CPSF3 inhibition blocks pancreatic cancer cell proliferation through disruption of core histone mRNA processing.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited effective treatment options, potentiating the importance of uncovering novel drug targets. Here, we target cleavage and polyadenylation specificity factor 3 (CPSF3), the 3' endonuclease that catalyzes mRNA cleavage during polyadenylation and histone mRNA processing. We find that CPSF3 is highly expressed in PDAC and is associated with poor prognosis. CPSF3 knockdown blocks PDAC cell proliferation and colony formation in vitro and tumor growth in vivo. Chemical inhibition of CPSF3 by the small molecule JTE-607 also attenuates PDAC cell proliferation and colony formation, while it has no effect on cell proliferation of nontransformed immortalized control pancreatic cells. Mechanistically, JTE-607 induces transcriptional readthrough in replication-dependent histones, reduces core histone expression, destabilizes chromatin structure, and arrests cells in the S-phase of the cell cycle. Therefore, CPSF3 represents a potential therapeutic target for the treatment of PDAC.

Alternative polyadenylation drives oncogenic gene expression in pancreatic ductal adenocarcinoma.

Alternative polyadenylation (APA) is a gene regulatory process that dictates mRNA 3'-UTR length, resulting in changes in mRNA stability and localization. APA is frequently disrupted in cancer and promotes tumorigenesis through altered expression of oncogenes and tumor suppressors. Pan-cancer analyses have revealed common APA events across the tumor landscape; however, little is known about tumor type-specific alterations that may uncover novel events and vulnerabilities. Here, we integrate RNA-sequencing data from the Genotype-Tissue Expression (GTEx) project and The Cancer Genome Atlas (TCGA) to comprehensively analyze APA events in 148 pancreatic ductal adenocarcinomas (PDACs). We report widespread, recurrent, and functionally relevant 3'-UTR alterations associated with gene expression changes of known and newly identified PDAC growth-promoting genes and experimentally validate the effects of these APA events on protein expression. We find enrichment for APA events in genes associated with known PDAC pathways, loss of tumor-suppressive miRNA binding sites, and increased heterogeneity in 3'-UTR forms of metabolic genes. Survival analyses reveal a subset of 3'-UTR alterations that independently characterize a poor prognostic cohort among PDAC patients. Finally, we identify and validate the casein kinase CSNK1A1 (also known as CK1alpha or CK1a) as an APA-regulated therapeutic target in PDAC. Knockdown or pharmacological inhibition of CSNK1A1 attenuates PDAC cell proliferation and clonogenic growth. Our single-cancer analysis reveals APA as an underappreciated driver of protumorigenic gene expression in PDAC via the loss of miRNA regulation.

Addressing Occupational Back Pain: A Systematic Review of Preventive and Therapeutic Strategies.

Occupational back pain has emerged as a significant public health concern. Despite several efforts to mitigate the adverse effects of occupational back pain, this issue still persists across the globe. This systematic review summarizes the preventive and therapeutic options available for managing occupational back pain. A systemic search was carried out in various databases including PubMed, Web of Science, CINAHL Ultimate, and Scopus to identify relevant literature. The search was also extended to Google Scholar to identify more relevant studies. A combination of keywords was used during the search. Studies were included if they focused on occupational back pain, investigated preventive and treatment options, and were published in English. A total of 20 relevant studies, including 62,176 participants, were included in this systemic review. Out of these 20 studies, 10 were randomized control trials, four were cross-sectional studies, two were longitudinal studies, one was a single-blinded clinical study, two were prospective studies, and the remaining one was a pilot study. This systemic review identified various interventions to improve occupational back pain. The common therapeutic strategies included educational programs, physio and rehab interventions, acupuncture, mixed treatment strategies, reflexology, massage, yoga, active physical therapy, and real-time occupational internet-based interventions. Some studies also reported the effectiveness of opioid therapy and non-steroidal anti-inflammatory drugs for managing back pain. Findings indicated that these therapies effectively reduced occupational back pain and improved quality of life. However, opioid therapy uses also raised safety concerns. The findings of this systemic review highlight the importance of adopting evidence-based strategies to address occupational back pain effectively.

Lorazepam Stimulates IL6 Production and Is Associated with Poor Survival Outcomes in Pancreatic Cancer.

PURPOSE: This research investigates the association between benzodiazepines (BZD) and cancer patient survival outcomes, the pancreatic cancer tumor microenvironment, and cancer-associated fibroblast (CAF) signaling. EXPERIMENTAL DESIGN: Multivariate Cox regression modeling was used to retrospectively measure associations between Roswell Park cancer patient survival outcomes and BZD prescription records. IHC, H&E, Masson's trichrome, RNAscope, and RNA sequencing were used to evaluate the impact of lorazepam (LOR) on the murine PDAC tumor microenvironment. ELISA and qPCR were used to determine the impact of BZDs on IL6 expression or secretion by human-immortalized pancreatic CAFs. PRESTO-Tango assays, reanalysis of PDAC single-cell sequencing/TCGA data sets, and GPR68 CRISPRi knockdown CAFs were used to determine the impact of BZDs on GPR68 signaling. RESULTS: LOR is associated with worse progression-free survival (PFS), whereas alprazolam (ALP) is associated with improved PFS, in pancreatic cancer patients receiving chemotherapy. LOR promotes desmoplasia (fibrosis and extracellular matrix protein deposition), inflammatory signaling, and ischemic necrosis. GPR68 is preferentially expressed on human PDAC CAFs, and n-unsubstituted BZDs, such as LOR, significantly increase IL6 expression and secretion in CAFs in a pH and GPR68-dependent manner. Conversely, ALP and other GPR68 n-substituted BZDs decrease IL6 in human CAFs in a pH and GPR68-independent manner. Across many cancer types, LOR is associated with worse survival outcomes relative to ALP and patients not receiving BZDs. CONCLUSIONS: We demonstrate that LOR stimulates fibrosis and inflammatory signaling, promotes desmoplasia and ischemic necrosis, and is associated with decreased pancreatic cancer patient survival.

Succinate dehydrogenase inversely regulates red cell distribution width and healthy life span in chronically hypoxic mice.

Increased red cell distribution width (RDW), which measures erythrocyte mean corpuscular volume (MCV) variability (anisocytosis), has been linked to early mortality in many diseases and in older adults through unknown mechanisms. Hypoxic stress has been proposed as a potential mechanism. However, experimental models to investigate the link between increased RDW and reduced survival are lacking. Here, we show that lifelong hypobaric hypoxia (~10% O2) increased erythrocyte numbers, hemoglobin, and RDW, while reducing longevity in male mice. Compound heterozygous knockout (hKO) mutations in succinate dehydrogenase (Sdh; mitochondrial complex II) genes Sdhb, Sdhc, and Sdhd reduced Sdh subunit protein levels, reduced RDW, and increased healthy life span compared with WT mice in chronic hypoxia. RDW-SD, a direct measure of MCV variability, and the SD of MCV showed the most statistically significant reductions in Sdh hKO mice. Tissue metabolomic profiling of 147 common metabolites showed the largest increase in succinate with elevated succinate/fumarate and succinate/oxoglutarate (2-ketoglutarate) ratios in Sdh hKO mice. These results demonstrate that mitochondrial complex II level is an underlying determinant of both RDW and healthy life span in hypoxia and suggest that therapeutic targeting of Sdh might reduce high RDW-associated clinical mortality in hypoxic diseases.

Drivers of Gene Expression Dysregulation in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) remains a devastating disease with a poor prognosis. The functional consequences of common genetic aberrations and their roles in treatment strategies have been extensively reviewed. In addition to these genomic aberrations, consideration of non-genetic drivers of altered oncogene expression is essential to account for the diversity in PDAC phenotypes. In this review we seek to assess our current understanding of mechanisms of gene expression dysregulation. We focus on four drivers of gene expression dysregulation, including mutations, transcription factors, epigenetic regulators, and RNA stability/isoform regulation, in the context of PDAC pathogenesis. Recent studies provide much-needed insight into the role of gene expression dysregulation in dissecting tumor heterogeneity and stratifying patients for the development of personalized treatment strategies.