Association between Resistin Levels and All-Cause and Cardiovascular Mortality: A New Study and a Systematic Review and Meta-Analysis.

CONTEXT: Studies concerning the association between circulating resistin and mortality risk have reported, so far, conflicting results. OBJECTIVE: To investigate the association between resistin and both all-cause and cardiovascular (CV) mortality risk by 1) analyzing data from the Gargano Heart Study (GHS) prospective design (n=359 patients; 81 and 58 all-cause and CV deaths, respectively); 2) performing meta-analyses of all published studies addressing the above mentioned associations. DATA SOURCE AND STUDY SELECTION: MEDLINE and Web of Science search of studies reporting hazard ratios (HR) of circulating resistin for all-cause or CV mortality. DATA EXTRACTION: Performed independently by two investigators, using a standardized data extraction sheet. DATA SYNTHESIS: In GHS, adjusted HRs per one standard deviation (SD) increment in resistin concentration were 1.28 (95% CI: 1.07-1.54) and 1.32 (95% CI: 1.06-1.64) for all-cause and CV mortality, respectively. The meta-analyses included 7 studies (n=4016; 961 events) for all-cause mortality and 6 studies (n=4,187: 412 events) for CV mortality. Pooled HRs per one SD increment in resistin levels were 1.21 (95% CI: 1.03-1.42, Q-test p for heterogeneity<0.001) and 1.05 (95% CI: 1.01-1.10, Q-test p for heterogeneity=0.199) for all-cause and CV mortality, respectively. At meta-regression analyses, study mean age explained 9.9% of all-cause mortality studies heterogeneity. After adjusting for age, HR for all-cause mortality was 1.24 (95% CI: 1.06-1.45). CONCLUSIONS: Our results provide evidence for an association between circulating resistin and mortality risk among high-risk patients as are those with diabetes and coronary artery disease

Somatostatin: A Novel Substrate and a Modulator of Insulin-Degrading Enzyme Activity

Insulin-degrading enzyme (IDE) is an interesting pharmacological target for Alzheimer's disease (AD), since it hydrolyzes beta-amyloid, producing non-neurotoxic fragments. It has also been shown that the somatostatin level reduction is a pathological feature of AD and that it regulates the neprilysin activity toward beta-amyloid. In this work, we report for the first time that IDE is able to hydrolyze somatostatin [k(cat) (s(-1)) = 0.38 (+/-0.05); K-m (M) = 7.5 (+/-0.9) x 10(-6)] at the Phe6-Phe7 amino acid bond. On the other hand, somatostatin modulates IDE activity, enhancing the enzymatic cleavage of a novel fluorogenic beta-amyloid through a decrease of the K-m toward this substrate, which corresponds to the 10-25 amino acid sequence of the A beta(1-40). Circular dichroism spectroscopy and surface plasmon resonance imaging experiments show that somatostatin binding to IDE brings about a concentration-dependent structural change of the secondary and tertiary structure(s) of the enzyme, revealing two possible binding sites. The higher affinity binding site disappears upon inactivation of IDE by ethylenediaminetetra acetic acid, which chelates, the catalytic Zn2+ ion. As a whole, these features suggest that the modulatory effect is due to an allosteric mechanism: somatostatin binding to the active site of one IDE subunit (where somatostatin is cleaved) induces an enhancement of IDE proteolytic activity toward fluorogenic beta-amyloid by another subunit. Therefore, this investigation on IDE-somatostatin interaction contributes to a more exhaustive knowledge about the functional and structural aspects of IDE and its pathophysiological implications in the amyloid deposition and somatostatin homeostasis in the brain. (C) 2008 Elsevier Ltd. All rights reserved

TWAM: A Certifying Abstract Machine for Logic Programs

Type-preserving (or typed) compilation uses typing derivations to certify correctness properties of compilation. We have designed and implemented a type-preserving compiler for a simply-typed dialect of Prolog we call T-Prolog. The crux of our approach is a new certifying abstract machine which we call the Typed Warren Abstract Machine (TWAM). The TWAM has a dependent type system strong enough to specify the semantics of a logic program in the logical framework LF. We present a soundness metatheorem which constitutes a partial correctness guarantee: well-typed programs implement the logic program specified by their type. This metatheorem justifies our design and implementation of a certifying compiler from T-Prolog to TWAM.Comment: 41 pages, under submission to ACM Transactions on Computational Logi

Bevacizumab in association with de Gramont 5-fluorouracil/folinic acid in patients with oxaliplatin-, irinotecan-, and cetuximab-refractory colorectal cancer: a single-center phase 2 trial.

BACKGROUND: The aim of the current study was the investigation of the value of bevacizumab+5-fluorouracil(5-FU)/folinic acid in patients with advanced colorectal cancers who have exhausted standard chemotherapy options. METHODS: The authors included 48 heavily pretreated patients (colon:rectum, 33:15; men:women, 23:25; median age, 63 years; range, 27-79 years) whose disease had progressed during or within an oxaliplatin-based first-line chemotherapy, an irinotecan-based second-line regimen, and a third-line treatment with cetuximab plus weekly irinotecan. Bevacizumab was given at a dose of 5 mg/kg. 5-FU/folinic acid was administered according to the de Gramont schedule. RESULTS: The response rate was 6.25%, and 30.4% of patients demonstrated stable disease as the best response. The median time to disease progression was 3.5 months (95% confidence interval [95% CI], 2.3-6.9 months), and the median survival time was 7.7 months (95% CI, 3.9-11.9 months). The most common grade 3 to 4 side toxicities (graded according to the National Cancer Institute Common Toxicity Criteria [version 2.0]) were: diarrhea (20.8%), fatigue (14.5%), and stomatitis (12.5%). Grade 3 to 4 hemorrhage occurred in 8 patients (16.6%), including 4 cases of bleeding in the gastrointestinal tract. Other relatively common adverse events such as hypertension, thrombosis, and bowel perforation were reported in 50%, 18.7%, and 4.16%, of patients respectively. CONCLUSIONS: The data from the current study suggest a modest but significant clinical benefit of bevacizumab+de Gramont schedule in heavily pretreated colorectal cancer patients. Copyright (c) 2009 American Cancer Society

Prognostic role of human equilibrative transporter 1 (hENT1) in patients with resected gastric cancer

Nucleoside transporter proteins are specialized proteins that mediate the transport of nucleosides and nucleoside analog drugs across the plasma membrane. The human equilibrative nucleoside transporter 1 (hENT1) is a member of these proteins and mediates cellular entry of gemcitabine, cytarabine, and fludarabine. The hENT1 expression has been demonstrated to be related with prognosis and activity of gemcitabine-based therapy in breast, ampullary, lung, and pancreatic cancer. We investigated the immunohistochemical expression of hENT in tumor samples from III patients with resected gastric adenocarcinoma, correlating these data with clinical parameters and disease outcomes. None of the patients received chemotherapy or radiation therapy before or after surgery as a part of an adjuvant or neoadjuvant program. On univariate survival analysis, the hENT1 expression was associated with overall survival (OS) and disease free survival (DFS). Specifically, those patients with overexpression of hENT1 showed a shorter OS ( P=0.021) and a shorter DFS ( P=0.033). Considering only the node positive patients, higher hENT levels were associated with significantly shorter median DFS (21.7 months; 95% CI 11.1-32.4) compared with patients with low expression of hENT1. The hENT1 expression was defined, in the lymph-node positive patients, as an independent prognostic factor ( P=0.019). Furthermore, considering only patients with diffuse or mixed tumors and lymph-node positive, the expression of hENT1 was strongly related with DFS and OS. Immunohistochemistry for the hENT1 protein carries prognostic information in patients with resected gastric cancer and holds promise as a predictive factor in chemotherapy decisions

Analyzing program termination and complexity automatically with AProVE

In this system description, we present the tool AProVE for automatic termination and complexity proofs of Java, C, Haskell, Prolog, and rewrite systems. In addition to classical term rewrite systems (TRSs), AProVE also supports rewrite systems containing built-in integers (int-TRSs). To analyze programs in high-level languages, AProVE automatically converts them to (int-)TRSs. Then, a wide range of techniques is employed to prove termination and to infer complexity bounds for the resulting rewrite systems. The generated proofs can be exported to check their correctness using automatic certifiers. To use AProVE in software construction, we present a corresponding plug-in for the popular Eclipse software development environment

Ground-based astrometry calibrated by Gaia DR1: new perspectives in asteroid orbit determination

Context. The Gaia Data Release 1 (GDR1) is a first, important step on the path of evolution of astrometric accuracy towards a much improved situation. Although asteroids are not present in GDR1, this intermediate release already impacts asteroid astrometry. Aims. Our goal is to investigate how the GDR1 can change the approach to a few typical problems, including the determination of orbits from short-arc astrometry, the exploitation of stellar occultations, and the impact risk assessment. Methods.We employ optimised asteroid orbit determination tools, and study the resulting orbit accuracy and post-fit residuals. For this goal, we use selected ground-based asteroid astrometry, and occultation events observed in the past. All measurements are calibrated by using GDR1 stars. Results. We show that, by adopting GDR1, very short measurement arcs can already provide interesting orbital solutions, capable of correctly identifying near-Earth asteroids (NEAs) and providing a much more accurate risk rating. We also demonstrate that occultations, previously used to derive asteroid size and shapes, now reach a new level of accuracy at which they can be fruitfully used to obtain astrometry at the level of accuracy of Gaia star positions

Volatile Sulfur Compounds in Foods as a Result of Ionizing Radiation

Ionizing radiation improves food safety and extends shelf life by inactivating food-borne pathogens and spoilage microorganisms. However, irradiation may induce the development of an off-odor, particularly at high doses. The off-odor has been called “irradiation odor”. Substantial evidence suggests that volatile sulfur compounds (VSCs) play an important role in the development of the off-odor. These compounds include hydrogen sulfide, methanethiol, methyl sulfide, dimethyl disulfide and dimethyl trisulfide among others. The formation of off-odor and VSCs due to irradiation in meat, and fruit juices is presented. It is known that irradiation exerts its effect through radiolysis of water in foods where water is a dominant component. Irradiation of water produces three primary free radicals: hydroxyl, hydrogen atoms, and hydrated electrons. Use of specific scavengers in a model system revealed that hydroxyl radicals are involved in the formation of VSCs. Possible mechanisms for formation of VSC are also discussed. Also discussed are possible remedies for formation of VSCs and off-odor, such as use of antioxidants and double packaging

The future of Cybersecurity in Italy: Strategic focus area

This volume has been created as a continuation of the previous one, with the aim of outlining a set of focus areas and actions that the Italian Nation research community considers essential. The book touches many aspects of cyber security, ranging from the definition of the infrastructure and controls needed to organize cyberdefence to the actions and technologies to be developed to be better protected, from the identification of the main technologies to be defended to the proposal of a set of horizontal actions for training, awareness raising, and risk management