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

MRI versus mammography plus ultrasound in women at intermediate breast cancer risk: study design and protocol of the MRIB multicenter, randomized, controlled trial

In women at high/intermediate lifetime risk of breast cancer (BC-LTR), contrast-enhanced magnetic resonance imaging (MRI) added to mammography ± ultrasound (MX ± US) increases sensitivity but decreases specificity. Screening with MRI alone is an alternative and potentially more cost-effective strategy. Here, we describe the study protocol and the characteristics of enrolled patients for MRIB feasibility, multicenter, randomized, controlled trial, which aims to compare MRI alone versus MX+US in women at intermediate breast cancer risk (aged 40-59, with a 15-30% BC-LTR and/or extremely dense breasts). Two screening rounds per woman were planned in ten centers experienced in MRI screening, the primary endpoint being the rate of cancers detected in the 2 arms after 5 years of follow-up. From July 2013 to November 2015, 1254 women (mean age 47 years) were enrolled: 624 were assigned to MX+US and 630 to MRI. Most of them were aged below 50 (72%) and premenopausal (45%), and 52% used oral contraceptives. Among postmenopausal women, 15% had used hormone replacement therapy. Breast and/or ovarian cancer in mothers and/or sisters were reported by 37% of enrolled women, 79% had extremely dense breasts, and 41% had a 15-30% BC-LTR. The distribution of the major determinants of breast cancer risk profiles (breast density and family history of breast and ovarian cancer) of enrolled women varied across centers

Uniformità e differenziazione nella legislazione regionale in tema di servizi sociali

Il contributo, attraverso lo studio della legislazione regionale successiva alla riforma del Titolo V, analizza i profili di uniformità e di differenziazione che esistono tra le diverse Regioni in materia di servizi sociali, con partcolare attenzione per i destinatari di tali politiche

Late-Pleistocene Wedge Structures Along the Patagonian Coast (Argentina): Chronological Constraints and Palaeo-Environmental Implications

This paper investigates several wedge structures formed in continental deposits covering marine sediments deposited during MIS 5 along the central Patagonian coast of Argentina. The size and surface microtexture characteristics of the infilling sediments are consistent with a depositional environment dominated by aeolian transport. Fragments of Andean volcanic rocks (glass shards) in the wedge-fill suggest long-distance transport via a westerly component of wind direction. The wedges are interpreted as products of deep seasonal frost action in frozen ground, which produced open cracks that filled rapidly with partially non-local aeolian sediments. Many wedges cross cut carbonate crusts that formed under permafrost conditions in coastal Patagonia. The radiocarbon dating of carbonate crusts yielded an age of 25–27 kyr bp, while wedge-fill sediments are OSL dated to 14 670 ± 750 yr bp. This indicates that ground wedge formation occurred during a cold event (the Antarctic Cold Reversal period) that interrupted the permafrost degradation following the Last Glacial Maximum

Vascular Aging and Disease of the Large Vessels: Role of Inflammation

Structural and functional arterial properties commonly impair with aging process. These effects on vasculature could act at many levels from microcirculation to large vessels. Above normal aging process classic cardio-vascular risk factors (hypertension, diabetes mellitus, dyslipidemia, etc.) accelerate the physiological process leading to premature structural and functional alterations that has also been termed early vascular aging. Target organ damage evaluation could be clinically important since these alterations precede by many years' cardiovascular events and so their assessment can predict the onset of more serious and costly events giving the opportunity to prevent CV events by earlier therapeutic intervention. This review will focus on large artery functional properties and particularly on the role of inflammation on the aortic stiffening process

From Neandertals to modern humans: New data on the Uluzzian

Having thrived in Eurasia for 350,000 years Neandertals disappeared from the record around 40,000–37,000 years ago, after modern humans entered Europe. It was a complex process of population interactions that included cultural exchanges and admixture between Neandertals and dispersing groups of modern humans. In Europe Neandertals are always associated with the Mousterian while the Aurignacian is associated with modern humans only. The onset of the Aurignacian is preceded by “transitional” industries which show some similarities with the Mousterian but also contain modern tool forms. Information on these industries is often incomplete or disputed and this is true of the Uluzzian. We present the results of taphonomic, typological and technological analyses of two Uluzzian sites, Grotta La Fabbrica (Tuscany) and the newly discovered site of Colle Rotondo (Latium). Comparisons with Castelcivita and Grotta del Cavallo show that the Uluzzian is a coherent cultural unit lasting about five millennia, replaced by the Protoaurignacian before the eruption of the Campanian Ignimbrite. The lack of skeletal remains at our two sites and the controversy surrounding the stratigraphic position of modern human teeth at Cavallo makes it difficult to reach agreement about authorship of the Uluzzian, for which alternative hypotheses have been proposed. Pending the discovery of DNA or further human remains, these hypotheses can only be evaluated by archaeological arguments, i.e. evidence of continuities and discontinuities between the Uluzzian and the preceding and succeeding culture units in Italy. However, in the context of “transitional” industries with disputed dates for the arrival of modern humans in Europe, and considering the case of the Châtelperronian, an Upper Paleolithic industry made by Neandertals, typo-technology used as an indicator of hominin authorship has limited predictive value. We corroborate previous suggestions that the Middle-to-Upper Paleolithic transition occurred as steps of rapid changes and geographically uneven rates of spread

The DECON pilot project investigates predictive markers for successful bariatric surgery

Abstract Obesity is a chronic, multifactorial disease which is linked to a number of adverse endocrinological and metabolic conditions. Currently, bariatric surgery is one of the most effective treatments for individuals diagnosed with severe obesity. However, the current indications for bariatric surgery are based on inadequate metrics (i.e., BMI) which do not account for the complexity of the disease, nor the heterogeneity among the patient population. Moreover, there is a lack of understanding with respect to the biological underpinnings that influence successful and sustained weight loss post-bariatric surgery. Studies have implicated age and pre-surgery body weight as two factors that are associated with favorable patient outcomes. Still, there is an urgent medical need to identify other potential factors that could improve the specificity of candidate selection and better inform the treatment plan of patients with obesity. In this report, we present and describe the cohort of the DECON pilot project, a multicenter study which aims to identify predictive biomarkers of successful weight loss after bariatric surgery

Legislative Documents

Also, variously referred to as: Senate bills; Senate documents; Senate legislative documents; legislative documents; and General Court documents