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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.

Analysis of lower respiratory tract microbiome of mechanically ventilated COVID-19 patients rules out a role for secondary respiratory infections as drivers of increased mortality.

Whether intermittent strategies of delivering drugs can improve cancer patients survival is still unclear. Here, the authors reports the results of a randomized phase II clinical trial aimed to compare the efficacy and safety of two dosing regimens (continuous and intermittent) of vemurafenib and cobimetinib combination as first-line treatment of patients with unresectable or metastatic advanced melanoma with BRAFV600 mutation

In the Tumor Profiler proof-of-concept observational study, a multiomics approach for profiling tumors from patients with melanoma was feasible, returning data within 4 weeks and informing treatment recommendations in 75% of cases.

Type I interferons have been described to have protumor or antitumor functions depending on context. Here the authors show a protumor function for type I interferons in that they promote cancer stem cells by upregulating the chromatin remodeling factor KDM1B.

The antibacterial agent colistin displays synergistic activity with azoles and echinocandins against various pathogenic fungi. Here, the authors show that the mechanisms involve disruption of cell membrane permeability and calcium homeostasis.

The RNA methyltransferase activity of SPOUT1/CENP-32 is crucial for accurate mitotic spindle organization. Here, the authors describe a neurodevelopmental disorder caused by bi-allelic pathogenic SPOUT1 variants with reduced activity and compromised function in spindle organization.

α-Synuclein accumulation in putaminal synapses is hypothesised to drive Parkinson’s disease progression. This study demonstrates synaptic pSer129 α-synuclein enrichment in early-stage Parkinson’s disease, and its link with dopaminergic denervation and cortical Lewy body pathology.

The burden of mosaic chromosomal alterations in blood-derived DNA, a type of clonal hematopoiesis, is associated with an increased risk for diverse types of infections, including sepsis and pneumonia.

Treatment with the oncolytic herpes virus CAN-3110 is associated with improved survival responses in patients with recurrent glioblastoma, particularly in individuals who are seropositive for HSV1.

Immune surveillance is critical to prevent the development and progression of cutaneous squamous cell carcinoma (cSCC). Here, the authors show that epithelial-mesenchymal plasticity in cancer cells is associated with changes in their immune checkpoint ligand profile during mouse cSCC progression, which dictates differential responses to immune checkpoint blockade.

Here the authors show that BTLA on effector T cells interacts with HVEM on other immunosuppressive cells in the tumor microenvironment. The authors also present evidence that overcoming this checkpoint can ehance CAR T functionality.

A proteomic aging clock, developed using data from the UK Biobank and validated using data from the China Kadoorie Biobank and FinnGen, predicts the incidence of 18 major chronic diseases, as well as multimorbidity and all-cause mortality.

The clinical management of metastatic melanoma requires predictors of the response to checkpoint blockade. Here, the authors use immunological assays to identify potential prognostic/predictive biomarkers in circulating blood cells and in tumor-infiltrating lymphocytes from patients with resected stage III melanoma.

‘T cell engagers promote antitumor immunity, but how macrophage modulates this activity in tumor is still unclear. Here the authors show, using biopsies from patients with uveal melanoma and single cell analyses, that a T cell engager, tebentafusp, reprograms tumor-associated macrophages and ameliorates, in synergy with IL-2, immunosuppression to cancer.

In a multicenter, single-arm, open-label phase 2 study of patients with previously treated metastatic uveal melanoma, treatment with tebentafusp, a soluble TCR bispecific (gp100xCD3) showed promising clinical activity with an acceptable safety profile.

A comprehensive analysis of models of brain metastasis and multiple cohorts of patient samples identifies a targetable molecular mechanism underlying the resistance to whole-brain radiotherapy that can inform patient selection for personalized radiotherapy.

The heparan sulfate proteoglycan-binding cytokine APRIL has a protective role against atherosclerotic disease.

The genomic features of precursor conditions of multiple myeloma provide multiple biological insights into disease origins and evolution, together with opportunities to identify those at highest risk of progression.

A meta-analysis of genome-wide association studies of type 2 diabetes (T2D) identifies more than 600 T2D-associated loci; integrating physiological trait and single-cell chromatin accessibility data at these loci sheds light on heterogeneity within the T2D phenotype.

KRAS-driven cancers remain refractory to current clinical therapies. In this study, the authors show that lung and pancreatic cancers expressing oncogenic KRAS can be targeted by genetic inhibition of FOSL1, which involves downregulation of genes of the mitotic machinery.

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

Multiomic brain tissue analysis identified sex-specific molecular changes in Amyotrophic lateral sclerosis (ALS), revealing subgroups within the disease and pointing to the MAPK pathway as an early disease mechanism and potential therapeutic target.

Metformin may serve as a non-toxic intervention to inhibit mitochondrial metabolism and slow DNMT3A-R882 clonal haematopoiesis expansion, thus delaying or averting progression to acute myeloid leukaemia.

IL-1 blockade prevents cytokine-release syndrome and neurotoxicity by CAR T cells.

The function of wild-type KRAS in KRAS mutant cancers remains to be explored. Here, the authors show that deletion of the tumour-suppressive wild-type Kras in a KRASG12D driven colon cancer model exacerbates tumour initiation in a MAPK dependent manner, while acting to suppress metastasis through impaired immune suppression.

A newly identified population of neurons in the ventral medial preoptic area of the hypothalamus regulate stereotypical symptoms of illness, including fever and appetite suppression.

Genome-wide association meta-analyses identify 26 risk loci for epilepsy, including 19 loci specific to genetic generalized epilepsy. Prioritized candidate genes implicate synaptic processes and overlap with targets of antiseizure medications.

A region on chromosome 19p13 is associated with the risk of developing ovarian and breast cancer. Here, the authors genotyped SNPs in this region in thousands of breast and ovarian cancer patients and identified SNPs associated with three genes, which were analysed with functional studies.

We uncover key processes of the genomic evolution of small cell lung cancer under therapy, identify the common ancestor as the source of clonal diversity at relapse and show central genomic patterns associated with drug response.

Genome-wide association meta-analysis of AAA identifies 121 independent risk loci and highlights potential therapeutic targets such as proprotein convertase, subtilisin/kexin-type 9 (PCSK9).

Alzheimer’s disease is heterogeneous in its neuroimaging and clinical phenotypes. Here the authors present a semi-supervised deep learning method, Smile-GAN, to show four neurodegenerative patterns and two progression pathways providing prognostic and clinical information.

Understanding the dynamics of the gut microbiota over the course of cancer treatment regimens and their associated adverse events can help identify microbial features that associate with response to immune checkpoint blockade.

A study shows that clonal haematopoiesis of indeterminate potential is associated with an increased risk of chronic liver disease specifically through the promotion of liver inflammation and injury.

The oncoprotein c-Myc is often overexpressed in triple negative breast cancer and has a role in tumor progression and resistance to therapy. Here the authors show that elevated MYC expression is correlated with low immune infiltration, diminished MHC-I pathway expression and that CpG/aOX40 treatment could overcome resistance to PD-L1 blockade in MYC-high breast tumors.

There is increasing evidence of a functional interaction between acute myeloid leukemia (AML) and immune cells, influencing disease outcome. Here the authors study how distinct oncogenes differentially affect the host immune response to leukemic cells in preclinical models of AML.

The oncogenic splicing factor TRA2β is reported to be upregulated in human cancers partly by increased TRA2β poison exon (PE) skipping. Here the authors show that forced inclusion of this PE using antisense oligonucleotides depletes TRA2β protein levels and generates long non-coding RNAs that sequester nuclear proteins, leading to cancer toxicity.

Myelomagenesis progresses through well-defined pre-malignant states. Here, using single-cell RNA sequencing and T cell receptor repertoire analysis of bone marrow T cells in patients at different stages of myelomagenesis, the authors identify large clonotypic expansions characterized by the expression of multiple immune checkpoints.

Brain-iron elevation is implicated in Alzheimer’s disease (AD), but the impact of the metal on disease outcomes has not been analysed in a longitudinal study. Here, the authors examine the association between the levels of ferritin, an iron storage protein, in the cerebrospinal fluid (CSF) of AD patients and show that CSF ferritin levels predict AD outcomes.

Heo, Xu et al. used comprehensive plasma proteomics to identify 416 plasma proteins (294 new) associated with Alzheimer’s disease and applied machine learning to select 7 proteins that were highly predictive of Alzheimer’s disease across multiple cohorts.

Metabolic compensation equips tumours with the plasticity to circumvent individual nutrient pathway perturbation. Méndez-Lucas et al. demonstrate the power of synergistic targeting of multiple metabolic pathways to stymie liver tumourigenesis.

The authors identify copy number signatures from shallow whole-genome sequencing of high-grade serous ovarian cancer (HGSOC) cases. HGSOC comprises a continuum of genomes shaped by multiple mutational processes that result in genomic aberration.

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis involving evasion of immune control. Here, the authors perform a comprehensive analysis of single-cell multi-omic data revealing either a myeloid-enriched or adaptive-enriched tumour microenvironment, linked to distinct B and T cell clonal selection and differentiation, distinct overall survival, and potential therapeutic approaches.

Vaccination is effective in protecting from COVID-19. Here the authors report immune responses and breakthrough infections in twice-vaccinated patients receiving anti-TNF treatments for inflammatory bowel disease, and find dampened vaccine responses that implicate the need of adapted vaccination schedules for these patients.

Metformin holds the potential to extend healthy lifespan in aged, insulin-resistant individuals. Using C. elegans, Espada et al. uncover a deleterious metabolic response to metformin treatment in aged worms with unaltered insulin signalling.

Functional CRISPR screens in patient-matched pre-treatment and post-treatment glioblastoma models identify the PTP4A–ROBO1 axis as a driver of tumorigenicity and enriched ROBO1 expression in recurrent glioblastoma that can be targeted with CAR T cell therapy.