Statin use and survival in resectable pancreatic cancer: confounders and mechanisms.

A first point regards the possible activity of drugs other than statins, such as aspirin or metformin, against pancreatic cancer. As many patients use a combination of these drugs, one might speculate that the association between simvastatin and overall survival in resected pancreatic cancer patients might also be explained by the concomitant use of aspirin or metformin, or that these drugs might result synergistic, as hypothesized for colorectal cancer (3). We wonder whether the authors had access to data on aspirin or metformin use for their population. A second point regards the very high 45% rate of simvastatin or lovastatin users reported by the authors. This figure is different from that of many European countries, thus possibly limiting the attributable fraction of cases for whom the observed findings can be replicated

Burgers, Doughnuts, and Expatriations: An Analysis of the Tax Inversion Epidemic and a Solution Presented Through the Lens of the Burger King-Tim Hortons Merger

Currently, the concept of tax inversion is a major corporate phenomenon. In the United States, companies pay taxes on all earnings, whether or not they were accumulated here. With one of the highest corporate tax rates in the world, this is a major expense for U.S. corporations competing in the world market. While most companies simply deal with the tax burden, some U.S. corporations buy foreign companies and relocate the company headquarters to the acquisitions home country. This corporate expatriation allows companies to avoid U.S. taxes on earnings in a number of ways. This Note will examine tax inversion through the lens of the 2014 Burger King-Tim Hortons merger and the resulting expatriation of the American burger purveyor from Florida to Canada. In particular, this Note will (1) examine why tax inversions have come about, (2) look at how politicians and academics have reacted to the phenomenon, (3) analyze the intricacies of the Burger King-Tim Hortons merger, and (4) propose a new solution that would actually curtail tax inversions and corporate expatriations within the United States

The use of complementary and alternative medicine is frequent in patients with pancreatic disorder

BACKGROUND: Herbal remedies and other complementary and alternative medicine (CAM) are used by 30% of the patients with liver and inflammatory bowel diseases. However, there are no data regarding CAM use in patients with pancreatic disorders, including potential pancreatotoxicity. AIM OF THE STUDY: The aim of the study was to assess the prevalence of CAM use in patients with pancreatic disorders and screen for pancreatotoxicity. MATERIALS AND METHODS: This was a cross-sectional survey of consecutive outpatients seen at a Pancreas Center. Data were collected in a specific questionnaire. Descriptive statistics were used to analyze the prevalence and the patterns of CAM use. Characteristics associated with CAM use were analyzed by appropriate statistics. RESULTS: Of 108 patients (52% male; mean age, 65±13 years), 47 (43.5%) used CAM. The use of CAM was more frequent among patients with previous acute pancreatitis (47%). Reported reasons for the use of CAM were to help standard therapies and for an overall better feeling. About 61% of the patients reported advantages with treatment. As compared with nonusers, CAM users were more often female (55% vs. 42%), with a higher school degree (43% vs. 36%), more frequently performing physical activity (51% vs. 41%), and reporting anxiety (45% vs. 31%). However, none of these differences were statistically significant. Three patients with previous acute pancreatitis reported the use of Serenoa repens that is potentially pancreatotoxic. DISCUSSION: The rate of CAM use in patients with pancreatic disorders is similar to those reported for other digestive diseases. CAM use seems to be more frequent in women with a higher education level and a "healthier lifestyle." Patients might not be aware of the potential pancreatotoxicity of CAM, which should be carefully considered by physician

An Android-Based Mechanism for Energy Efficient Localization Depending on Indoor/Outdoor Context

Today, there is widespread use of mobile applications that take advantage of a user\u27s location. Popular usages of location information include geotagging on social media websites, driver assistance and navigation, and querying nearby locations of interest. However, the average user may not realize the high energy costs of using location services (namely the GPS) or may not make smart decisions regarding when to enable or disable location services-for example, when indoors. As a result, a mechanism that can make these decisions on the user\u27s behalf can significantly improve a smartphone\u27s battery life. In this paper, we present an energy consumption analysis of the localization methods available on modern Android smartphones and propose the addition of an indoor localization mechanism that can be triggered depending on whether a user is detected to be indoors or outdoors. Based on our energy analysis and implementation of our proposed system, we provide experimental results-monitoring battery life over time-and show that an indoor localization method triggered by indoor or outdoor context can improve smartphone battery life and, potentially, location accuracy

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

Alternative polyadenylation of ZEB1 promotes its translation during genotoxic stress in pancreatic cancer cells

Pancreatic ductal adenocarcinoma (PDAC) is characterized by extremely poor prognosis. The standard chemotherapeutic drug, gemcitabine, does not offer significant improvements for PDAC management due to the rapid acquisition of drug resistance by patients. Recent evidence indicates that epithelial-to-mesenchymal transition (EMT) of PDAC cells is strictly associated to early metastasization and resistance to chemotherapy. However, it is not exactly clear how EMT is related to drug resistance or how chemotherapy influences EMT. Herein, we found that ZEB1 is the only EMT-related transcription factor that clearly segregates mesenchymal and epithelial PDAC cell lines. Gemcitabine treatment caused upregulation of ZEB1 protein through post-transcriptional mechanisms in mesenchymal PDAC cells within a context of global inhibition of protein synthesis. The increase in ZEB1 protein correlates with alternative polyadenylation of the transcript, leading to shortening of the 3' untranslated region (UTR) and deletion of binding sites for repressive microRNAs. Polysome profiling indicated that shorter ZEB1 transcripts are specifically retained on the polysomes of PDAC cells during genotoxic stress, while most mRNAs, including longer ZEB1 transcripts, are depleted. Thus, our findings uncover a novel layer of ZEB1 regulation through 3'-end shortening of its transcript and selective association with polysomes under genotoxic stress, strongly suggesting that PDAC cells rely on upregulation of ZEB1 protein expression to withstand hostile environments

Epidemiology, clinical features and treatment of chronic pancreatitis. current knowledge and future perspectives [Epidemiologia, clinica e terapia medica della pancreatite cronica: evidenze attuali e sviluppi per il futuro]

La pancreatite cronica è una patologia dal complesso inquadramento sia dal punto di vista epidemiologico, con dati incerti sull’esatta prevalenza, sia dell’eziologia, a volte non individuabile e per la quale si sta delineando sempre più la rilevanza delle forme post-pancreatite acuta, con il fumo come fattore di rischio spesso sottovalutato rispetto all’alcol. La pancreatite cronica si associa ad aumento della mortalità e morbilità, legate soprattutto a patologie extrapancreatiche. L’eventuale presenza di insufficienza esocrina o endocrina pancreatica può essere, inoltre, alla base di complicanze anche gravi e spesso non prevenute per tempo. I deficit vitaminici e di micro- e macronutrienti vanno attentamente ricercati e corretti; questo sarà inoltre fondamentale per evitare complicanze quali l’osteoporosi. Il dolore è il sintomo più rilevante, ha una patogenesi complessa, legata non solo a fattori ostruttivi e meccanici o alla flogosi, ma anche un’alterazione cronica del processo di adattamento al dolore a livello del sistema nervoso centrale. Anche per questo la terapia del dolore è spesso inefficace. La chirurgia derivativa è indicata nelle forme con ostruzione duttale con risultati che sembrano superiori a quelli dell’endoscopia, e quella resettiva in quelle associate a massa infiammatoria. Una nuova frontiera è rappresentata poi dalla pancreasectomia totale con trapianto di insule, che offre ottimi risultati in termini di controllo del dolore con possibilità di evitare il diabete in una buona percentuale di pazienti. Questa rassegna discute tali “hot topics” racchiudendo sia le evidenze più recenti sull’argomento sia una riflessione su come evolveranno le nostre conoscenze su tale patologia.Chronic pancreatitis is a complex disease both for the epidemiology, with uncertain data on the exact prevalence, but also for the etiology, often not identified and for whom, compared to the past, post acute pancreatitis forms are showing a high impact; also smoking is an etiological factor often underestimated compared to alcohol. Chronic pancreatitis is associated with high mortality and morbidity, mostly due to extrapancreatic diseases. The eventual occurrence of exocrine or endocrine pancreatic insufficiency can lead to complications, often serious and not prevented in time. It is, in fact, well known how this can cause micro or macronutrient and vitamin deficit which, if not screened and corrected, can cause complications such as osteoporosis. Abdominal pain is the most relevant symptom, with a complex pathogenesis, due not only to obstructive or mechanical factors or inflammation, but also to a chronic alteration of the adaptation process of pain in the central nervous system. Also for this reason, therapies are often not effective. Derivative surgery is indicated in obstructive forms, with results superior to those of endoscopy, while resective surgery is indicated when an inflammatory mass is present. A new opportunity is total pancreatectomy with islet autotransplantation, which offers excellent results in terms of pain relief and possibility to avoid diabetes in a high percentage of patients. This review will discuss these hot topics comprehending both most recent evidence and a view on how our knowledge on this disease will change in the upcoming years

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

Clinical risk factors for underlying gastrointestinal malignancy in iron deficiency anaemia: the IDIOM study

Objective : Ten percent of adults presenting with iron deficiency anaemia (IDA) have underlying cancer. This study was undertaken to assess whether five simple clinical parameters can usefully predict the likelihood of gastrointestinal (GI) malignancy on subsequent investigation of patients with IDA. Design : Retrospective observational study, with multivariable analysis of the predictive value of sex, age, haemoglobin concentration (Hb), mean red cell volume (MCV) and iron studies for the risk of underlying GI malignancy. Setting : District General Hospital IDA clinic. Patients : 720 adults with confirmed IDA. Results : Sex, age, and Hb were strongly associated with the risk of GI malignancy - the parsimonious model including only these variables yielded odds ratios of 4.0 (95% confidence interval (CI): 2.3, 7.0) for males compared to females; 3.3 (95% CI: 1.7, 6.4) for age > 70 years compared to ≤70 years; and 5.3 (95% CI: 2.4, 11.7) for an Hb of ≤91.4g/l compared to ≥111.5g/l. Combining these risk factors identified a sub-group (12% of the study population) at particularly low risk (20% likelihood) of underlying GI malignancy. Conclusions : Three simple and objective clinical parameters can be combined to provide a clinically useful cancer risk stratification model for subjects with IDA. This may assist with patient counselling and the prioritization of investigational resources

L’effetto della liberalizzazione ferroviaria sulle politiche di prezzo delle compagnie aeree e ferroviarie. Evidenze preliminari sui principali collegamenti ad Alta Velocità in Italia

Il mercato italiano del trasporto ferroviario passeggeri è stato recentemente caratterizzato dall'ingresso di un nuovo operatore nel settore dell'Alta Velocità, Nuovo Trasporto Viaggiatori (NTV). L'ingresso di NTV ha stimolato sia la concorrenza intramodale con l’incumbent Trenitalia sia la concorrenza intermodale con le compagnie aeree. Il presente lavoro si propone di studiare le strategie di pricing nel mercato del trasporto passeggeri, con il duplice l'obiettivo di esplorare l'effetto della concorrenza intramodale sulle tariffe degli operatori ferroviari - applicate sulle principali rotte Italiane servite dall’Alta Velocità (AV) - e di analizzare l'effetto della concorrenza intermodale sulle strategie di prezzo delle compagnie aeree. I risultati dell'analisi evidenziano che le due compagnie ferroviarie che operano nel segmento AV pongono in essere una politica di prezzo strategica, sebbene eterogenea fra le rotte. Inoltre, le compagnie aeree riducono in misura consistente le tariffe quando operano in concorrenza diretta con i servizi ad AV