Hyponatremia in acute heart failure syndromes: a potential therapeutic target

Mild hyponatremia is common in patients hospitalized for worsening heart failure, and it is a major predictor of post-discharge mortality and morbidity irrespective of left ventricular ejection fraction. Recent data also suggest that standard therapy for heart failure does not improve or normalize serum sodium concentration during hospitalization. There are conclusive data that vasopressin antagonists improve or normalize serum sodium in this patient population. However, it is not known if this improvement or normalization in serum sodium is associated with an improvement in post-discharge outcomes. Future trials with vasopressin antagonists in patients hospitalized with worsening heart failure and hyponatremia are in order

Corporate digital responsibility

We propose that digital technologies and related data become increasingly prevalent and that, consequently, ethical concerns arise. Looking at four principal stakeholders, we propose corporate digital responsibility (CDR) as a novel concept. We define CDR as the set of shared values and norms guiding an organization\u27s operations with respect to four main processes related to digital technology and data. These processes are the creation of technology and data capture, operation and decision making, inspection and impact assessment, and refinement of technology and data. We expand our discussion by highlighting how to managerially effectuate CDR compliant behavior based on an organizational culture perspective. Our conceptualization unlocks future research opportunities, especially regarding pertinent antecedents and consequences. Managerially, we shed first light on how an organization\u27s shared values and norms regarding CDR can get translated into actionable guidelines for users. This provides grounds for future discussions related to CDR readiness, implementation, and success

Peripheral neurological disturbances, autonomic dysfunction, and antineuronal antibodies in adult celiac disease before and after a gluten-free diet

Thirty-two consecutive adult celiac disease (CD) patients (pts), complaining of peripheral neuropathy (12 pts), autonomic dysfunction (17 pts), or both (3 pts), were evaluated to assess the presence of neurological damage (by clinical neurological evaluation and electrophysiological study) and antineuronal antibodies and to assess the effect of a gluten-free diet (GFD) on the course of the neurological symptoms and on antineuronal antibodies. At entry, 12 of 32 (38%) pts showed signs and symptoms of neurological damage: 7 of 12 (58%), peripheral neurological damage; 3 of 12 (25%), autonomic dysfunction; and 2 (17%), both peripheral neurological damage and autonomic dysfunction. The overall TNS score was 105 at entry. Anti-GM1 antibodies were present in 5 of 12 (42%) pts: 3 showed peripheral neurological damage and 2 showed both peripheral neurological damage and autonomic dysfunction. One year after the GFD was started, histological lesions were still present in only 10 of 12 (83%) pts. TNS score was 99, 98, 98, and 101 at the 3rd, 6th, 9th, and 12th month after the GFD was started, so it did not improve throughout the follow-up. None of the pts showed disappearance of antineuronal antibodies throughout the follow-up. We conclude that adult CD patients may show neurological damage and presence of antineuronal antibodies. Unfortunately, these findings do not disappear with a GFD

P473 Histological inflammation in ulcerative colitis in deep remission under treatment with infliximab

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Recovery of gastric function in patients affected by chronic atrophic gastritis using L-cysteine (Acetium®): one year survey in comparison with a control group

Background and aim: Chronic Atrophic Gastritis (CAG) is a precancerous condition for gastric cancer (GC) as single risk factor, being a consequence of a previous Helicobacter pylori (Hp) infection or based on autoimmune mechanisms. Achlorhydria plays an important role towards the formation of a class I carcinogen, acetaldehyde, after food intake. L-cysteine has been claimed to be able to bind in a covalent way acetaldehyde when administered at meals. Methods: In this study we enrolled two CAG groups of patients, one treated whit 300 mg/daily of L-cysteine for one year, the other one untreated. We assessed gastric function lasting the one-year follow-up by using noninvasive surrogates, i.e. Pepsinogen I (PGI) and gastrin 17 (G17). Results: In the group of 77 CAG on therapy we found a statistically significant increase in PGI values and a decrease in G17 levels, in comparison with unchanged values in control group. Conclusions: L-cysteine seems able to provide a recovery in gastric function when administered in CAG patients and could be proposed as a possible therapy in such patients. (www.actabiomedica.it)

Nampt over-expression recapitulates the braf inhibitor resistant phenotype plasticity in melanoma

Serine–threonine protein kinase B-RAF (BRAF)-mutated metastatic melanoma (MM) is a highly aggressive type of skin cancer. Treatment of MM patients using BRAF/MEK inhibitors (BRAFi/MEKi) eventually leads to drug resistance, limiting any clinical benefit. Herein, we demonstrated that the nicotinamide adenine dinucleotide (NAD)-biosynthetic enzyme nicotinamide phosphoribosyltransferase (NAMPT) is a driving factor in BRAFi resistance development. Using stable and inducible NAMPT over-expression systems, we showed that forced NAMPT expression in MM BRAF-mutated cell lines led to increased energy production, MAPK activation, colony-formation capacity, and enhance tumorigenicity in vivo. Moreover, NAMPT over-expressing cells switched toward an invasive/mesenchymal phenotype, up-regulating expression of ZEB1 and TWIST, two transcription factors driving the epithelial to mesenchymal transition (EMT) process. Consistently, within the NAMPT-overexpressing cell line variants, we observed an increased percentage of a rare, drug-effluxing stem cell-like side population (SP) of cells, paralleled by up-regulation of ABCC1/MRP1 expression and CD133-positive cells. The direct correlation between NAMPT expression and gene set enrichments involving metastasis, invasiveness and mesenchymal/stemness properties were verified also in melanoma patients by analyzing The Cancer Genome Atlas (TCGA) datasets. On the other hand, CRISPR/Cas9 full knock-out NAMPT BRAFi-resistant MM cells are not viable, while inducible partial silencing drastically reduces tumor growth and aggressiveness. Overall, this work revealed that NAMPT over-expression is both necessary and sufficient to recapitulate the BRAFi-resistant phenotype plasticity

Nampt over-expression recapitulates the braf inhibitor resistant phenotype plasticity in melanoma

Serine–threonine protein kinase B-RAF (BRAF)-mutated metastatic melanoma (MM) is a highly aggressive type of skin cancer. Treatment of MM patients using BRAF/MEK inhibitors (BRAFi/MEKi) eventually leads to drug resistance, limiting any clinical benefit. Herein, we demonstrated that the nicotinamide adenine dinucleotide (NAD)-biosynthetic enzyme nicotinamide phosphoribosyltransferase (NAMPT) is a driving factor in BRAFi resistance development. Using stable and inducible NAMPT over-expression systems, we showed that forced NAMPT expression in MM BRAF-mutated cell lines led to increased energy production, MAPK activation, colony-formation capacity, and enhance tumorigenicity in vivo. Moreover, NAMPT over-expressing cells switched toward an invasive/mesenchymal phenotype, up-regulating expression of ZEB1 and TWIST, two transcription factors driving the epithelial to mesenchymal transition (EMT) process. Consistently, within the NAMPT-overexpressing cell line variants, we observed an increased percentage of a rare, drug-effluxing stem cell-like side population (SP) of cells, paralleled by up-regulation of ABCC1/MRP1 expression and CD133-positive cells. The direct correlation between NAMPT expression and gene set enrichments involving metastasis, invasiveness and mesenchymal/stemness properties were verified also in melanoma patients by analyzing The Cancer Genome Atlas (TCGA) datasets. On the other hand, CRISPR/Cas9 full knock-out NAMPT BRAFi-resistant MM cells are not viable, while inducible partial silencing drastically reduces tumor growth and aggressiveness. Overall, this work revealed that NAMPT over-expression is both necessary and sufficient to recapitulate the BRAFi-resistant phenotype plasticity

Tumors carrying BRAF-mutations over-express NAMPT that is genetically amplified and possesses oncogenic properties

Background: Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in nicotinamide adenine dinucleotide (NAD) biosynthesis, is up-regulated in several cancers, including metastatic melanoma (MM). The BRAF oncogene is mutated in different cancer types, among which MM and thyroid carcinoma (THCA) are prominent. Drugs targeting mutant BRAF are effective, especially in MM patients, even though resistance rapidly develops. Previous data have linked NAMPT over-expression to the acquisition of BRAF resistance, paving the way for therapeutic strategies targeting the two pathways. Methods: Exploiting the TCGA database and a collection of MM and THCA tissue microarrays we studied the association between BRAF mutations and NAMPT expression. BRAF wild-type (wt) cell lines were genetically engineered to over-express the BRAF V600E construct to demonstrate a direct relationship between over-activation of the BRAF pathway and NAMPT expression. Responses of different cell line models to NAMPT (i)nhibitors were studied using dose–response proliferation assays. Analysis of NAMPT copy number variation was performed in the TCGA dataset. Lastly, growth and colony forming assays were used to study the tumorigenic functions of NAMPT itself. Results: The first finding of this work is that tumor samples carrying BRAF-mutations over-express NAMPT, as demonstrated by analyzing the TCGA dataset, and MM and THC tissue microarrays. Importantly, BRAF wt MM and THCA cell lines modified to over-express the BRAF V600E construct up-regulated NAMPT, confirming a transcriptional regulation of NAMPT following BRAF oncogenic signaling activation. Treatment of BRAF-mutated cell lines with two different NAMPTi was followed by significant reduction of tumor growth, indicating NAMPT addiction in these cells. Lastly, we found that several tumors over-expressing the enzyme, display NAMPT gene amplification. Over-expression of NAMPT in BRAF wt MM cell line and in fibroblasts resulted in increased growth capacity, arguing in favor of oncogenic properties of NAMPT. Conclusions: Overall, the association between BRAF mutations and NAMPT expression identifies a subset of tumors more sensitive to NAMPT inhibition opening the way for novel combination therapies including NAMPTi with BRAFi/MEKi, to postpone and/or overcome drug resistance. Lastly, the over-expression of NAMPT in several tumors could be a key and broad event in tumorigenesis, substantiated by the finding of NAMPT gene amplification

Challenges of keyword-based location disclosure

A practical solution to location privacy should be incremen-tally deployable. We claim it should hence reconcile the eco-nomic value of location to aggregators, usually ignored by prior works, with a user’s control over her information. Loca-tion information indeed is being collected and used by many mobile services to improve revenues, and this gives rise to a heated debate: Privacy advocates ask for stricter regula-tion on information collection, while companies argue that it would jeopardize the thriving economy of the mobile web. We describe a system that gives users control over their information and does not degrade the data given to aggre-gators. Recognizing that the first challenge is to express lo-cations in a way that is meaningful for advertisers and users, we propose a keyword based design. Keywords characterize locations, let the users inform the system about their sen-sitivity to disclosure, and build information directly usable by an advertiser’s targeting campaign. Our work makes two main contributions: we design a market of location infor-mation based on keywords and we analyze its robustness to attacks using data from ad-networks, geo-located services, and cell networks. Categories and Subject Descriptors Security and Privacy [Human and societal aspects of security and privacy]: Usability in security and privac