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Oncolytic virus holds potential as a cancer therapy, but further optimization is desirable. Here the authors screen existing drug to find talazoparib, a PARP inhibitor, synergizing with reovirus type 3 Dearing (RT3D) to induce cancer cell apoptosis, anti-tumor immunity, as well as control of primary and rechallenge tumor in mouse models.

Rudalska et al. describe a novel class of p38α inhibitors with increased target residence time. They explore the drugs’ specificity, pharmacokinetics and toxicity profile and show that they are efficacious in the context of colorectal cancer.

Glioblastoma stem cells co-opt lysine uptake and degradation to shunt the production of crotonyl-CoA, remodelling the chromatin landscape to evade interferon-induced intrinsic effects on glioblastoma stem cell maintenance and extrinsic effects on immune response.

Birds have evolved a unique sex chromosome dosage compensation mechanism involving the male-biased microRNA (miR-2954), which is essential for male survival by regulating the expression of dosage-sensitive Z-linked genes.

Using a natural experiment that avoids common bias concerns, this study finds that the live-attenuated shingles vaccine reduced the probability of a new dementia diagnosis within a follow-up period of 7 years by approximately one-fifth.

Cancer associated fibroblasts are known to promote the progression of cancer. Here, the authors show that two particular subsets of cancer associated fibroblasts induce metastasis but work via distinct mechanisms including, chemokine signalling and Notch signalling.

Sepsis induces a period of immunosuppression which can be problematic in the face of subsequent infectious challenge. Here the authors show the presence of PD-L1 expressing regulatory plasma cells that can inhibit T cells in a murine model and in patients with sepsis.

Although it has shown high efficacy in many tumor types, interleukin-12 (IL-12) treatment provokes severe systemic toxicity. Here, the authors discover that use of an IL-12Fc fusion cytokine with abolished binding to the neonatal Fc receptor presents efficacy in local glioblastoma therapy while preventing toxicity.

Studies in macaques have shown that neutralizing antibodies can offer robust protection from infection with a simian counterpart of HIV, yet these studies have also suggested that high concentrations of antibodies are required for efficient protection. Unfortunately, it's not generally thought to be feasible to elicit such high neutralizing antibody titers by vaccination. Dennis Burton and his colleagues now show that lower concentrations of antibodies can offer protection to macaques if a repeated low-dose challenge model is used—a model that may better recapitulate the acquisition of infection in humans.

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

Some cancer cells exhibit high loads of reactive iron in lysosomes, and this feature is exploited by using fentomycin-1, a newly developed small molecule, to induce ferroptosis.

In this paper and the related paper from Lugli and colleagues the authors show that high levels of NaCl inside the tumor have a beneficial effect on CD8⁺ T cells and their ability to control tumor growth as a result of enhanced T cell receptor activity.

Na+ /H+ exchangers regulate intracellular pH, sodium levels, and cell volume. Cryo-EM structures reveal lipid coordination at the dimer interfaces of NhaA with cardiolipin and endosomal NHE9 with PI(3,5)P2. These findings demonstrate how specific lipids can regulate ion-exchange activity by stabilizing dimerization with physiological ramifications.

Whole-genome sequencing of chronic lymphocytic leukemia from 485 patients identifies putative coding and noncoding drivers of disease. Genomically defined subgroups show distinct clinical and biological characteristics.

Cell-free expression with engineered DNA enables rapid production of bacteriocin cocktails, overcoming antimicrobial resistance and clearing pathogenic infections in animal models.

Rapid and effective molecular subtyping of pancreatic adenocarcinoma (PDAC) is important for prognosis and treatment. Here, the authors develop PACpAInt, a deep learning model for PDAC molecular subtyping from whole-slide histological imaging that enables the analysis of heterogeneity and prognostic predictions.

Pattern recognition receptors (PRR) critically modulate innate immunity. Here the authors show in cancer cells that interferon responses and anti-tumor immunity activated by dsRNA-induced PRR signaling is enhanced by palbociclib-induced ER stress, with epigenetic changes and altered antigen presentation potentially contributing to this effect.

Murcy et al. show that increasing the plasma glutamine-to-glutamate ratio in atherosclerosis can distally reprogram transcriptional and post-transcriptional remodeling of the aorta by GLS2-dependent hepatic glutaminolysis.

Defects in non-canonical Wnt/planar cell polarity signalling have recently been linked to breast cancer aggressiveness. Puvirajesinghe et al. identify VANGL2, p62/SQSTM1 and JNK as important players in this pathway which may be amenable to therapeutic intervention in breast cancer.

Gastrointestinal stromal tumors can respond to imatinib mesylate therapy owing to its inhibitory action on tumor cells as well as off-target effects on NK cells. This report shows that a different frequency of genetically determined expression profiles of isoforms of the NK cell receptor NKp30, which show various functional properties, is associated with GIST and influences survival after imatinib treatment.

Excessive glucose production by the liver contributes to poor blood glucose control in type 2 diabetes. Here the authors report that the liver kinase B1 (Lkb1) suppresses amino acid driven postprandial glucose production in the liver through the aminotransferase Agxt.

Quezada and colleagues develop improved anti-CD25 antibodies that preserve IL-2 signaling and enhance single-agent antitumor immunity and immunotherapy through specific and efficient T_reg cell depletion.

Chromosome arm-level aneuploidies (CAAs) are frequently observed in cancer. Here, the authors analyse CAA landscapes across different tumour types, relating these chromosome arm gains and losses to tumour evolution, metastasis, patient survival and response to a range of anti-cancer therapies.

Immune cells contribute to adverse remodeling following myocardial infarction. Here the authors show in mice and pigs that CD8⁺ lymphocytes release Granzyme B in the infarcted heart leading to cardiomyocyte death, enhanced inflammation and deterioration of cardiac function.

Genome-wide studies of 1,916 plasma and urine metabolites from 5,023 participants of the German Chronic Kidney Disease study provide insights into systemic and kidney-specific enzymatic and transport processes.

The dynamics of DNA replication factors is crucial for cell cycle progression. Arabidopsis encode two origin recognition complex 1 proteins, ORC1a and ORC1b, with distinct roles in DNA replication and deposition of heterochromatic H3K27me1, respectively.

In triple-negative breast cancer, the kinase PIM1, which is highly expressed, functions through the transcription factor c-MYC to promote tumor cell survival and growth.

Cell competition among epithelial cells allows removal of unfit or dangerous cells. Here, the authors show that the NMDA receptor is an important determinant of cell fitness in the Drosophila wing, also in the context of Myc super-competitor cells, with “loser” cells contributing metabolitic fuel to “winner” cells.

Sinonasal tumour diagnosis can be complicated by the heterogeneity of disease and classification systems. Here, the authors use machine learning to classify sinonasal undifferentiated carcinomas into 4 molecular classe with differences in differentiation state and clinical outcome.