Translational genomics in pancreatic ductal adenocarcinoma: A review with re-analysis of TCGA dataset.

Malignancy of the pancreas is a leading cause of cancer-related mortality, with the highest case-fatality of all cancers. Nevertheless, the lack of sensitive biomarkers and presence of biological heterogeneity precludes its early detection and effective treatment. The recent introduction of next-generation sequencing allows characterization of multiple driver mutations at genome- and exome-wide levels. Sequencing of DNA and RNA from circulating tumour cells has also opened an exciting era of non-invasive procedures for tumour detection and prognostication. This massively-parallel sequencing technology has uncovered the previously obscure molecular mechanisms, providing clues for better stratification of patients and identification of druggable targets for the disease. Identification of active oncogenic pathways and gene-gene interactions may reveal oncogene addiction and synthetic lethality. Relevant findings can be extrapolated to develop targeted and personalized therapeutic interventions. In addition to known mutational events, the role of chromosomal rearrangements in pancreatic neoplasms is gradually uncovered. Coupled with bioinformatics pipelines and epidemiological analyses, a better framework for risk stratification and prognostication of pancreatic cancer will be possible in the near future. In this review, we discuss how translational genomic studies facilitate our understanding of pathobiology, and development of novel diagnostics and therapeutics for pancreatic ductal adenocarcinoma with emphases on whole genome sequencing, whole exome sequencing, and liquid biopsies. We have also re-analyzed The Cancer Genome Atlas (TCGA) dataset to look for genetic features associated with altered survival in patients with pancreatic ductal adenocarcinoma.

Cathelicidin preserves intestinal barrier function in polymicrobial sepsis.

OBJECTIVES: The intestinal epithelium compartmentalizes the sterile bloodstream and the commensal bacteria in the gut. Accumulating evidence suggests that this barrier is impaired in sepsis, aggravating systemic inflammation. Previous studies reported that cathelicidin is differentially expressed in various tissues in sepsis. However, its role in sepsis-induced intestinal barrier dysfunction has not been investigated. DESIGN: To examine the role of cathelicidin in polymicrobial sepsis, cathelicidin wild-(Cnlp+/+) and knockout (Cnlp-/-) mice underwent cecal-ligation and puncture (CLP) followed by the assessment of septic mortality and morbidity as well as histological, biochemical, immunological, and transcriptomic analyses in the ileal tissues. We also evaluated the prophylactic and therapeutic efficacies of vitamin D3 (an inducer of endogenous cathelicidin) in the CLP-induced murine polymicrobial sepsis model. RESULTS: The ileal expression of cathelicidin was increased by three-fold after CLP, peaking at 4 h. Knockout of Cnlp significantly increased 7-day mortality and was associated with a higher murine sepsis score. Alcian-blue staining revealed a reduced number of mucin-positive goblet cells, accompanied by reduced mucin expression. Increased number of apoptotic cells and cleavage of caspase-3 were observed. Cnlp deletion increased intestinal permeability to 4kD fluorescein-labeled dextran and reduced the expression of tight junction proteins claudin-1 and occludin. Notably, circulating bacterial DNA load increased more than two-fold. Transcriptome analysis revealed upregulation of cytokine/inflammatory pathway. Depletion of Cnlp induced more M1 macrophages and neutrophils compared with the wild-type mice after CLP. Mice pre-treated with cholecalciferol (an inactive form of vitamin D3) or treated with 1alpha, 25-dihydroxyvitamin D3 (an active form of VD3) had decreased 7-day mortality and significantly less severe symptoms. Intriguingly, the administration of cholecalciferol after CLP led to worsened 7-day mortality and the associated symptoms. CONCLUSIONS: Endogenous cathelicidin promotes intestinal barrier integrity accompanied by modulating the infiltration of neutrophils and macrophages in polymicrobial sepsis. Our data suggested that 1alpha, 25-dihydroxyvitamin D3 but not cholecalciferol is a potential therapeutic agent for treating sepsis.