MCL1 is a pivot member of the anti-apoptotic BCL-2 family proteins. While a distinctive feature of MCL1 resides in its efficient ubiquitination and destruction, the deubiquitinase USP9X has been ...implicated in the preservation of MCL1 expression by removing the polyubiquitin chains. Here we perform an unbiased siRNA screen and identify that the second deubiquitinase, USP13, regulates MCL1 stability in lung and ovarian cancer cells. Mechanistically, USP13 interacts with and stabilizes MCL1 via deubiquitination. As a result, USP13 depletion using CRISPR/Cas9 nuclease system inhibits tumor growth in xenografted nude mice. We further report that genetic or pharmacological inhibition of USP13 considerably reduces MCL1 protein abundance and significantly increases tumor cell sensitivity to BH3 mimetic inhibitors targeting BCL-2 and BCL-XL. Collectively, we nominate USP13 as a novel deubiquitinase which regulates MCL1 turnover in diverse solid tumors and propose that USP13 may be a potential therapeutic target for the treatment of various malignancies.
Molecular mechanisms of ovarian aging and female age-related fertility decline remain unclear. We surveyed the single-cell transcriptomic landscape of ovaries from young and aged non-human primates ...(NHPs) and identified seven ovarian cell types with distinct gene-expression signatures, including oocyte and six types of ovarian somatic cells. In-depth dissection of gene-expression dynamics of oocytes revealed four subtypes at sequential and stepwise developmental stages. Further analysis of cell-type-specific aging-associated transcriptional changes uncovered the disturbance of antioxidant signaling specific to early-stage oocytes and granulosa cells, indicative of oxidative damage as a crucial factor in ovarian functional decline with age. Additionally, inactivated antioxidative pathways, increased reactive oxygen species, and apoptosis were observed in granulosa cells from aged women. This study provides a comprehensive understanding of the cell-type-specific mechanisms underlying primate ovarian aging at single-cell resolution, revealing new diagnostic biomarkers and potential therapeutic targets for age-related human ovarian disorders.
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•Single-cell transcriptomic roadmap of NHP ovarian aging•Molecular signatures revealed for NHP oocytes at stepwise developmental stages•Cell-type-specific inactivation of antioxidant genes in aged monkey and human ovaries
Single-cell transcriptomic analysis in ovaries of young and old cynomolgus monkeys identifies aging-associated and cell-type-specific dysregulation of antioxidative pathways.
Background and aim
Dietary strategies that contribute to reducing incidence of Helicobacter pylori infection without negative side effects are highly desirable owing to worldwide bacterial prevalence ...and carcinogenesis potential. The aim of this study was to determine dosage effect of daily cranberry consumption on H. pylori suppression over time in infected adults to assess the potential of this complementary management strategy in a region with high gastric cancer risk and high prevalence of H. pylori infection.
Methods
This double‐blind, randomized, placebo‐controlled trial on 522 H. pylori‐positive adults evaluated dose–response effects of proanthocyanidin‐standardized cranberry juice, cranberry powder, or their placebos on suppression of H. pylori at 2 and 8 weeks by 13C‐urea breath testing and eradication at 45 days post‐intervention.
Results
H. pylori‐negative rates in placebo, low‐proanthocyanidin, medium‐proanthocyanidin, and high‐proanthocyanidin cranberry juice groups at week 2 were 13.24%, 7.58%, 1.49%, and 13.85% and at week 8 were 7.35%, 7.58%, 4.48%, and 20.00%, respectively. Consumption of high‐proanthocyanidin juice twice daily (44 mg proanthocyanidin/240‐mL serving) for 8 weeks resulted in decreased H. pylori infection rate by 20% as compared with other dosages and placebo (P < 0.05). Percentage of H. pylori‐negative participants increased from 2 to 8 weeks in subjects who consumed 44 mg proanthocyanidin/day juice once or twice daily, showing a statistically significant positive trend over time. Encapsulated cranberry powder doses were not significantly effective at either time point. Overall trial compliance was 94.25%. Cranberry juice and powder were well‐tolerated.
Conclusions
Twice‐daily consumption of proanthocyanidin‐standardized cranberry juice may help potentiate suppression of H. pylori infection. Trial registration: ChiCTR1800017522, per WHO ICTRP.
Recent genomic analyses have revealed substantial tumor heterogeneity across various cancers. However, it remains unclear whether and how genomic heterogeneity is constrained during tumor evolution. ...Here, we sequence a unique cohort of multiple synchronous lung cancers (MSLCs) to determine the relative diversity and uniformity of genetic drivers upon identical germline and environmental background. We find that each multicentric primary tumor harbors distinct oncogenic alterations, including novel mutations that are experimentally demonstrated to be functional and therapeutically targetable. However, functional studies show a strikingly constrained tumorigenic pathway underlying heterogeneous genetic variants. These results suggest that although the mutation-specific routes that cells take during oncogenesis are stochastic, genetic trajectories may be constrained by selection for functional convergence on key signaling pathways. Our findings highlight the robust evolutionary pressures that simultaneously shape the expansion and constraint of genomic diversity, a principle that holds important implications for understanding tumor evolution and optimizing therapeutic strategies.Across cancer types tumor heterogeneity has been observed, but how this relates to tumor evolution is unclear. Here, the authors sequence multiple synchronous lung cancers, highlighting the evolutionary pressures that simultaneously shape the expansion and constraint of genomic heterogeneity.
A country can be well-comprehended through its core cities. Similarly, we can learn about a city from its hotspots, as they manifest the concentration of urban infrastructures and human activities. ...Following this philosophy, this paper studies the intra-urban form and function from a complexity science perspective by exploring the power law distribution of hotspot sizes and related socio-economic attributes. To detect hotspots, we rely on spatial clustering of geospatial big data sets, including street data from OpenStreetMap platform and nighttime light (NTL) data from the visible infrared imaging radiometer suite (VIIRS) imagery. Unlike conventional spatial units, which are imposed by governments or authorities (such as census block), the delineation of hotspots is done in a totally bottom-up manner and, more importantly, can help us examine precisely the scaling pattern of urban morphological and functional aspects. This results in two types of urban hotspots—street-based and NTL-based hotspots—being generated across 20 major cities in China. We find that Zipf’s law of hotspot sizes (both types) holds remarkably well for each city, as do the city-size distributions at the country level, indicating a statistically self-similar structure of geographic space. We further find that the urban scaling law can be effectively detected when using NTL-based hotspots as basic units. Furthermore, the comparison between two types of hotspots enables us to gain in-depth insights of urban planning and urban economic development.
The young circulatory milieu capable of delaying aging in individual tissues is of interest as rejuvenation strategies, but how it achieves cellular- and systemic-level effects has remained unclear. ...Here, we constructed a single-cell transcriptomic atlas across aged tissues/organs and their rejuvenation in heterochronic parabiosis (HP), a classical model to study systemic aging. In general, HP rejuvenated adult stem cells and their niches across tissues. In particular, we identified hematopoietic stem and progenitor cells (HSPCs) as one of the most responsive cell types to young blood exposure, from which a continuum of cell state changes across the hematopoietic and immune system emanated, through the restoration of a youthful transcriptional regulatory program and cytokine-mediated cell-cell communications in HSPCs. Moreover, the reintroduction of the identified rejuvenating factors alleviated age-associated lymphopoiesis decline. Overall, we provide comprehensive frameworks to explore aging and rejuvenating trajectories at single-cell resolution and revealed cellular and molecular programs that instruct systemic revitalization by blood-borne factors.
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•A single-cell transcriptomic atlas across aged tissues and their rejuvenation in HP•HP systemically rejuvenated senile adult stem cells and their niches across tissues•Youthful transcriptomes were restored in resident HSPCs upon young blood exposure•Reintroduction of rejuvenating factors in aged HSCs mitigated lymphopoiesis decline
Ma and colleagues report a multi-tissue single-cell transcriptomic atlas of HP. They reveal that adult stem cells, especially bone marrow HSPCs, are responsive to the changing milieu. Focusing on HSPCs, they uncover HP-induced rejuvenating programs with underlying key mediators, overexpression of which recharges the lymphopoiesis potential of aged HSCs.
Abstract
Background
People living with HIV/AIDS not only require effective treatment for the alleviation of physical discomfort but also require social support to help them address difficulties in ...life and relieve their psychological anxiety and uneasiness. The social support network is of tremendous importance in helping people living with HIV/AIDS maintain good physical and mental health. This study aims to analyse the social support status among people living with HIV/AIDS in Kunming and explore associated factors.
Method
The Social Support Rating Scale (SSRS) was used, and a questionnaire survey was conducted using convenience sampling to select people living with HIV/AIDS from 14 counties of Kunming. It collected information on general demographic information and social support status. Univariate and multivariate linear regression models were used to explore the associated factors.
Results
A total of 990 valid questionnaires were completed. Data from all participants were analysed. Univariate analysis suggested that the factors associated with social support may include marital status, monthly income, and antiretroviral therapy. On the other hand, factors including monthly income and antiretroviral therapy accounted for the social support total score in the multivariate analysis.
Conclusion
Social support among people living with HIV/AIDS in Kunming was generally low. This study identified a number of factors associated with social support among people living with HIV/AIDS. Based on our findings, appropriate interventions should be introduced to provide social support for those living with HIV/AIDS.
Neuroendocrine bladder cancer is a relatively rare but often lethal malignancy, with cell of origin, oncogenomic architecture and standard treatment poorly defined. Here we performed comprehensive ...whole-genome and transcriptome sequencing on a unique cohort of genitourinary neuroendocrine neoplasms, mainly small cell carcinomas of the urinary bladder. The mutational landscape and signatures of neuroendocrine bladder cancer strikingly resembled those in conventional urothelial carcinoma, along with typically mixed histologies, supporting a common cellular origin. We identified pervasive age-related and APOBEC-mediated mutagenesis patterns, and one patient displayed a somatic fingerprint attributable to aristolochic acid exposure, an established etiology of urothelial cell carcinoma. Deep RNA sequencing revealed dysregulated tumorigenic pathways and novel fusion transcripts, including a targetable in-frame PVT1-ERBB2 variant associated with aberrant expression of ERBB2 gene (encoding HER2 receptor). Furthermore, we provided preliminary evidence that combined TP53 and RB1 depletion favored lineage switching from oncogene-addicted urothelial cancer cells to neuroendocrine-like tumor cells, and resulted in decreased response to targeted agents. Together, these data present the first high-resolution genomic portrait of neuroendocrine bladder cancer, which holds important implications for the biological understanding and rational treatment of this deadly disease.
Ovarian cancer remains a significant cause of gynecologic cancer mortality, and novel therapeutic strategies are urgently needed in clinic as new treatment options. We previously showed that BET ...bromodomain inhibitors displayed promising efficacy for the treatment of epithelial ovarian cancer by downregulating pivot transcription factors. However, the potential antitumor activities and molecular mechanisms of other epigenetic or transcriptional therapies have not been systematically determined. Here, by performing an unbiased high-throughput drug screen to identify candidate compounds with antineoplastic effects, we identified THZ1, a recently developed covalent CDK7 inhibitor, as a new transcription-targeting compound that exerted broad cytotoxicity against ovarian tumors. Mechanistically, CDK7 represented a previously unappreciated actionable vulnerability in ovarian cancer, and CDK7 inhibition led to a pronounced dysregulation of gene transcription, with a preferential repression of E2F-regulated genes and transcripts associated with super-enhancers. Our findings revealed the molecular underpinnings of THZ1 potency and established pharmaceutically targeting transcriptional addiction as a promising therapeutic strategy in aggressive ovarian cancer.
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