Modulation of PKM alternative splicing by PTBP1 promotes gemcitabine resistance in pancreatic cancer cells

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and incurable disease. Poor prognosis is due to multiple reasons, including acquisition of resistance to gemcitabine, the first-line chemotherapeutic approach. Thus, there is a strong need for novel therapies, targeting more directly the molecular aberrations of this disease. We found that chronic exposure of PDAC cells to gemcitabine selected a subpopulation of cells that are drug-resistant (DR-PDAC cells). Importantly, alternative splicing (AS) of the pyruvate kinase gene (PKM) was differentially modulated in DR-PDAC cells, resulting in promotion of the cancer-related PKM2 isoform, whose high expression also correlated with shorter recurrence-free survival in PDAC patients. Switching PKM splicing by antisense oligonucleotides to favor the alternative PKM1 variant rescued sensitivity of DR-PDAC cells to gemcitabine and cisplatin, suggesting that PKM2 expression is required to withstand drug-induced genotoxic stress. Mechanistically, upregulation of the polypyrimidine-tract binding protein (PTBP1), a key modulator of PKM splicing, correlated with PKM2 expression in DR-PDAC cell lines. PTBP1 was recruited more efficiently to PKM pre-mRNA in DR- than in parental PDAC cells. Accordingly, knockdown of PTBP1 in DR-PDAC cells reduced its recruitment to the PKM pre-mRNA, promoted splicing of the PKM1 variant and abolished drug resistance. Thus, chronic exposure to gemcitabine leads to upregulation of PTBP1 and modulation of PKM AS in PDAC cells, conferring resistance to the drug. These findings point to PKM2 and PTBP1 as new potential therapeutic targets to improve response of PDAC to chemotherapy.Oncogene advance online publication, 3 August 2015; doi:10.1038/onc.2015.270

Common features between neoplastic and preneoplastic lesions of the biliary tract and the pancreas

The bile duct system and pancreas show many similarities due to their anatomical proximity and common embryological origin. Consequently, preneoplastic and neoplastic lesions of the bile duct and pancreas share analogies in terms of molecular, histological and pathophysiological features. Intraepithelial neoplasms are reported in biliary tract, as biliary intraepithelial neoplasm (BilIN), and in pancreas, as pancreatic intraepithelial neoplasm (PanIN). Both can evolve to invasive carcinomas, respectively cholangiocarcinoma (CCA) and pancreatic ductal adenocarcinoma (PDAC). Intraductal papillary neoplasms arise in biliary tract and pancreas. Intraductal papillary neoplasm of the biliary tract (IPNB) share common histologic and phenotypic features such as pancreatobiliary, gastric, intestinal and oncocytic types, and biological behavior with the pancreatic counterpart, the intraductal papillary mucinous neoplasm of the pancreas (IPMN). All these neoplastic lesions exhibit similar immunohistochemical phenotypes, suggesting a common carcinogenic process. Indeed, CCA and PDAC display similar clinic-pathological features as growth pattern, poor response to conventional chemotherapy and radiotherapy and, as a consequence, an unfavorable prognosis. The objective of this review is to discuss similarities and differences between the neoplastic lesions of the pancreas and biliary tract with potential implications on a common origin from similar stem/progenitor cells

Effects of Mindfulness Training on School Teachers\u2019 Self-Reported Personality Traits As Well As Stress and Burnout Levels

Among a sample of only female school teachers, we compared a mindfulness meditation (MM) training group (n = 19) with a waiting-list control group (n = 20) on several participant-completed questionnaires: the Five Facet Mindfulness Questionnaire, the Big Five Personality Inventory, the Teacher Stress Inventory, and the Maslach Burnout Inventory. With these measures, we assessed the participants\u2019 dispositional mindfulness, personality styles, and their stress and burnout. Following mindfulness training, teachers in the MM group showed higher trait mindfulness and conscientiousness and lower neuroticism and stress and burnout levels than teachers in the waiting-list control group. These results support the beneficial role of MM in individuals\u2019 effective management of stressful conditions in the workplace

Clinical application of mindfulness-oriented meditation: A preliminary study in children with ADHD

Mindfulness-oriented meditation (MOM) is a self-regulatory training used for attentional and behavioral problems. With its focus on attention, MOM is a promising form of training that is gaining empirical support as a complementary or alternative intervention for attention deficit/hyperactivity disorder (ADHD). In this study, we tested the preliminary efficacy of MOM training in children with ADHD, by comparing its efficacy with an active control condition (Emotion Education Program, EEP). Twenty-five children with ADHD aged 7\u201311 years participated in MOM training (n = 15) or EEP (n = 10) 3 times per week for 8 weeks. Neuropsychological and academic measures and behavioral, emotional, and mindfulness ratings were collected before and after the two programs. On average, MOM training had positive effects on neuropsychological measures, as evidenced by a significant mean improvement in all outcome measures after training. Moreover, positive effects on ADHD symptoms were found only in the MOM group. Although they are preliminary, our results documented that MOM training promotes changes in neuropsychological measures and in certain behavioral symptoms, suggesting it as a promising tool for ameliorating cognitive and clinical manifestations of ADHD

Development and experimental validation of kinetic models for the hydrogenation/dehydrogenation of Mg/Al based metal waste for energy storage

With the increased use of renewable energy sources, the need to store large amounts of energy will become increasingly important in the near future. A cost efficient possibility is to use the reaction of recycled Mg waste with hydrogen as thermo-chemical energy storage. Owing to the high reaction enthalpy, the moderate pressure and appropriate temperature conditions, the broad abundance and the recyclability, the Mg/Al alloy is perfectly suitable for this purpose. As further development of a previous work, in which the performance of recycled Mg/Al waste was presented, a kinetic model for hydro- and dehydrogenation is derived in this study. Temperature and pressure dependencies are determined, as well as the rate limiting step of the reaction. First experiments are carried out in an autoclave with a scaled-up powder mass, which is also used to validate the model by simulating the geometry with the scaled-up experiments at different conditions

The effects of new 2030 scenario: Reduction of short-circuit power and widening of voltage dips

In Italy, 80% of PV installations are at MV and LV levels, which makes it particularly challenging to control them from the national dispatch centre; this leads to an increase of the reverse power flow in the primary and secondary substations, increasing pressure on the existing measuring and protection systems and on voltage control. The National Strategic Plan, approved on November 10 th , 2017 by the Ministry of Economic Development and the Ministry of the Environment, has launched an ambitious challenge, e.g., phasing-out of coal and the increase of electricity from renewable sources: more than 55% by 2030 of gross final consumption. The power system must be able to withstand unplanned events and manage their impacts on the network, thus reducing the risk of cascading effects and maintaining suitable quality of supply. During operation with a high percentage of RES connected to the network through inverters, the system is weaker (lower short circuit power) and, with currently adopted controls, less able to react to emerging faults. With the increase of PV installations, also due to reduction of rotating synchronous machines connected to transmission grid, there is lower Short-circuit-Power available and therefore voltage dips generated at transmission level have larger impact (c.g. area impacting supply quality widens hundreds of kilometers away from the event). This paper summarizes the main challenges in terms of impacting supply quality for the Italian Power system in a new scenario with more than 50% RES by 2030 of gross final consumption and suggests some computation procedures to investigate the phenomenon

IL-6-174 G/C and -572 C/G Polymorphisms and Risk of Alzheimer’s Disease

Associations between interleukin 6 (IL-6) polymorphisms and Alzheimer’s disease (AD) remain controversial and ambiguous. The aim of this meta-analysis is to explore more precise estimations for the relationship between IL-6-174 G/C and -572 C/G polymorphisms and risk for AD. Electronic searches for all publications in databases PubMed and EMBASE were conducted on the associations between IL-6 polymorphisms and risk for AD until January 2012. Odds ratio (OR) and 95% confidence intervals (CIs) were calculated using fixed and random effects models. Twenty-seven studies were included with a total of 19,135 individuals, involving 6,632 AD patients and 12,503 controls. For IL-6-174 G/C polymorphism, the combined results showed significant differences in recessive model (CC vs. CG+GG: OR = 0.65, 95%CI = 0.52–0.82). As regards IL-6-572 C/G polymorphism, significant associations were shown in dominant model (CG+GG vs. CC: OR  = 0.73, 95% CI = 0.62–0.86) and in additive model (GG vs. CC, OR  = 0.66, 95% CI = 0.46–0.96). In conclusion, genotype CC of IL-6-174 G/C and genotype GG plus GC of IL-6-572 C/G could decrease the risk of AD

Resequencing Candidate Genes Implicates Rare Variants in Asthma Susceptibility

Common variation in over 100 genes has been implicated in the risk of developing asthma, but the contribution of rare variants to asthma susceptibility remains largely unexplored. We selected nine genes that showed the strongest signatures of weak purifying selection from among 53 candidate asthma-associated genes, and we sequenced the coding exons and flanking noncoding regions in 450 asthmatic cases and 515 nonasthmatic controls. We observed an overall excess of p values <0.05 (p = 0.02), and rare variants in four genes (AGT, DPP10, IKBKAP, and IL12RB1) contributed to asthma susceptibility among African Americans. Rare variants in IL12RB1 were also associated with asthma susceptibility among European Americans, despite the fact that the majority of rare variants in IL12RB1 were specific to either one of the populations. The combined evidence of association with rare noncoding variants in IL12RB1 remained significant (p = 3.7 × 10−4) after correcting for multiple testing. Overall, the contribution of rare variants to asthma susceptibility was predominantly due to noncoding variants in sequences flanking the exons, although nonsynonymous rare variants in DPP10 and in IL12RB1 were associated with asthma in African Americans and European Americans, respectively. This study provides evidence that rare variants contribute to asthma susceptibility. Additional studies are required for testing whether prioritizing genes for resequencing on the basis of signatures of purifying selection is an efficient means of identifying novel rare variants that contribute to complex disease