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Collecting duct carcinoma (CDC) is an aggressive rare subtype of kidney cancer with unmet clinical needs. Little is known about its underlying molecular alterations and etiology, primarily due to its rarity, and lack of preclinical models. This study aims to comprehensively characterize molecular alterations in CDC and identify its therapeutic vulnerabilities. Through whole-exome and transcriptome sequencing, we identified KRAS hotspot mutations (G12A/D/V) in 3/13 (23%) of the patients, in addition to known TP53, NF2 mutations. 3/13 (23%) patients carried a mutational signature (SBS22) caused by aristolochic acid (AA) exposures, known to be more prevalent in Asia, highlighting a geologically specific disease etiology. We further discovered that cell cycle-related pathways were the most predominantly dysregulated pathways. Our drug screening with our newly established CDC preclinical models identified a CDK9 inhibitor LDC000067 that specifically inhibited CDC tumor growth and prolonged survival. Our study not only improved our understanding of oncogenic molecular alterations of Asian CDC, but also identified cell-cycle machinery as a therapeutic vulnerability, laying the foundation for clinical trials to treat patients with such aggressive cancer.

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Gallbladder cancer (GBC) has a lower incidence rate among the population relative to other cancer types but is a major contributor to the total number of biliary tract system cancer cases. GBC is distinguished from other malignancies by its high mortality, marked geographical variation and poor prognosis. To date no systemic targeted therapy is available for GBC. The main objective of this study is to determine the molecular signatures correlated with GBC development using integrative systems level approaches. We performed analysis of publicly available transcriptomic data to identify differentially regulated genes and pathways. Differential co-expression network analysis and transcriptional regulatory network analysis was performed to identify hub genes and hub transcription factors (TFs) associated with GBC pathogenesis and progression. Subsequently, we assessed the epithelial-mesenchymal transition (EMT) status of the hub genes using a combination of three scoring methods. The identified hub genes including, CDC6, MAPK15, CCNB2, BIRC7, L3MBTL1 were found to be regulators of cell cycle components which suggested their potential role in GBC pathogenesis and progression.

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Obesity is associated with germ cell apoptosis, spermatogenesis arrest, and testicular endocrine suppression. The aim of the present study was to investigate the crosstalk between germ cell apoptosis and cell cycle machinery in sedentary and obese rats after moderate-intensity continuous (MICT), high-intensity continuous (HICT) and High-intensity interval (HIIT) exercise trainings. Male Wistar rats (n = 30) were randomly divided into 5 groups; the control, sedentary high-fat diet (HFD)-received (HFD-sole), MICT, HICT and HIIT-induced HFD-received groups. The serum levels of LDL-C, HDL-C, triglyceride, and testosterone, mRNA and protein levels of Cyclin D1, Cdk4, p21, apoptotic cell number/mm2 of testicular tissue and testicular DNA fragmentation ratio were investigated. The obese animals in HFD-sole group represented a significant (p < 0.05) reduction in serum HDL-C and testosterone levels, Cyclin D1, Cdk4 expressions, and exhibited a remarkable (p < 0.05) increment in LDL-C, triglyceride, p21 expression, apoptotic cell number and DNA fragmentation ratio versus control animals. However, the animals in MICT, HICT, HIIT groups exhibited a significant (p < 0.05) increment in serum HDL-C and testosterone, Cyclin D1 and Cdk4 expressions and showed a significant (p < 0.05) reduction in serum LDL-C and triglyceride, p21 expression, apoptotic cell number and DNA fragmentation versus the HFD-sole group. In conclusion, a crosslink between cell cycle machinery and apoptosis of germ cells was revealed in the testicles of HFD-sole animals, and MICT, HICT and HIIT could ameliorate the obesity-induced impairments, respectively. This effect may be attributed to the effect of exercise training protocols on maintaining Cyclin D1 and Cdk4 and suppressing p21 expression levels in the testicles.

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BACKGROUND: Understanding the embryonic stem cell (ESC) fate decision between self-renewal and proper differentiation is important for developmental biology and regenerative medicine. Attention has focused on mechanisms involving histone modifications, alternative pre-messenger RNA splicing, and cell-cycle progression. However, their intricate interrelations and joint contributions to ESC fate decision remain unclear. RESULTS: We analyze the transcriptomes and epigenomes of human ESC and five types of differentiated cells. We identify thousands of alternatively spliced exons and reveal their development and lineage-dependent characterizations. Several histone modifications show dynamic changes in alternatively spliced exons and three are strongly associated with 52.8% of alternative splicing events upon hESC differentiation. The histone modification-associated alternatively spliced genes predominantly function in G2/M phases and ATM/ATR-mediated DNA damage response pathway for cell differentiation, whereas other alternatively spliced genes are enriched in the G1 phase and pathways for self-renewal. These results imply a potential epigenetic mechanism by which some histone modifications contribute to ESC fate decision through the regulation of alternative splicing in specific pathways and cell-cycle genes. Supported by experimental validations and extended datasets from Roadmap/ENCODE projects, we exemplify this mechanism by a cell-cycle-related transcription factor, PBX1, which regulates the pluripotency regulatory network by binding to NANOG. We suggest that the isoform switch from PBX1a to PBX1b links H3K36me3 to hESC fate determination through the PSIP1/SRSF1 adaptor, which results in the exon skipping of PBX1. CONCLUSION: We reveal the mechanism by which alternative splicing links histone modifications to stem cell fate decision.

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