Synthesis of amides from aldehydes and amines via C-H bond activation and discovery and development of novel and selective carbonic anhydrase inhibitors

This doctoral dissertation consists of two chapters. In the first chapter is described the methodology developed for the synthesis of amides from aldehydes and amines by activating the aldehyde C-H bond. The technique involves the formation of N-chloro amine in situ, without being isolated from the reaction mixture, to which is then added the aldehyde. The two reagents in the presence of TBHP and Cu(OAc)2, forming the new CN bond. The method allowed to synthesize amides variously substituted in good yields. In the second chapter is detailed a project focused on the development of new original and selective carbonic anhydrases inhibitors. This chapter is divided into four topics which include a) the application of the click chemistry as a powerful synthetic approach for the generation of sulfonamide-based inhibitors; b) the synthesis of a set of derivatives belonging to a previously indentified hit compound bearing the trifluorodihydroxypropanone moiety, and the strategy adopted for its biological optimization; c) the design and development of novel pyrazole-carboxylic acids derived from a previously identified lead compound, as well as its pharmacobiological optimization; d) the synthesis of potential carbonic anhydrase inhibitors carrying a benzoxaborole scaffold

Financial crisis: a new measure for risk of pension fund portfolios

It has been argued that pension funds should have limitations on their asset allocation, based on the risk profile of the different financial instruments available on the financial markets. This issue proves to be highly relevant at times of market crisis, when a regulation establishing limits to risk taking for pension funds could prevent defaults. In this paper we present a framework for evaluating the risk level of a single financial instrument or a portfolio. By assuming that the log asset returns can be described by a multifractional Brownian motion, we evaluate the risk using the time dependent Hurst parameter H(t) which models volatility. To provide a measure of the risk, we model the Hurst parameter with a random variable with mixture of beta distribution. We prove the efficacy of the methodology by implementing it on different risk level financial instruments and portfolios

Searching for novel carbonic anhydrase inhibitors: from virtual screening to the lab bench

Carbonic Anhydrases (CAs) are zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide to bicarbonate both in prokaryotes and eukaryotes. In this context, Computer Aided Drug Design strategies have emerged as powerful tools in the modern drug discovery paradigm. In particular, using ligand- and pharmacophore-based virtual screening approaches, we identified novel chemical entities with original chemotypes, that showed an interesting and selective inhibitory activity in nanomolar/low micromolar range toward CA I and CAII, isoforms. Herein, we present the hit-to-lead optimization process for these prototypes

Plasma miR-151-3p as a Candidate Diagnostic Biomarker for Head and Neck Cancer: A Cross-sectional Study within the INHANCE Consortium

Background: Identification of screening tests for the detection of head and neck cancer (HNC) at an early stage is an important strategy to improving prognosis. Our objective was to identify plasma circulating miRNAs for the diagnosis of HNC (oral and laryngeal subsites), within a multicenter International Head and Neck Cancer Epidemiology consortium. Methods: A high-throughput screening phase with 754 miRNAs was performed in plasma samples of 88 cases and 88 controls, followed by a validation phase of the differentially expressed miRNAs, identified in the screening, in samples of 396 cases and 396 controls. Comparison of the fold changes (FC) was carried out using the Wilcoxon rank-sum test and the Dunn multiple comparison test. Results: We identified miR-151-3p (FC = 1.73, P = 0.007) as differentially expressed miRNAs in the screening and validation phase. The miR-151-3p was the only overexpressed miRNA in validation sample of patients with HNC with early stage at diagnosis (FC = 1.81, P = 0.008) and it was confirmed upregulated both in smoker early-stage cases (FC = 3.52, P = 0.024) and in nonsmoker early-stage cases (FC = 1.60, P = 0.025) compared with controls. Conclusions: We identified miR-151-3p as an early marker of HNC. This miRNA was the only upregulated in patients at early stages of the disease, independently of the smoking status. Impact: The prognosis for HNC is still poor. The discovery of a new diagnostic biomarker could lead to an earlier tumor discovery and therefore to an improvement in patient prognosis

Alcohol and cigarette consumption predict mortality in patients with head and neck cancer: A pooled analysis within the International Head and Neck Cancer Epidemiology (INHANCE) Consortium

Background: This study evaluated whether demographics, pre-diagnosis lifestyle habits and clinical data are associated with the overall survival (OS) and head and neck cancer (HNC)-specific survival in patients with HNC. Patients and methods: We conducted a pooled analysis, including 4759 HNC patients from five studies within the International Head and Neck Cancer Epidemiology (INHANCE) Consortium. Cox proportional hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) were estimated including terms reported significantly associated with the survival in the univariate analysis. Results: Five-year OS was 51.4% for all HNC sites combined: 50.3% for oral cavity, 41.1% for oropharynx, 35.0% for hypopharynx and 63.9% for larynx. When we considered HNC-specific survival, 5-year survival rates were 57.4% for all HNC combined: 54.6% for oral cavity, 45.4% for oropharynx, 37.1% for hypopharynx and 72.3% for larynx. Older ages at diagnosis and advanced tumour staging were unfavourable predictors of OS and HNC-specific survival. In laryngeal cancer, low educational level was an unfavourable prognostic factor for OS (HR=2.54, 95% CI 1.01-6.38, for high school or lower versus college graduate), and status and intensity of alcohol drinking were prognostic factors both of the OS (current drinkers HR=1.73, 95% CI 1.16-2.58) and HNC-specific survival (current drinkers HR=2.11, 95% CI 1.22-3.66). In oropharyngeal cancer, smoking status was an independent prognostic factors for OS. Smoking intensity ( > 20 cigarettes/day HR=1.41, 95% CI 1.03-1.92) was also an independent prognostic factor for OS in patients with cancer of the oral cavity. Conclusions: OS and HNC-specific survival differ among HNC sites. Pre-diagnosis cigarette smoking is a prognostic factor of the OS for patients with cancer of the oral cavity and oropharynx, whereas pre-diagnosis alcohol drinking is a prognostic factor of OS and HNC-specific survival for patients with cancer of the larynx. Low educational level is an unfavourable prognostic factor for OS in laryngeal cancer patients

Small-bowel capsule endoscopy with panoramic view: results of the first multicenter, observational study (with videos).

BACKGROUND AND AIMS: The first small-bowel video-capsule endoscopy (VCE) with 360° panoramic view has been recently developed. This new capsule has a wire-free technology, 4 high frame-rate cameras, and a long-lasting battery life. The present study was aimed at assessing performances and the safety profile of the 360° panoramic-view capsule in a large series of patients from a multicenter clinical practice setting. METHODS: Consecutive patients undergoing a 360° panoramic-view capsule procedure in 7 European Institutions between January 2011 and November 2015 were included. Both technical (ie, technical failures, completion rate) and clinical (ie, indication, findings, retention rate) data were collected by means of a structured questionnaire. VCE findings were classified according to the likelihood to explain reason for referral: P0-low, P1-intermediate and P2-high. RESULTS: Among 172 patients (94 men; median age: 68 years, IQR: 53-75), 142 underwent VCE for obscure (32 overt, 110 occult) GI bleeding (OGIB) and 28 for suspected (17) or established (2) Crohn's disease (CD). Overall, 560 findings were detected; 252 of them were P2. The overall diagnostic yield was 40.1%; 42.2% and 30.0% in patients with OGIB and CD, respectively. The rate of complete enteroscopy was 90.2%. All of the patients but one, who experienced capsule retention (1/172: 0.6%), excreted and retrieved the capsule. VCE failure occurred in 4 of 172 (2.3%) cases for technical problems. CONCLUSION: The present multicenter study, conducted in clinical practice setting and based on a large consecutive series of patients, showed that DY and safety profile of 360° panoramic-view capsule are similar to those of forward-view VCEs

Plasma miR-151-3p as a candidate diagnostic biomarker for head and neck cancer: a cross-sectional study within the INHANCE consortium

Identification of screening tests for the detection of head and neck cancer at an early stage is an important strategy to improving prognosis. Our objective was to identify plasma circulating microRNAs for the diagnosis of head and neck cancer (oral and laryngeal subsites), within a multicenter International Head and Neck Cancer Epidemiology (INHANCE) consortium

Acute Delta Hepatitis in Italy spanning three decades (1991–2019): Evidence for the effectiveness of the hepatitis B vaccination campaign

Updated incidence data of acute Delta virus hepatitis (HDV) are lacking worldwide. Our aim was to evaluate incidence of and risk factors for acute HDV in Italy after the introduction of the compulsory vaccination against hepatitis B virus (HBV) in 1991. Data were obtained from the National Surveillance System of acute viral hepatitis (SEIEVA). Independent predictors of HDV were assessed by logistic-regression analysis. The incidence of acute HDV per 1-million population declined from 3.2 cases in 1987 to 0.04 in 2019, parallel to that of acute HBV per 100,000 from 10.0 to 0.39 cases during the same period. The median age of cases increased from 27 years in the decade 1991-1999 to 44 years in the decade 2010-2019 (p < .001). Over the same period, the male/female ratio decreased from 3.8 to 2.1, the proportion of coinfections increased from 55% to 75% (p = .003) and that of HBsAg positive acute hepatitis tested for by IgM anti-HDV linearly decreased from 50.1% to 34.1% (p < .001). People born abroad accounted for 24.6% of cases in 2004-2010 and 32.1% in 2011-2019. In the period 2010-2019, risky sexual behaviour (O.R. 4.2; 95%CI: 1.4-12.8) was the sole independent predictor of acute HDV; conversely intravenous drug use was no longer associated (O.R. 1.25; 95%CI: 0.15-10.22) with this. In conclusion, HBV vaccination was an effective measure to control acute HDV. Intravenous drug use is no longer an efficient mode of HDV spread. Testing for IgM-anti HDV is a grey area requiring alert. Acute HDV in foreigners should be monitored in the years to come

Portfolios composition.

<p>Portfolios composition.</p

Financial Crisis: A New Measure for Risk of Pension Fund Portfolios - Fig 5

<p>(a) Mixture of beta distribution fit to the Hölder exponent of High Risk Portfolio 2, High Risk Portfolio 1, and Low Risk Portfolio 1. (b) Mean and variance of the <i>beta mixture</i> distribution for the seven portfolios.</p