Centromere protein‐A (CENP‐A), a histone‐H3 variant, plays an essential role in cell division by ensuring proper formation and function of centromeres and kinetochores. Elevated CENP‐A expression has been associated with cancer development. This study aimed to establish whether elevated CENP‐A expression can be used as a prognostic and predictive cancer biomarker. Molecular profiling of CENP‐A in human cancers was investigated using genomic, transcriptomic and patient information from databases, including COSMIC, Oncomine, Kaplan–Meier plotter and cBioPortal. A network of CENP‐A co‐expressed genes was derived from cBioPortal and analyzed using Ingenuity Pathway Analysis (IPA) and Oncomine protocols to explore the function of CENP‐A and its predictive potential. Transcriptional and post‐transcriptional regulation of CENP‐A expression was analyzed in silico. It was found that CENP‐A expression was elevated in 20 types of solid cancer compared with normal counterparts. Elevated CENP‐A expression highly correlated with cancer progression and poor patient outcome. Genomic analysis indicated that the elevated CENP‐A expression was not due to alterations in the sequence or copy number of the CENP‐A gene. Furthermore, CENP‐A can be regulated by key oncogenic proteins and tumor‐suppressive microRNAs. CENP‐A co‐expression network analysis indicated that CENP‐A function is associated with cell cycle progression. Oncomine analysis showed a strong correlation between elevated CENP‐A expression and oncolytic response of breast cancer patients to taxane‐based chemotherapy. In conclusion, elevated CENP‐A expression is coupled to malignant progression of numerous types of cancer. It may be useful as a biomarker of poor patient prognosis and as a predictive biomarker for taxane‐based chemotherapy.
BackgroundUrinary tract infections (UTIs) are one of the most common infections worldwide, but little is known about their global scale and long-term trends. We aimed to estimate the spatiotemporal patterns of UTIs' burden along with its attributable risk factors at a global level, as well as the variations of the burdens according to socio-demographic status, regions, nations, sexes, and ages, which may be helpful in guiding targeted prevention and treatment programs.MethodsData from the Global Burden of Disease Study 2019 were analyzed to depict the incidence, mortality, and disability-adjusted life years (DALYs) of UTIs in 204 countries and territories from 1990 to 2019 by socio-demographic status, nations, region, sex, and age.ResultsGlobally, 404.61 million cases, 236,790 deaths, and 520,200 DALYs were estimated in 2019. In particular, 2.4 times growth in deaths from 1990 to 2019 was observed, along with an increasing age-standardized mortality rate (ASMR) from 2.77/100,000 to 3.13/100,000. Age-standardized incidence rate (ASIR) was consistently pronounced in regions with higher socio-demographic index (SDI), which presented remarkable upward trends in ASMR and age-standardized DALY rate (ASDR). In contrast, countries with a low SDI or high baseline burden achieved a notable decline in burden rates over the past three decades. Although the ASIR was 3.6-fold higher in females than males, there was no sex-based difference in ASMR and ASDR. The burden rate typically increased with age, and the annual increasing trend was more obvious for people over 60 years, especially in higher SDI regions.ConclusionsThe burden of UTIs showed variations according to socio-demographic status, nation, region, sex, and age in the last three decades. The overall increasing burden intimates that proper prevention and treatment efforts should be strengthened, especially in high-income regions and aging societies.
Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer arising mostly from adenocarcinoma via neuroendocrine transdifferentiation following androgen deprivation therapy. Mechanisms contributing to both NEPC development and its aggressiveness remain elusive. In light of the fact that hyperchromatic nuclei are a distinguishing histopathologic feature of NEPC, we utilized transcriptomic analyses of our patient-derived xenograft (PDX) models, multiple clinical cohorts, and genetically engineered mouse models to identify 36 heterochromatin-related genes that are significantly enriched in NEPC. Longitudinal analysis using our unique, first-in-field PDX model of adenocarcinoma-to-NEPC transdifferentiation revealed that, among those 36 heterochromatin-related genes, heterochromatin protein 1α (HP1α) expression increased early and steadily during NEPC development and remained elevated in the developed NEPC tumor. Its elevated expression was further confirmed in multiple PDX and clinical NEPC samples. knockdown in the NCI-H660 NEPC cell line inhibited proliferation, ablated colony formation, and induced apoptotic cell death, ultimately leading to tumor growth arrest. Its ectopic expression significantly promoted NE transdifferentiation in adenocarcinoma cells subjected to androgen deprivation treatment. Mechanistically, HP1α reduced expression of androgen receptor and RE1 silencing transcription factor and enriched the repressive trimethylated histone H3 at Lys9 mark on their respective gene promoters. These observations indicate a novel mechanism underlying NEPC development mediated by abnormally expressed heterochromatin genes, with HP1α as an early functional mediator and a potential therapeutic target for NEPC prevention and management. Heterochromatin proteins play a fundamental role in NEPC, illuminating new therapeutic targets for this aggressive disease. .
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