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Vestibulodynia is vulvodynia localized to the vulvar vestibule and is a chronic disease defined as vulvar pain of at least three months’ duration, without a defined cause, that severely affects women’s health and quality of life with limited treatment options. We collected stool and vaginal samples from 30 women affected by vestibulodynia and 27 healthy women. Bacterial gut and vaginal microbiomes were characterized by amplicon sequencing, and compositional and functional differences between the control and the patient groups were assessed. No differences in vaginal or fecal alpha and beta diversity were found, but vaginal microbiota of patients was found to be associated with Lactobacillus iners. Moreover, the relative abundance of L. iners negatively correlated with the relative abundance of L. crispatus, and positive correlations between commensals and pathobionts were found in the vestibulodynia vaginal microbiota but not in the healthy controls. The bacterial functions and contributors were defined in the study groups for the fecal and vaginal microbiota. Our results portrayed the vaginal microbiome of patients with vestibulodynia as potentially not as efficient at living in an anaerobic environment as the healthy microbiome is and too inclined to acidify this environment, exposing it to the risk of developing other ailments.

Comprehensive genomic studies have delineated key driver mutations linked to disease progression for most cancers. However, corresponding transcriptional changes remain largely elusive because of the bias associated with cross-study analysis. Here, we overcome these hurdles and generate a comprehensive prostate cancer transcriptome atlas that describes the roadmap to tumor progression in a qualitative and quantitative manner. Most cancers follow a uniform trajectory characterized by upregulation of polycomb-repressive-complex-2, G2-M checkpoints, and M2 macrophage polarization. Using patient-derived xenograft models, we functionally validate our observations and add single-cell resolution. Thereby, we show that tumor progression occurs through transcriptional adaption rather than a selection of pre-existing cancer cell clusters. Moreover, we determine at the single-cell level how inhibition of EZH2 - the top upregulated gene along the trajectory – reverts tumor progression and macrophage polarization. Finally, a user-friendly web-resource is provided enabling the investigation of dynamic transcriptional perturbations linked to disease progression. Transcriptional changes during prostate cancer progression are not yet fully understood. Here, the authors integrate a transcriptomics atlas of prostate cancer and validate it with preclinical models and single-cell RNA-seq, revealing the role of EZH2 and macrophage polarisation in tumour progression.

Intensive efforts have been made to identify features that could serve as biomarkers of aging. Yet, drug-based interventions aimed at lessening the detrimental effects of getting older are lacking. This is largely attributable to tissue-specificity, sex-related differences, and to the difficulty of identifying actionable targets, which continues to pose a significant challenge. Here, we implement a bioinformatics approach revealing that aging-associated increase of the transmembrane Ectodysplasin-A2-Receptor is a prominent tissue-independent alteration occurring in humans and other species, and is particularly pronounced in models of accelerated aging. We show that strengthening of the Ectodysplasin-A2-Receptor signalling axis in myogenic precursors and differentiated myotubes suffices to trigger potent parainflammatory responses, mirroring aspects of aging-driven sarcopenia. Intriguingly, obesity, insulin-resistance, and aging-related comorbidities, such as type-2-diabetes, result in heightened levels of the Ectodysplasin-A2 ligand. Our findings suggest that targeting the Ectodysplasin-A2 surface receptor represents a promising pharmacological strategy to mitigate the development of aging-associated phenotypes. In a broad cross-tissue analysis, the authors show that a receptor called EDA2R steadily increases with age in both humans and animal models, and becomes even more active in conditions like obesity and diabetes, intensifying inflammation-like processes in muscle cells.

Tumor evolution is one of the major mechanisms responsible for acquiring therapy-resistant and more aggressive cancer clones. Whether the tumor microenvironment through immune-mediated mechanisms might promote the development of more aggressive cancer types is crucial for the identification of additional therapeutic opportunities. Here, we identify a subset of tumor-associated neutrophils, defined as tumor-associated neutrophil precursors (PreNeu). These PreNeu are enriched in highly proliferative hormone-dependent breast cancers and impair DNA repair capacity. Mechanistically, succinate secreted by tumor-associated PreNeu inhibits homologous recombination, promoting error-prone DNA repair through non-homologous end-joining regulated by PARP-1. Consequently, breast cancer cells acquire genomic instability promoting tumor editing and progression. Selective inhibition of these pathways induces increased tumor cell killing in vitro and in vivo. Tumor-associated PreNeu score correlates with copy number alterations in highly proliferative hormone-dependent tumors from breast cancer patients. Treatment with PARP-1 inhibitors counteract the pro-tumoral effect of these neutrophils and synergize with endocrine therapy. Tumor-associated neutrophils exhibit heterogeneity in breast cancer. Here, the authors identify a distinct precursor population (PreNeu) in estrogen receptor-positive tumors. PreNeu suppress homologous recombination in cancer cells, promoting error-prone DNA repair and enhancing sensitivity to PARP inhibitors.