RESUMEN
Cancer vaccines have been increasingly studied and developed to prevent or treat various types of cancers. To systematically survey and analyze different reported cancer vaccines, we developed CanVaxKB (https://violinet.org/canvaxkb), the first web-based cancer vaccine knowledgebase that compiles over 670 therapeutic or preventive cancer vaccines that have been experimentally verified to be effective at various stages. Vaccine construction and host response data are also included. These cancer vaccines are developed against various cancer types such as melanoma, hematological cancer, and prostate cancer. CanVaxKB has stored 263 genes or proteins that serve as cancer vaccine antigen genes, which we have collectively termed 'canvaxgens'. Top three mostly used canvaxgens are PMEL, MLANA and CTAG1B, often targeting multiple cancer types. A total of 193 canvaxgens are also reported in cancer-related ONGene, Network of Cancer Genes and/or Sanger Cancer Gene Consensus databases. Enriched functional annotations and clusters of canvaxgens were identified and analyzed. User-friendly web interfaces are searchable for querying and comparing cancer vaccines. CanVaxKB cancer vaccines are also semantically represented by the community-based Vaccine Ontology to support data exchange. Overall, CanVaxKB is a timely and vital cancer vaccine source that facilitates efficient collection and analysis, further helping researchers and physicians to better understand cancer mechanisms.
RESUMEN
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.