1,157 research outputs found

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

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    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

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

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    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

    The use of platelet-rich plasma for treatment of tenodesmic lesions in horses: A systematic review and meta-analysis of clinical and experimental data

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    The use of platelet-rich plasma (PRP) to enhance tenodesmic lesion healing has been questioned over the years. The aim of this study was to evaluate current literature to establish the effectiveness of PRP for treating tenodesmic lesions through a systematic review, in accordance with the PRISMA guidelines, and a meta-analysis. Studies comparing PRP with placebo or other treatments for horses with tenodesmic injuries or evaluated PRP effect on tendon and ligament explants were included. Outcomes were clinical, ultrasound, histologic, molecular evaluation, and adverse effects. Two authors independently extracted data and assessed each study’s risk of bias. Treatment effects were evaluated using risk ratios for dichotomous data, together with 95% CI. Data were pooled using the random-effects model. The quality of the evidence for each outcome was assessed using GRADE criteria. Twenty-four trials met inclusion criteria for systematic review, while fifteen studies were included in the meta-analysis. Results showed no significant differences in the outcomes between PRP and control groups. Finally, there is no definitive evidence that PRP enhances tendons and ligaments healing. Therefore, there is a need for more controlled trials to draw a firmer conclusion about the efficacy of PRP as a treatment for tenodesmic lesions in the horse

    Targeting PDZ domains as potential treatment for viral infections, neurodegeneration and cancer

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    The interaction between proteins is a fundamental event for cellular life that is generally mediated by specialized protein domains or modules. PDZ domains are the largest class of protein–protein interaction modules, involved in several cellular pathways such as signal transduction, cell–cell junctions, cell polarity and adhesion, and protein trafficking. Because of that, dysregulation of PDZ domain function often causes the onset of pathologies, thus making this family of domains an interesting pharmaceutical target. In this review article we provide an overview of the structural and functional features of PDZ domains and their involvement in the cellular and molecular pathways at the basis of different human pathologies. We also discuss some of the strategies that have been developed with the final goal to hijack or inhibit the interaction of PDZ domains with their ligands. Because of the generally low binding selectivity of PDZ domain and the scarce efficiency of small molecules in inhibiting PDZ binding, this task resulted particularly difficult to pursue and still demands increasing experimental efforts in order to become completely feasible and successful in vivo

    Gain-of-Function STIM1 L96V Mutation Causes Myogenesis Alteration in Muscle Cells From a Patient Affected by Tubular Aggregate Myopathy

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    Tubular Aggregate Myopathy (TAM) is a hereditary ultra-rare muscle disorder characterized by muscle weakness and cramps or myasthenic features. Biopsies from TAM patients show the presence of tubular aggregates originated from sarcoplasmic reticulum due to altered Ca2+ homeostasis. TAM is caused by gain-of-function mutations in STIM1 or ORAI1, proteins responsible for Store-Operated-Calcium-Entry (SOCE), a pivotal mechanism in Ca2+ signaling. So far there is no cure for TAM and the mechanisms through which STIM1 or ORAI1 gene mutation lead to muscle dysfunction remain to be clarified. It has been established that post-natal myogenesis critically relies on Ca2+ influx through SOCE. To explore how Ca2+ homeostasis dysregulation associated with TAM impacts on muscle differentiation cascade, we here performed a functional characterization of myoblasts and myotubes deriving from patients carrying STIM1 L96V mutation by using fura-2 cytofluorimetry, high content imaging and real-time PCR. We demonstrated a higher resting Ca2+ concentration and an increased SOCE in STIM1 mutant compared with control, together with a compensatory down-regulation of genes involved in Ca2+ handling (RyR1, Atp2a1, Trpc1). Differentiating STIM1 L96V myoblasts persisted in a mononuclear state and the fewer multinucleated myotubes had distinct morphology and geometry of mitochondrial network compared to controls, indicating a defect in the late differentiation phase. The alteration in myogenic pathway was confirmed by gene expression analysis regarding early (Myf5, Mef2D) and late (DMD, Tnnt3) differentiation markers together with mitochondrial markers (IDH3A, OGDH). We provided evidences of mechanisms responsible for a defective myogenesis associated to TAM mutant and validated a reliable cellular model usefull for TAM preclinical studies

    Targeting the Interaction between the SH3 Domain of Grb2 and Gab2

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    Gab2 is a scaffolding protein, overexpressed in many types of cancers, that plays a key role in the formation of signaling complexes involved in cellular proliferation, migration, and differentiation. The interaction between Gab2 and the C-terminal SH3 domain of the protein Grb2 is crucial for the activation of the proliferation-signaling pathway Ras/Erk, thus representing a potential pharmacological target. In this study, we identified, by virtual screening, seven potential inhibitor molecules that were experimentally tested through kinetic and equilibrium binding experiments. One compound showed a remarkable effect in lowering the affinity of the C-SH3 domain for Gab2. This inhibitory effect was subsequently validated in cellula by using lung cancer cell lines A549 and H1299. Our results are discussed under the light of previous works on the C-SH3:Gab2 interaction

    The Air Microwave Yield (AMY) experiment - A laboratory measurement of the microwave emission from extensive air showers

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    The AMY experiment aims to measure the microwave bremsstrahlung radiation (MBR) emitted by air-showers secondary electrons accelerating in collisions with neutral molecules of the atmosphere. The measurements are performed using a beam of 510 MeV electrons at the Beam Test Facility (BTF) of Frascati INFN National Laboratories. The goal of the AMY experiment is to measure in laboratory conditions the yield and the spectrum of the GHz emission in the frequency range between 1 and 20 GHz. The final purpose is to characterise the process to be used in a next generation detectors of ultra-high energy cosmic rays. A description of the experimental setup and the first results are presented.Comment: 3 pages -- EPS-HEP'13 European Physical Society Conference on High Energy Physics (July, 18-24, 2013) at Stockholm, Swede

    Calibration of the Logarithmic-Periodic Dipole Antenna (LPDA) Radio Stations at the Pierre Auger Observatory using an Octocopter

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    An in-situ calibration of a logarithmic periodic dipole antenna with a frequency coverage of 30 MHz to 80 MHz is performed. Such antennas are part of a radio station system used for detection of cosmic ray induced air showers at the Engineering Radio Array of the Pierre Auger Observatory, the so-called Auger Engineering Radio Array (AERA). The directional and frequency characteristics of the broadband antenna are investigated using a remotely piloted aircraft (RPA) carrying a small transmitting antenna. The antenna sensitivity is described by the vector effective length relating the measured voltage with the electric-field components perpendicular to the incoming signal direction. The horizontal and meridional components are determined with an overall uncertainty of 7.4^{+0.9}_{-0.3} % and 10.3^{+2.8}_{-1.7} % respectively. The measurement is used to correct a simulated response of the frequency and directional response of the antenna. In addition, the influence of the ground conductivity and permittivity on the antenna response is simulated. Both have a negligible influence given the ground conditions measured at the detector site. The overall uncertainties of the vector effective length components result in an uncertainty of 8.8^{+2.1}_{-1.3} % in the square root of the energy fluence for incoming signal directions with zenith angles smaller than 60{\deg}.Comment: Published version. Updated online abstract only. Manuscript is unchanged with respect to v2. 39 pages, 15 figures, 2 table
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