Vitamin-C-dependent downregulation of the citrate metabolism pathway potentiates pancreatic ductal adenocarcinoma growth arrest.

In pancreatic ductal adenocarcinoma (PDAC), metabolic rewiring and resistance to standard therapy are closely associated. PDAC cells show enormous requirements for glucose-derived citrate, the first rate-limiting metabolite in the synthesis of new lipids. Both the expression and activity of citrate synthase (CS) are extraordinarily upregulated in PDAC. However, no previous relationship between gemcitabine response and citrate metabolism has been documented in pancreatic cancer. Here, we report for the first time that pharmacological doses of vitamin C are capable of exerting an inhibitory action on the activity of CS, reducing glucose-derived citrate levels. Moreover, ascorbate targets citrate metabolism towards the de novo lipogenesis pathway, impairing fatty acid synthase (FASN) and ATP citrate lyase (ACLY) expression. Lowered citrate availability was found to be directly associated with diminished proliferation and, remarkably, enhanced gemcitabine response. Moreover, the deregulated citrate-derived lipogenic pathway correlated with a remarkable decrease in extracellular pH through inhibition of lactate dehydrogenase (LDH) and overall reduced glycolytic metabolism. Modulation of citric acid metabolism in highly chemoresistant pancreatic adenocarcinoma, through molecules such as vitamin C, could be considered as a future clinical option to improve patient response to standard chemotherapy regimens.

Trophic assessment in South American Atlantic coastal lagoons: Linking water, sediment and diatom indicators.

Within two coastal shallow lagoons, trophic state was assessed by integrating water and sediment chemical indicators such as the TRIX and the benthic biopolymeric carbon (BPC) trophic indicator, altogether with biological environmental indicators (diatom species characterization). Spatial and temporal behavior of TRIX and BPC indices suggest that water column trophic indicators reflect rather short-term variations in water quality changes, while benthic trophic indicators rather reflect consistent long-term trends which make them useful as enduring indicators of eutrophication. Canonical Correspondence Analysis (CCA) showed that both sediment and transitional water trophic state indices increased eutrophic conditions with a decreasing salinity and increasing total nutrients. Diatom species associated with elevated eutrophic condition such as Staurosirella martyi, Staurosira breviestriata, Amphora copulata, Amphora veneta, Nitzschia sp., and Bacillaria paradoxa, showed a positive correlation with both trophic indices. We highlight the need for considering sediment eutrophication indicators towards in monitoring programmes within shallow coastal lagoons.

MicroRNA-21 predicts response to preoperative chemoradiotherapy in locally advanced rectal cancer.

PURPOSE: The treatment of choice for locally advanced rectal cancer is preoperative chemoradiotherapy. Despite half of patients do not respond and suffer unnecessary toxicities and surgery delays, there are no biomarkers to guide preoperative CRT outcome. MicroRNA-21 has been related to acquisition of 5-fluorouracil resistance; however, its potential predictive value of response to preoperative chemoradiotherapy in locally advanced rectal cancer remains unknown. METHODS: Nighty-two patients diagnosed with locally advanced rectal cancer who were preoperatively treated with chemoradiotherapy were selected for this study. Moreover, microRNA-21 expression was quantified in formalin-fixed paraffin-embedded biopsies from this cohort, and the results obtained were correlated with clinical and molecular characteristics, pathological response, and outcome. RESULTS: MicroRNA-21 was found overexpressed in 77.6% cases, and significantly correlated with tumor grade after preoperative chemoradiotherapy (P = 0.013) and with pathological response (P = 0.013). The odds ratio of having miR-21 overexpression and not getting a respond to chemoradiotherapy resulted in 9.75 CI 2.24 to 42. Sensitivity, specificity, negative predictive values, and positive predictive value were 86.6, 60, 42.8, and 92%, respectively. Multivariate analysis confirmed the clinical significance of miR-21 determining preoperative chemoradiotherapy response. CONCLUSIONS: MicroRNA-21 expression efficiently predicts preoperative chemoradiotherapy pathological response in locally advanced rectal cancer.