK2 enhances GATA1 and KLF1 expression, while suppressing other transcription factors like RUNX3, SPI1 and GATA2.

The components of the glioma immune microenvironment and their roles in promoting tumourigenesis remain poorly understood. Here, the use of single-cell RNA sequencing and multiplexed tissue-imaging in adult and pediatric high-grade gliomas reveals the activity and spatial organization of the immunomodulatory purinergic signaling pathway.

Resistance mutations in BCL-2 reduce the clinical efficacy of venetoclax. DeAngelo et al. show stapled BAD BH3 peptides can retain and even enhance binding to these mutants, offering a structurally informed strategy to overcome this mechanism of cancer drug resistance.

In preclinical studies, the FDA approved TSP-1 antagonist gabapentin has been shown to disrupt neuronal-glioma interactions, slowing glioblastoma progression. Here, authors report a retrospective cohort study demonstrating a survival benefit associated with gabapentin in patients with newly diagnosed glioblastoma.

The EWSR1::FLI1 fusion protein is the oncogenic driver of Ewing sarcoma (EwS). Here, the authors find that EWSR1::FLI1 plays a non-canonical role in mRNA decay via interactions with the CCR4-NOT deadenylation complex and the RNA-binding protein HuR. This role uncovers a new therapeutic vulnerability of EwS to HuR inhibition.

It is notoriously difficult to target transcription factors with aberrant activity in cancer. Inappropriate activation of the NOTCH complex of transcription factors is directly implicated in the pathogenesis of several disease states, including T-cell acute lymphoblastic leukaemia. The design of synthetic, cell-permeable, stabilized α-helical peptides that disrupt protein–protein interactions in NOTCH is now described.

Identifying therapeutic targets in rare cancers is challenging due to the lack of relevant pre-clinical models. Here, the authors generate a cancer cell line from a paediatric patient with a rare undifferentiated sarcoma and through functional genomics and chemical screens identified CDK4 and XPO1 as potential therapeutic targets in this cancer.

β-cell dysfunction in diabetes is caused by glucose and inflammation toxicity. Here, Fu et al. show that β-cell glucose metabolism can be protective though pyruvate carboxylase–mediated shunting of arginine to ureagenesis and away from toxic nitric oxide production, thus suppressing inflammation.

Micronuclei, which are common features of nuclei in cancer cells, can generate heritable sources of transcriptional suppression, a finding that establishes an inherent relationship between chromosomal instability and variation in chromatin state and gene expression.

DNA methylation from cell-free DNA (cfDNA) can be profiled using whole genome bisulfite sequencing (WGBS). Here, the authors develop a computational method, FinaleMe, that predicts DNA methylation and tissues of-origin in cfDNA and validate its performance using paired deep and shallow-coverage whole-genome sequencing (WGS) and WGBS data.

Regeneration of cardiac endothelial cells is challenging as these cells must receive proper cues for tissue formation and integrate in the pre-existing vasculature. Here, Farber et. al identify Sox17-Erg as an efficient combination to reprogram cardiac fibroblasts into endothelial-like cells both in vivo and in vitro.

A graph neural network that leverages spatial protein profiles in tissue specimens to model tumour microenvironments as local subgraphs captures distinctive cellular interactions associated with differential clinical outcomes.

Choi et al. highlight the centrality of glycolysis in squamous cell carcinoma, revealing the glycolysis-dampening tumour suppressor role of Sirt6, and identifying a subset of highly glycolytic tumour-propagating cells with elevated antioxidant capacity.

Mutations inactivating ARID1A, a subunit of the chromatin remodeling SWI/SNF complex, have been identified in some human cancers. This study reveals that cancer cells with mutated ARID1A are dependent on the residual activity of the complex for proliferation and that even if concomitant alterations in the ARID1A homolog ARID1B can occur, loss of ARID1B activity confers a specific vulnerability to ARID1A-mutant cells that may in the future be explored for targeting purposes.

A study finds that a protease called granzyme K can activate the entire complement cascade, explaining how it can drive destructive inflammation in inflammatory diseases such as rheumatoid arthritis.

In patients with DNA damage response-deficient solid tumors, the oral ATR kinase inhibitor camonsertib was well tolerated; a recommended phase 2 dose was identified; and encouraging anti-tumor activity was observed, with the highest response rate observed in patients with ovarian cancer.

An observational study reports the joint effects of polygenic risk scores and radiation treatment exposure with a subsequent increased risk of multiple solid cancers in two large cohorts of survivors of childhood cancer.

De Blank and colleagues examine data from childhood cancer survivors diagnosed between 1970 and 1999 and find that exposure to radiation decreased over time, and radiation was associated with a higher risk of late mortality and subsequent neoplasms.

A study generates a clinicogenomics dataset resource, MSK-CHORD, that combines natural language processing-derived clinical annotations with patient medical data from various sources to improve models of cancer outcome.

Identifying the mutational landscape of tumours from cell-free DNA in the blood could help diagnostics in cancer. Here, the authors present ichorCNA, software that quantifies tumour content in cell free DNA, and they demonstrate that cell-free DNA whole-exome sequencing is concordant with metastatic tumour whole-exome sequencing.

The origin and nature of rebound HIV-1 virus following antiretroviral therapy (ART) discontinuation still remains unclear. Here, Liu et al. suggest that intact proviral DNA in peripheral blood and lymph node mononuclear cells during ART suppression likely is the source of viral rebound following ART discontinuation.

Single-cell transcriptional profiling of primary human synovial sarcoma tumors suggests that combinatorial treatment with HDAC and CDK4/CDK6 inhibitors could enhance tumor immunogenicity.

Fine-mapping of causal variants and integration of epigenetic and chromatin conformation data identify likely target genes for 150 breast cancer risk regions.

A report from large cohorts of adult survivors of childhood cancer demonstrates that genetic risk scores improve the risk prediction of developing severe obesity, providing opportunities for surveillance and mitigation interventions

Jason Locasale, Lewis Cantley, Matthew Vander Heiden and colleagues show that PHGDH is amplified in some human cancers and diverts a relatively large amount of glycolytic carbon into serine and glycine biosynthesis. They further show that PHGDH-amplified cancer cells become dependent on PHGDH for their growth, suggesting that the altered metabolic flux driven by this amplification contributes to oncogenesis.

Whole-exome sequencing (WES) has emerged as a transformative technology for biological discovery, but technical difficulties have so far prevented its widespread clinical use. Here, Eliezer Van Allen and colleagues are able to perform production-scale WES on small amounts of clinically acquired formalin-fixed, paraffin-embedded tumor tissues. Using a newly created WES clinical interpretation algorithm, they apply the complete clinical WES framework prospectively to patients and demonstrate how it can be used to directly affect patient care.

A proteomic risk score for cardiorespiratory fitness, comprising as few as 21 proteins, is dynamic with exercise training and helps predict the risk of mortality and a range of cardiovascular, metabolic and neurological conditions.

African ancestry is a known risk factor for prostate cancer development, but the genetic determinants of this are incompletely understood. Here, the authors identify 172 potentially pathogenic variants which are enriched in an African population.