Overexpression of PD2 leads to increased tumorigenicity and metastasis in pancreatic ductal adenocarcinoma.

Pancreatic differentiation 2 (PD2), an important subunit of the human PAF complex, was identified after differential screening analysis of 19q13 amplicon, and its overexpression induces oncogenic transformation of NIH3T3 cells, hence raising the possibility of a role for PD2 in tumorigenesis and metastasis. To test this hypothesis, we analyzed here the functional role and clinical significance of PD2 in pancreatic ductal adenocarcinoma (PDAC) and its pathogenesis. Using immunohistochemical analysis, we found that PD2 is detected in the acini but not in the ducts in the normal pancreas. In human PDAC specimens, PD2 was instead primarily detected in the ducts (12/48 patients 25%; p-value \u3c 0.0001), thereby showing that PDAC correlates with increased ductal expression of PD2. Consistently, PD2 expression was increased in telomerase-immortalized human pancreatic ductal cells (HPNE cells) modified to express the HPV16 E6 and E7 proteins, whose respective functions are to block p53 and RB. In addition, ectopic expression of PD2 in PDAC cells (Capan-1 and SW1990) led to increased clonogenicity and migration in vitro, and tumor growth and metastasis in vivo. Interestingly, PD2 overexpression also resulted in enrichment of cancer stem cells (CSCs) and upregulation of oncogenes such as c-Myc and cell cycle progression marker, cyclin D1. Taken together, our results support that PD2 is overexpressed in the ducts of PDAC tissues, and results in tumorigenesis and metastasis via upregulation of oncogenes such as c-Myc and cyclin hence D1 implicating PD2 upregulation in pancreatic oncogenesis with targeted therapeutic potential

The killer within: Endogenous bacteria accelerate oyster mortality during sustained anoxia

16 pages, 5 figures, 2 tablesSustained periods of anoxia, driven by eutrophication, threaten coastal marine systems and can lead to mass mortalities of even resilient animals such as bivalves. While mortality rates under anoxia are well-studied, the specific mechanism(s) of mortality are less clear. We used a suite of complementary techniques (LT50, histology, 16S rRNA amplicon sequencing, and valvometry) to show that the proliferation of anaerobic bacteria within eastern oysters (Crassostrea virginica) accelerates mortality rate under anoxic conditions. Manipulative laboratory experiments revealed that oyster survival under anoxic conditions was halved when bacteria were present compared to when they were excluded by the broad-spectrum antibiotic chloramphenicol. Histological assessments supported this mechanism and showed infiltration of bacteria in oysters that were not treated with antibiotics compared to a general lack of bacteria when oysters were treated with antibiotics. 16S rRNA amplicon sequencing failed to identify any particular genera of bacteria responsible for mortality, rather a diversity of endogenous anaerobic and/or sulfate-reducing bacteria were common among oysters. In addition, monitoring of oyster valve gaping behavior in the field revealed that oysters showed remarkable valve closure synchrony when first exposed to anoxia. However, oysters periodically opened throughout anoxia/hypoxia in both the lab and field, suggesting that the infiltration of exogenous bacteria from the environment may also influence mortality rates under natural settings. Coupled with previous studies, we posit that mass mortality events in a wide range of coastal bivalves are likely the result of co-morbidity from asphyxiation and bacterial processesThis study was funded by L'Étang Ruisseau Bar Ltd. in partnership with the Department of Fisheries and Oceans of Canada (Aquaculture Collaborative Research and Development Program, project 17-G-02 led by M.R.S.C.), a NSERC Discovery Grant to R.F. (RGPIN-2017-04294), and a Total Development Fund from the New Brunswick Department of Agriculture, Aquaculture and Fisheries to R.F.Peer reviewe