Antidiabetic Drug Metformin Prevents Progression of Pancreatic Cancer by Targeting in Part Cancer Stem Cells and mTOR Signaling

Epidemiologic studies have shown that diabetes mellitus is associated positively with increased risk of pancreatic ductal adenocarcinoma (PDAC), and recent meta-analysis studies showed that metformin, reduces the risk of pancreatic cancer (PC). We tested the effects of metformin on pancreatic intraepithelial neoplasia (PanIN) and their progression to PDAC in p48Cre/+.LSL-KrasG12D/+ transgenic mice. Mice fed control diet showed 80% and 62% incidence of PDAC in males and females, respectively. Male mice showed 20% and 26%, and female mice showed 7% and 0% PDAC incidence with 1000- and 2000-ppm metformin treatments, respectively. Both doses of metformin decreased pancreatic tumor weights by 34% to 49% (P < 0.03–0.001). The drug treatment caused suppression of PanIN 3 (carcinoma in situ) lesions by 28% to 39% (P < .002) and significant inhibition of carcinoma spread in the pancreas. The pancreatic tissue and/or serum of mice fed metformin showed a significant inhibition of mammalian target of rapamycin (mTOR), extracellular signal-regulated kinases (ERK), phosphorylated extracellular signal-regulated kinases (pErk), and insulin-like growth factor 1 (IGF-1) with an increase in phosphorylated 5′ adenosine monophosphate kinase (pAMPK), tuberous sclerosis complex 1 (TSC1, TSC2), C-protein and an autophagy related protein 2 (ATG2). The cancer stem cell (CSC) markers were significantly decreased (P < 0.04–0.0002) in the pancreatic tissue. These results suggest that biologic effects of metformin are mediated through decreased CSC markers cluster of differentiation 44 (CD44 and CD133), aldehyde dehydrogenase isoform 1 (ALDH1), and epithelial cell adhesion molecule (EPCAM) and modulation of the mTOR signaling pathway. Our preclinical data indicate that metformin has significant potential for use in clinical trials for PC chemoprevention.     

Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis

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Chromosome aberrations in a natural population of Tetrix tenuicornis (Sahlb.) (Tetrigidae: Orthoptera).

In the natural population of Tetrix tenuicornis from the Kraków-Czestochowa Upland 26.7% of males showed various aberrations of the morphology and behaviour of chromosomes. The high frequency of chromosome aberrations found in this population indicates their genetic instability.     

Selected dehydrogenases in Yarrowia lipolytica JMY 861: their role in the synthesis of flavor compounds

The presence of selected dehydrogenases, including alcohol dehydrogenase (ADH-YL) and aldehyde dehydrogenase (ALDH-YL), in Yarrowia lipolytica JMY 861, and their potential role in flavor synthesis were investigated. The experimental findings showed that using reduced form of nicotinamide adenine dinucleotide (NADH) as cofactor, the ADH-YL activity in vitro was 6-fold higher than that with reduced form of nicotinamide adenine dinucleotide phosphate (NADPH); however, under the experimental conditions used in this study, an ALDH-YL activity was not detected. The in situ hexanal reduction reaction was found to be instantaneous; however, when the yeast cells suspension was diluted 150 times, the initial relative hexanal concentration was increased by 84.1%. The chromatographic analyses indicated the conversion, in situ, of linoleic acid hydroperoxides (HPODs) into volatile C₆-compounds after 60 min of HPODs addition to the yeast cells suspension.