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The bladder undergoes large shape changes as it fills and empties and experiences complex mechanical forces. These forces become abnormal in diseases of the lower urinary tract such as overactive bladder, neurogenic bladder, and urinary retention. As the primary mechanosensors linking the actin cytoskeleton to the extracellular matrix (ECM), integrins are likely to play vital roles in maintaining bladder smooth muscle (BSM) homeostasis. In a tamoxifen-inducible smooth muscle conditional knockout of β1-integrin, there was concomitant loss of α1- and α3-integrins from BSM and upregulation of αV- and β3-integrins. Masson's staining showed a reduction in smooth muscle with an increase in collagenous ECM. Functionally, mice exhibited a changing pattern of urination by voiding spot assay up to 8 wk after tamoxifen. By 8 wk, there was increased frequency with reductions in voided volume, consistent with overactivity. Cystometrograms confirmed that there was a significant reduction in intercontractile interval with reduced maximal bladder pressure. Muscle strip myography revealed a loss of contraction force in response to electrical field stimulation, that was entirely due to the loss of muscarinic contractility. Quantitative western blotting showed a loss of M3 receptor and no change in P2X1. qPCR on ECM and interstitial genes revealed loss of Ntpd2, a marker of an interstitial cell subpopulation; and an upregulation of S100A4, which is often associated with fibroblasts. Collectively, the data show that the loss of appropriate mechanosensation through integrins results in cellular and extracellular remodeling, and concomitant bladder dysfunction that resembles lower urinary tract symptoms seen in older people. Graphical Abstract Graphical Abstract

We showed that loss of the orphan G protein-coupled receptor GPR52 in human breast cell lines leads to increased cell clustering, hybrid/partial EMT, and increased tumor burden in zebrafish. G protein-coupled receptors (GPCRs) are the largest class of membrane-bound receptors that transmit critical signals from extracellular to intracellular spaces. Transcriptomic data of resected breast tumors show that low mRNA expression of orphan GPCR GPR52 correlates with reduced overall survival in patients with breast cancer, leading to the hypothesis that loss of GPR52 supports breast cancer progression. CRISPR-Cas9 was used to knockout GPR52 in the human triple-negative breast cancer (TNBC) cell lines MDA-MB-468 and MDA-MB-231, and in the non-cancerous breast epithelial cell line MCF10A. 2D and 3D studies, electron microscopy, Matrigel culture, and a zebrafish xenograft model were used to assess the morphology and behavior of GPR52 KO cells. RNA-sequencing and proteomic analyses were also conducted on these cell lines, and transcriptomic data from The Cancer Genome Atlas (TCGA) database were used to compare GPR52-null and wild-type (WT) signatures in breast cancer. Loss of GPR52 was found to be associated with increased cell-cell interaction in 2D cultures, altered 3D spheroid morphology, and increased propensity to organize and invade collectively in Matrigel. Furthermore, GPR52 loss was associated with features of EMT in MDA-MB-468 cells, and zebrafish injected with GPR52 KO cells developed a greater total cancer area than those injected with control cells. RNA sequencing and proteomic analyses of GPR52-null breast cancer cells revealed an increased cAMP signaling signature. Consistently, we found that treatment of wild-type (WT) cells with forskolin, which stimulates the production of cAMP, induces phenotypic changes associated with GPR52 loss, and inhibition of cAMP production rescued some GPR52 KO phenotypes. GPR52 is an orphan GPCR and its role in cancer progression has not been previously characterized. We found that GPR52 loss in breast cancer cells can lead to increased cell clustering, collective invasion, and EMT . These are features of increased cancer aggression. Our results reveal that GPR52 loss is a potential mechanism by which breast cancer progression may occur and support the investigation of GPR52 agonism as a therapeutic option for breast cancer.

Breast adipose tissue is an important contributor to the obesity-breast cancer link. Dysregulated cell metabolism is now an accepted hallmark of cancer. Extracellular vesicles (EVs) are nanosized particles containing selective cargo, such as miRNAs, that act locally or circulate to distant sites to modulate target cell functions. Here, we found that long-term education of breast cancer cells (MCF7, T47D) with EVs from breast adipose tissue of women who are overweight or obese (O-EVs) leads to sustained increased proliferative potential. RNA-Seq of O-EV-educated cells demonstrates increased expression of genes, such as ATP synthase and NADH: ubiquinone oxidoreductase, involved in oxidative phosphorylation. O-EVs increase respiratory complex protein expression, mitochondrial density, and mitochondrial respiration in tumor cells. Mitochondrial complex I inhibitor, metformin, reverses O-EV-induced cell proliferation. Several miRNAs, miR-155-5p, miR-10a-3p, and miR-30a-3p, which promote mitochondrial respiration and proliferation, are enriched in O-EVs relative to EVs from lean women. O-EV-induced proliferation and mitochondrial activity are associated with stimulation of the Akt/mTOR/P70S6K pathway, and are reversed upon silencing of P70S6K. This study reveals a new facet of the obesity-breast cancer link with human breast adipose tissue-derived EVs causing the metabolic reprogramming of ER+ breast cancer cells.

IntroductionEarly life soil-transmitted helminth (STH) infection and diarrhoea are associated with growth faltering, anaemia, impaired child development and mortality. Exposure to faecally contaminated soil inside the home may be a key contributor to enteric infections, and a large fraction of rural homes in low-income countries have soil floors. The objective of this study is to measure the effect of installing concrete floors in homes with soil floors on child STH infection and other maternal and child health outcomes in rural Bangladesh.Methods and analysisThe Cement-based flooRs AnD chiLd hEalth trial is an individually randomised trial in Sirajganj and Tangail districts, Bangladesh. Households with a pregnant woman, a soil floor, walls that are not made of mud and no plan to relocate for 3 years will be eligible. We will randomise 800 households to intervention or control (1:1) within geographical blocks of 10 households to account for strong geographical clustering of enteric infection. Laboratory staff and data analysts will be blinded; participants will be unblinded. We will instal concrete floors when the birth cohort is in utero and measure outcomes at child ages 3, 6, 12, 18 and 24 months. The primary outcome is prevalence of any STH infection (Ascaris lumbricoides, Necator americanus or Trichuris trichiura) detected by quantitative PCR at 6, 12, 18 or 24 months follow-up in the birth cohort. Secondary outcomes include household floor and child hand contamination with Escherichia coli, extended-spectrum beta-lactamase producing E. coli and STH DNA; child diarrhoea, growth and cognitive development; and maternal stress and depression.Ethics and disseminationStudy protocols have been approved by institutional review boards at Stanford University and the International Centre for Diarrheal Disease Research, Bangladesh. We will report findings on ClinicalTrials.gov, in peer-reviewed publications and in stakeholder workshops in Bangladesh.Trial registration number NCT05372068.