Design and synthesis of a novel non peptide CN-NFATc signaling inhibitor for tumor suppression in triple negative breast cancer

The Ca2+/calmodulin-mediated phosphatase activity of calcineurin (CN) integrates calcium-mediated signaling with gene expression programs involved in the control of essential cellular processes in health and disease, such as the immune response and the pathogenesis of cancer progression and metastasis. In addition, CN is the target of the immunosuppressive drugs cyclosporine A (CsA) and FK-506 which are the cornerstone of immunosuppressant therapy. Unfortunately, long-term administration of these drugs results in severe side effects. Herein, we describe the design, synthesis and evaluation of new synthetic compounds that are capable of inhibiting NFATc activity in a dose-dependent manner, without interfering on CN phosphatase activity. These compounds were designed using the structure-based pharmacophore model of a peptide-derived PxIxIT sequence binding to calcineurin A subunit. Moreover, these compounds inhibit NFATc-dependent cytokine gene expression, secretion and proliferation of human T CD4(+) cells. More importantly, compound 5a reduces tumor weight and shows a tendency to reduce tumor angiogenesis in an orthotopic immunocompetent mouse model of triple negative breast cancer, suggesting that 5a has tumor suppressor activity. These findings validate compound 5a as an agent with therapeutic activity against CN-NFATc and highlight its potential as a tool for drug development with therapeutic purposes

Buckling and ultimate strength study of a stiffened plate under compression using finite element method

Εθνικό Μετσόβιο Πολυτεχνείο--Μεταπτυχιακή Εργασία. Διεπιστημονικό-Διατμηματικό Πρόγραμμα Μεταπτυχιακών Σπουδών (Δ.Π.Μ.Σ.) “Ναυτική και Θαλάσσια Τεχνολογία και Επιστήμη

Structural and Functional Insights into CRF Peptides and Their Receptors

Corticotropin-releasing factor or hormone (CRF or CRH) and the urocortins regulate a plethora of physiological functions and are involved in many pathophysiological processes. CRF and urocortins belong to the family of CRF peptides (CRF family), which includes sauvagine, urotensin, and many synthetic peptide and non-peptide CRF analogs. Several of the CRF analogs have shown considerable therapeutic potential in the treatment of various diseases. The CRF peptide family act by interacting with two types of plasma membrane proteins, type 1 (CRF1R) and type 2 (CRF2R), which belong to subfamily B1 of the family B G-protein-coupled receptors (GPCRs). This work describes the structure of CRF peptides and their receptors and the activation mechanism of the latter, which is compared with that of other GPCRs. It also discusses recent structural information that rationalizes the selective binding of various ligands to the two CRF receptor types and the activation of receptors by different agonists

High-profile flow diverter (silk) implantation in the basilar artery : efficacy in the treatment of aneurysms and the role of the perforators

The introduction of flow diverters (FDs) has expanded the possibilities for reconstructive treatment of difficult intracranial aneurysms. Concern remains as to the long-term patency of the perforating arteries and side branches covered during stent placement. Our purpose was to evaluate the performance of and early effect on covered branches after implantation of the Silk FD in the treatment of basilar artery aneurysms

Evaluation of a West Nile virus surveillance and earlywarning system in Greece, based on domestic pigeons

In the summer of 2010 an epidemic of West Nile virus (WNV) occurred in Central Macedo-nia, Greece, with 197 human neuroinvasive disease (WNND) cases. In the following yearsthe virus spread to new areas, with a total of 76 WNND cases in 2011, and 109 WNNDcases in 2012 (14 and 12 WNND cases, respectively, in Central Macedonia). We establisheda surveillance system based on serological testing of domestic pigeons, using cELISA con-firmed by serum neutralization test. In Central Macedonia, pigeon seroprevalence was 54%(95% CI: 49â59%) and 31% (95% CI: 24â37%) at the end of the 2010 and 2011 epidemicseasons, respectively. One serum was positive for neutralizing antibodies directed againstUsutu virus. Pigeon WNV seroprevalence and incidence rates of human WNND after the2010 epidemic were positively correlated ( = 0.94, at the regional unit level), while in2011 the correlation ( = 0.56) was not statistically significant, possibly due to small num-ber of human WNND cases recorded. To evaluate the efficacy of the system at alerting uponWNV enzootic circulation before the onset of human cases, we tested 270 pigeons in 2011and 240 pigeons in 2012. In Central Macedonia, the first seroconversions in pigeons wererecorded 44 and 47 days, respectively, before the first human WNND cases. Pigeon surveil-lance was used successfully for identification of areas with WNV enzootic transmissionand for early warning. Timely diffusion of information to health authorities facilitated theimplementation of preparedness plans to protect public health

Evaluation of a West Nile virus surveillance and early warning system in Greece, based on domestic pigeons

In the summer of 2010 an epidemic of West Nile virus (WNV) occurred in Central Macedonia, Greece, with 197 human neuroinvasive disease (WNND) cases. In the following years the virus spread to new areas, with a total of 76 WNND cases in 2011, and 109 WNND cases in 2012 (14 and 12 WNND cases, respectively, in Central Macedonia). We established a surveillance system based on serological testing of domestic pigeons, using cELISA confirmed by serum neutralization test In Central Macedonia, pigeon seroprevalence was 54% (95% CI: 49-59%) and 31% (95% CI: 24-37%) at the end of the 2010 and 2011 epidemic seasons, respectively. One serum was positive for neutralizing antibodies directed against Usutu virus. Pigeon WNV seroprevalence and incidence rates of human WNND after the 2010 epidemic were positively correlated (rho = 0.94, at the regional unit level), while in 2011 the correlation (rho = 0.56) was not statistically significant, possibly due to small number of human WNND cases recorded. To evaluate the efficacy of the system at alerting upon WNV enzootic circulation before the onset of human cases, we tested 270 pigeons in 2011 and 240 pigeons in 2012. In Central Macedonia, the first seroconversions in pigeons were recorded 44 and 47 days, respectively, before the first human WNND cases. Pigeon surveillance was used successfully for identification of areas with WNV enzootic transmission and for early warning. Timely diffusion of information to health authorities facilitated the implementation of preparedness plans to protect public health. (C) 2014 Elsevier Ltd. All rights reserved