Drug design and synthesis of first in class PDZ1 targeting NHERF1 inhibitors as anticancer agents

Targeted approaches aiming at modulating NHERF1 activity, rather than its overall expression, would be preferred to preserve the normal functions of this versatile protein. We focused our attention on the NHERF1/PDZ1 domain that governs its membrane recruitment/displacement through a transient phosphorylation switch. We herein report the design and synthesis of novel NHERF1 PDZ1 domain inhibitors. These compounds have potential therapeutic value when used in combination with antagonists of β-catenin to augment apoptotic death of colorectal cancer cells refractory to currently available Wnt/β-catenin-targeted agents

Platinum(II)-Acyclovir Complexes: Synthesis, Antiviral and Antitumour Activity

A platinum(II) complex with the antiviral drug acyclovir was synthesized and its antiviral and anticancer properties were investigated in comparison to those of acyclovir and cisplatin. The platinum-acyclovir complex maintained the antiviral activity of the parent drug acyclovir, though showing a minor efficacy on a molar basis (ID50  =   7.85 and 1.02 μΜ for platinum-acyclovir and cisplatin, respectively). As anticancer agent, the platinum-acyclovir complex was markedly less potent than cisplatin on a mole-equivalent basis, but it was as effective as cisplatin when equitoxic dosages were administered in vivo to P388 leukaemia-bearing mice (%T/C = 209 and 211 for platinum-acyclovir and cisplatin, respectively). The platinum-acyclovir complex was also active against a cisplatin-resistant subline of the P388 leukaemia (%T/C = 140), thus suggesting a different mechanism of action. The DNA interaction properties (sequence specificity and interstrand cross-linking ability) of platinum-acyclovir were also investigated in comparison to those of cisplatin and [Pt(dien)Cl]+, an antitumour-inactive platinum-triamine compound. The results of this study point to a potential new drug endowed, at the same time, with antiviral and anticancer activity and characterized by DNA interaction properties different from those of cisplatin

ATLAS RPC Quality Assurance results at INFN Lecce

The main results of the quality assurance tests performed on the Resistive Plate Chamber used by the ATLAS experiment at LHC as muon trigger chambers are reported and discussed. Since July 2004, about 270 RPC units has been certified at INFN Lecce site and delivered to CERN, for being integrated in the final muon station of the ATLAS barrel region. We show the key RPC characteristics which qualify the performance of this detector technology as muon trigger chamber in the harsh LHC enviroments. These are dark current, chamber efficiency, noise rate, gas volume tomography, and gas leakage.Comment: Comments: 6 pages, 1 table, 9 figures Proceedings of XXV Physics in Collision-Prague, Czech Republic, 6-9 July 200

Left ventricular mass increase is associated with cognitive decline and dementia in the elderly independently of blood pressure

Aims Left ventricular (LV) mass increase is considered part of composite target organ damage in hypertension and an independent risk factor for cardiovascular (CV) events. This study was designed to explore whether left ventricular mass index (LVMI) is associated with cognitive decline and dementia in elderly subjects, independently of blood pressure (BP) levels. Methods and results Four hundred subjects (mean age 79 ± 6 years) were studied. Left ventricular mass was measured echocardiographically in accordance with American Society of Echocardiography and normalized for body height to the 2.7 (LVMI). Global cognitive function was evaluated with the mini-mental state examination (MMSE) (maximum score 30). Dementia was defined as an MMSE score <21. Arterial stiffness was evaluated as carotid–femoral pulse wave velocity by Complior®. Prevalence of hypertension was 70% and diabetes mellitus was diagnosed in 25%. No significant differences in traditional CV risk factors were observed across LVMI quartiles. Mini-mental state examination showed an inverse trend across LVMI quartiles (the higher the LVMI, the lower the MMSE, P for trend <0.05); systolic and diastolic BP levels were not different across LVMI quartiles. In multivariable logistic regression models, including age, sex, BP levels, and use of antihypertensive drugs as covariates, the highest LVMI was found to be independently associated with a two-fold higher likelihood of having dementia. The association persisted significant even after adjustment for arterial stiffness. Conclusion In elderly subjects, LVMI is associated with a progressive cognitive decline. This association is independent of BP levels and/or large artery stiffness

Dealing with adversity: religiosity or science? Evidence from the great influenza pandemic

How do societies respond to adversity? After a negative shock, separate strands of research document either an increase in religiosity or a boost in innovation efforts. In this paper, we show that both reactions can occur at the same time, driven by different individuals within society. The setting of our study is the 1918-1919 influenza pandemic in the United States. To measure religiosity, we construct a novel indicator based on naming patterns of newborns. We measure innovation through the universe of granted patents. Exploiting plausibly exogenous county-level variation in exposure to the pandemic, we provide evidence that more-affected counties become both more religious and more innovative. Looking within counties, we uncover heterogeneous responses: individuals from more religious backgrounds further embrace religion, while those from less religious backgrounds become more likely to choose a scientific occupation. Facing adversity widens the distance in religiosity between science-oriented individuals and the rest of the population, and it increases the polarization of religious beliefs

CORAM (COsmic RAy Mission): An outreach program one century after Pacini and Hess works

Abstract CORAM (COsmic RAy Mission) is an outreach program carried out by INFN and the University of Salento in close collaboration with high schools. Students and their teachers are involved in the design, construction, test and operation of detectors for the measurement of several properties of the cosmic ray flux. The results of a set of measurements, made with a first detector prototype at different altitudes and underground, will be described

Water-Soluble Ruthenium(III)-Dimethyl Sulfoxide Complexes: Chemical Behaviour and Pharmaceutical Properties

In this paper we report a review of the results obtained in the last few years by our group in the development of ruthenium(III) complexes characterized by the presence of sulfoxide ligands and endowed with antitumor properties. In particular, we will focus on ruthenates of general formula Na[trans-RuCl4(R1R2SO)(L)], where R1R2SO = dimethylsulfoxide (DMSO) or tetramethylenesulfoxide (TMSO) and L = nitrogen donor ligand. The chemical behavior of these complexes has been studied by means of spectroscopic techniques both in slightly acidic distilled water and in phosphate buffered solution at physiological pH. The influence of biological reductants on the chemical behavior is also described. The antitumor properties have been investigated on a number of experimental tumors. Out of the effects observed, notheworthy appears the capability of the tested ruthenates to control the metastatic dissemination of solid metastasizing tumors. The analysis of the antimetastatic action, made in particular on the MCa mammary carcinoma of CBA mouse, has demonstrated a therapeutic value for these complexes which are able to significantly prolong the survival time of the treated animals. The antimetastatic effect is not attributable to a specific cytotoxicity for metastatic tumor cells although in vitro experiments on pBR322 double stranded DNA has shown that the test ruthenates bind to the macromolecule, causing breaks corresponding to almost all bases, except than thymine, and are able to cause interstrand bonds, depending on the nature of the complex being tested, some of which results active as cisplatin itself

Modeling Epac1 interactions with the allosteric inhibitor AM-001 by co-solvent molecular dynamics

The exchange proteins activated by cAMP (EPAC) are implicated in a large variety of physiological processes and they are considered as promising targets for a wide range of therapeutic applications. Several recent reports provided evidence for the therapeutic effectiveness of the inhibiting EPAC1 activity cardiac diseases. In that context, we recently characterized a selective EPAC1 antagonist named AM-001. This compound was featured by a non-competitive mechanism of action but the localization of its allosteric site to EPAC1 structure has yet to be investigated. Therefore, we performed cosolvent molecular dynamics with the aim to identify a suitable allosteric binding site. Then, the docking and molecular dynamics were used to determine the binding of the AM-001 to the regions highlighted by cosolvent molecular dynamics for EPAC1. These analyses led us to the identification of a suitable allosteric AM-001 binding pocket at EPAC1. As a model validation, we also evaluated the binding poses of the available AM-001 analogues, with a different biological potency. Finally, the complex EPAC1 with AM-001 bound at the putative allosteric site was further refined by molecular dynamics. The principal component analysis led us to identify the protein motion that resulted in an inactive like conformation upon the allosteric inhibitor binding

ATLAS RPC Cosmic Ray Teststand at INFN Lecce

We describe the design and functionality of the cosmic ray teststand built at INFN Lecce for ATLAS RPC quality control assurance.Comment: XXIV Physics in Collisions Conference (PIC04), Boston, USA, June 2004, 3 pages, LaTex, 2 eps figures. MONP0

Ultrasonographic assessment of normal jugular veins in Standardbred horses

Ultrasonography (US) is the recommended imaging technique to evaluate jugular veins. This prospective randomized clinical study was designed to collect a series of B-mode US measurements of manually distended jugular veins in healthy Italian Standardbreds and to find possible correlations between ultrasound measurements and animal morphometric characteristics. Forty-two horses, eight males and 34 females (range 3-22 years; bodyweight 494.4 ± 41.7 kg), were included in the study. The diameters and wall thicknesses of both jugular veins were measured at three different sites of the neck. The differences in ultrasound measurements based on scans, age, gender, side, and site of the neck were evaluated by ANOVA or by the Kruskal-Wallis test. The effects of the morphometric measures on each ultrasound parameter were evaluated by MANOVA (P < 0.05)