Diabetes Mellitus and Reprogrammed Glucose Metabolism in Pancreatic Cancer: Features for Clinical Translation

The reprogrammed metabolism of cancer cells underlies the shift of glucose energetics from the highly efficient oxidative phosphorylation to the less efficient aerobic glycolysis, the Warburg effect. This phenomenon, with the activation of the glutamine pathway, advantage survival and proliferation of pancreatic ductal adenocarcinoma (PDAC) cells, which live in an adverse hypoxic and nutrient restricted microenvironment. In PDAC, glucose metabolic alterations occur also at the whole organism, diabetes mellitus (DM) being diagnosed in approximately 60% to 80% of patients. The association beteen PDAC and DM is a dual face phenomenon, DM being both a risk factor for and a consequence of this tumor type. Data from epidemiology indicate that longstanding DM increases PDAC risk 1.5 to 2.0 fold, probably because of the pro-proliferative effects of hyperinsulinemia. By contrast early onset DM, i.e. diabetes diagnosed no more than two years prior to cancer diagnosis, is considered a consequence of PDAC. Secondary DM is due to complex interactions between tumor cells, tumor microenvironment and pancreatic endocrine cells. In this scenario the role of the inflammatory S100A8 calcium binding protein, matrix metalloproteinases, Vanin1 or amylin has been experimentally demonstrated. However, the efforts made to translate in the clinical practice any individual new poteantial biomarker failed, because none reached enough sensitivity and specificity to be considered a reliable biomarker to diagnose PDAC even in high risk subjects as those with new onset DM. Therefore the identification and clinical validation of new biomarkers remains a challenge for future studies

Designing on subjective tolerance to approximated piano reproductions

Results from three experiments are presented, showing that the perceived acoustic and vibrotactile quality of a reproduced piano does not require models simulating every aspect of the original instrument with great accuracy. It was found that high-quality loudspeaker array passive listening at the pianist's position admits distortions of the sound field. Furthermore, pianists during playing seem to compensate for errors in the auditory scene description. Finally, they are particularly sensitive to the existence of vibrotactile feedback on their fingers meanwhile tolerant about the precision with which this feedback is reproduced. Based on these results we are currently working on a lightweight portable physics-based digital piano design, that should improve upon the experience a pianist with no keyboards at hand makes when interacting with a touch-screen piano software running on smartphones and laptops

Inflammatory bowel diseases: from pathogenesis to laboratory testing

Inflammatory bowel diseases (IBDs), which comprise the two major clinical subtypes, Crohn's disease and ulcerative colitis, incur high morbidity and potential mortality. The present study reviews data on the pathogenesis and diagnosis of IBDs. The pathogenesis depends on complex interactions between susceptibility genes, environmental factors, and innate and adaptive immunity, the understanding of which is crucial to discovering novel laboratory biomarkers. Traditional laboratory tests for the diagnosis, prognosis and assessment of disease activity of IBDs are reported on, and the biochemical properties, pre-analytical and analytical aspects and clinical utility of the fecal markers lactoferrin and calprotectin are described. DNA testing and established (ASCA and pANCA) and emerging (ACCA, ALCA, AMCA, OmpC) serum markers are described; a further aspect to be addressed is the clinical use of pharmacogenetics for the treatment of IBDs

Two circumstellar nebulae discovered with the Wide-field Infrared Survey Explorer and their massive central stars

We report the discovery of two mid-infrared nebulae in the northern hemisphere with the Wide-field Infrared Survey Explorer and the results of optical spectroscopy of their central stars, BD+60 2668 (composed of two components, separated from each other by \approx 3 arcsec) and ALS 19653, with the Calar Alto 3.5-m telescope and the Southern African Large Telescope (SALT), respectively. We classify the components of BD+60 2668 as stars of spectral types B0.5 II and B1.5 III. ALS 19653 is indicated in the SIMBAD data base as a planetary nebula, while our observations show that it is a massive B0.5 Ib star, possibly in a binary system. Using the stellar atmosphere code FASTWIND, we derived fundamental parameters of the three stars as well as their surface element abundances, implying that all of them are either on the main sequence or only recently left it. This provides further evidence that massive stars can produce circumstellar nebulae while they are still relatively unevolved. We also report the detection of optical counterparts to the mid-infrared nebulae and a second, more extended optical nebula around ALS 19653, and present the results of SALT spectroscopy of both nebulae associated with this star. The possible origin of the nebulae is discussed.Comment: 24 pages, 13 figures, 6 tables, accepted for publication in A

SMAD4 loss enables EGF, TGF\u3b21 and S100A8/A9 induced activation of critical pathways to invasion in human pancreatic adenocarcinoma cells

Epidermal Growth Factor (EGF) receptor overexpression, KRAS, TP53, CDKN2A and SMAD4 mutations characterize pancreatic ductal adenocarcinoma. This mutational landscape might influence cancer cells response to EGF, Transforming Growth Factor \u3b21 (TGF\u3b21) and stromal inflammatory calcium binding proteins S100A8/A9. We investigated whether chronic exposure to EGF modifies in a SMAD4-dependent manner pancreatic cancer cell signalling, proliferation and invasion in response to EGF, TGF\u3b21 and S100A8/A9. BxPC3, homozigously deleted (HD) for SMAD4, and BxPC3-SMAD4+ cells were or not stimulated with EGF (100 ng/mL) for three days. EGF pre-treated and non pretreated cells were stimulated with a single dose of EGF (100 ng/mL), TGF\u3b21 (0,02 ng/mL), S100A8/A9 (10 nM). Signalling pathways (Reverse Phase Protein Array and western blot), cell migration (Matrigel) and cell proliferation (XTT) were evaluated. SMAD4 HD constitutively activated ERK and Wnt/\u3b2-catenin, while inhibiting PI3K/AKT pathways. These effects were antagonized by chronic EGF, which increased p-BAD (anti-apoptotic) in response to combined TGF\u3b21 and S100A8/A9 stimulation. SMAD4 HD underlied the inhibition of NF-\u3baB and PI3K/AKT in response to TGF\u3b21 and S100A8/A9, which also induced cell migration. Chronic EGF exposure enhanced cell migration of both BxPC3 and BxPC3-SMAD4+, rendering the cells less sensitive to the other inflammatory stimuli. In conclusion, SMAD4 HD is associated with the constitutive activation of the ERK and Wnt/\u3b2-catenin signalling pathways, and favors the EGF-induced activation of multiple signalling pathways critical to cancer proliferation and invasion. TGF\u3b21 and S100A8/A9 mainly inhibit NF-\u3baB and PI3K/AKT pathways and, when combined, sinergize with EGF in enhancing anti-apoptotic p-BAD in a SMAD4-dependent manner

Correction: Impaired cellular bioenergetics caused by GBA1 depletion sensitizes neurons to calcium overload

n/

Let-7c down-regulation in Helicobacter pylori-related gastric carcinogenesis

open12siAberrant let-7c microRNA (miRNA) expression has been observed in Helicobacter pylori-related gastric cancer (GC) but fragmentary information is available on the let-7c dysregulation occurring with each phenotypic change involved in gastric carcinogenesis. Let-7c expression was assessed (qRT-PCR) in a series of 175 gastric biopsy samples representative of the whole spectrum of phenotypic changes involved in H. pylori-related gastric oncogenesis including: i) normal gastric mucosa, as obtained from dyspeptic controls (40 biopsy samples); ii) non-atrophic gastritis (40 samples); iii) atrophic-metaplastic gastritis (35 samples); iv) intra-epithelial neoplasia (30 samples); v) GC (30 samples). Let-7c expression was also tested in 20 biopsy samples obtained from 10 patients before and after H. pylori eradication therapy (median follow-up: 10 weeks; range: 7-14). The results obtained were further validated by in situ hybridization on multiple tissue specimens obtained from 5 surgically treated H. pylori-related GCs. The study also included 40 oxyntic biopsy samples obtained from serologically/histologically confirmed autoimmune gastritis (AIG: 20 corpus-restricted, non-atrophic; 20 corpus-restricted, atrophic-metaplastic). Let-7c expression dropped from non-atrophic gastritis to atrophic-metaplastic gastritis, intra-epithelial neoplasia, and invasive GC (p<0.001). It rose again significantly following H. pylori eradication (p=0.009). As in the H. pylori model, AIG also featured a significant let-7c down-regulation (p<0.001). The earliest phases of the two pathways to gastric oncogenesis (H. pylori-environmental and autoimmune host-related) are characterized by similar let-7c dysregulations. In H. pylori infection, let-7c down-regulation regresses after the bacterium's eradication, while it progresses significantly with the increasing severity of the histological lesions.openFassan, Matteo; Saraggi, Deborah; Balsamo, Laura; Cascione, Luciano; Castoro, Carlo; Coati, Irene; DE BERNARD, Marina; Farinati, Fabio; Guzzardo, Vincenza; Valeri, Nicola; Zambon, CARLO-FEDERICO; Rugge, MassimoFassan, Matteo; Saraggi, Deborah; Balsamo, Laura; Cascione, Luciano; Castoro, Carlo; Coati, Irene; DE BERNARD, Marina; Farinati, Fabio; Guzzardo, Vincenza; Valeri, Nicola; Zambon, CARLO-FEDERICO; Rugge, Massim

Variations in the amount of water ice on Ceres' surface suggest a seasonal water cycle.

The dwarf planet Ceres is known to host a considerable amount of water in its interior, and areas of water ice were detected by the Dawn spacecraft on its surface. Moreover, sporadic water and hydroxyl emissions have been observed from space telescopes. We report the detection of water ice in a mid-latitude crater and its unexpected variation with time. The Dawn spectrometer data show a change of water ice signatures over a period of 6 months, which is well modeled as ~2-km2 increase of water ice. The observed increase, coupled with Ceres' orbital parameters, points to an ongoing process that seems correlated with solar flux. The reported variation on Ceres' surface indicates that this body is chemically and physically active at the present time

SARS-CoV-2 RNA identification in nasopharyngeal swabs: issues in pre-analytics.

Abstract Objectives The direct identification of SARS-CoV-2 RNA in nasopharyngeal swabs is recommended for diagnosing the novel COVID-19 disease. Pre-analytical determinants, such as sampling procedures, time and temperature storage conditions, might impact on the end result. Our aim was to evaluate the effects of sampling procedures, time and temperature of the primary nasopharyngeal swabs storage on real-time reverse-transcription polymerase chain reaction (rRT-PCR) results. Methods Each nasopharyngeal swab obtained from 10 hospitalized patients for COVID-19 was subdivided in 15 aliquots: five were kept at room temperature; five were refrigerated (+4 °C); five were immediately mixed with the extraction buffer and refrigerated at +4 °C. Every day and for 5 days, one aliquot per condition was analyzed (rRT-PCR) for SARS-CoV-2 gene E and RNaseP and threshold cycles (Ct) compared. To evaluate manual sampling, 70 nasopharyngeal swabs were sampled twice by two different operators and analyzed separately one from the other. Results A total of 6/10 swabs were SARS-CoV-2 positive. No significant time or storage-dependent variations were observed in SARS-CoV-2 Ct. Re-sampling of swabs with SARS-CoV-2 Ct lower than 33 resulted in highly reproducible results (CV=2.9%), while a high variability was observed when Ct values were higher than 33 (CV=10.3%). Conclusions This study demonstrates that time and temperature of nasopharyngeal swabs storage do not significantly impact on results reproducibility. However, swabs sampling is a critical step, and especially in case of low viral load, might be a potential source of diagnostic errors