BACKGROUND: MicroRNAs (miRs) have been shown to play an important role in tumorigenesis, including in head and neck squamous cell carcinoma (HNSCC). The miR-34 family is thought to play a role in tumor suppression, but the exact mechanism of their action in HNSCC is not well understood. Moreover, the impact of chromosomal changes and mutation status on miR-34a expression remains unknown. METHODS: Differential expression of miR-34a, MET, and genomic alterations were assessed in the Cancer Genome Atlas (TCGA) datasets as well as in primary HNSCC and adjacent normal tissue. The biological functions of miR-34a in HNSCC were investigated in samples derived from primary human tumors and HNSCC cell lines. The expression of MET was evaluated using immunohistochemistry, and the molecular interaction of miR-34a and MET were demonstrated by RNA pulldown, RNA immunoprecipitation, luciferase reporter assay, and rescue experiments. Lastly, locked nucleic acid (LNA) miRs in mouse xenograft models were used to evaluate the clinical relevance of miR-34a in HNSCC tumor growth and modulation of the tumor microenvironment in vivo. RESULTS: Chromosome arm 1p loss and P53 mutations are both associated with lower levels of miR-34a. In HNSCC, miR-34a acts as a tumor suppressor and physically interacts with and functionally targets the proto-oncogene MET. Our studies found that miR-34a suppresses HNSCC carcinogenesis, at least in part, by downregulating MET, consequently inhibiting HNSCC proliferation. Consistent with these findings, administration of LNA-miR-34a in an in vivo model of HNSCC leads to diminished HNSCC cell proliferation and tumor burden in vitro and in vivo, represses expression of genes involved in epithelial-mesenchymal transition, and negates the oncogenic effect of MET in mouse tumors. Consistently, LNA-miR-34a induced a decreased number of immunosuppressive PDL1-expressing tumor-associated macrophages in the tumor microenvironment. In HNSCC patient samples, higher levels of miR-34a are significantly associated with a higher frequency of Th1 cells and CD8 naive T cells. CONCLUSIONS: Our results demonstrate that miR-34a directly targets MET and maintains anti-tumor immune activity. We propose miR-34a as a potential new therapeutic approach for HNSCC.

Background: There is a reported association between proton pump inhibitor (PPI) exposure and increased risk of Clostridium difficile infection (CDI), but less is known about how this class of medications taken during treatment might influence mortality after CDI. Here we examine 180-day mortality rates in a cohort of CDI elders and its association with exposure to PPIs. We conducted a retrospective cohort study of elderly patients ( > 65 years of age) diagnosed and treated for CDI in the years 2014-2016 (n = 874) in the Umass Memorial Health Care system, which represents both academic and community healthcare. Patient characteristics and medication use was extracted from the electronic medical record (EMR) and 6 month mortality data was obtained via the Center for Disease Control National Death Index. A Cox proportional hazards model was used to estimate hazard ratios associated with medication exposures and other relevant variables. Results: Of the 874 elderly adults treated for CDI, 180-day all-cause mortality was 12.4%. Exposure to a PPI was associated with a 55% reduced risk of mortality (adjusted hazard ratio (aHR) 0.45; 95% confidence interval (CI) 0.28-0.72). In our Cox model, increasing age (aHR 1.45; 95% CI 1.14-1.84), those with severe CDI infections (aHR 1.87; 95% CI 1.22-2.88), and those with hospital acquired CDI (aHR 3.01; 95% CI 1.81-4.99) also had increased 180 day mortality risk. There were similar associations noted with both 90 day and 1-year mortality. Conclusion: Use of PPIs during CDI treatment in elderly patients is associated with decreased 180-day mortality. Although use of PPIs has been associated with an increased risk of CDI, it appears to be protective against mortality when used during the treatment phase.

BACKGROUND/OBJECTIVES: It is unclear how medication exposures differ in their association with recurrent Clostridium difficile infection (rCDI) in elderly nursing home (NH) residents and community-dwelling individuals. This study examined these exposures to determine whether the risk of rCDI differs according to living environment. DESIGN: Retrospective. SETTING: Academic and community healthcare settings. PARTICIPANTS: Individuals aged 65 and older with CDI (N = 616). MEASUREMENTS: Information on participant characteristics and medications was extracted from the electronic medical record (EMR). We used separate extended Cox models according to living environment to identify the association between medication use and risk of rCDI. RESULTS: Of the 616 elderly adults treated for CDI, 24.1% of those living in the community and 28.1% of NH residents experienced recurrence within 1 year. For community-dwelling participants, the risk of rCDI was 1.6 times as high with antibiotic exposure and 2.5 times as high with acid-reducing medication exposure, but corticosteroid exposure was associated with a 39% lower risk of recurrence. For NH residents, the risk of rCDI was 2.9 times as high with acid-reducing medication exposure and 5.9 times as high with corticosteroid medication exposure. Antibiotic exposure was associated with an increased risk of recurrence only in community-dwelling participants (adjusted hazard ratio = 1.63, 95% confidence interval = 1.00-2.67). CONCLUSION: Risk of rCDI is greater with acid-reducing medication use than antibiotic use after initial CDI treatment, although the risk varied depending on living environment. Corticosteroid use is associated with greater risk of recurrence in NH residents but lower risk in community-dwelling elderly adults.