Design and Synthesis of Hsp90 Inhibitors with B-Raf and PDHK1 Multi-Target Activity

5noopenThe design of multi-target ligands has become an innovative approach for the identification of effective therapeutic treatments against complex diseases, such as cancer. Recent studies have demonstrated that the combined inhibition of Hsp90 and B-Raf provides synergistic effects against several types of cancers. Moreover, it has been reported that PDHK1, which presents an ATP-binding pocket similar to that of Hsp90, plays an important role in tumor initiation, maintenance and progression, participating also to the senescence process induced by B-Raf oncogenic proteins. Based on these premises, the simultaneous inhibition of these targets may provide several benefits for the treatment of cancer. In this work, we set up a design strategy including the assembly and integration of molecular fragments known to be important for binding to the Hsp90, PDHK1 and B-Raf targets, aided by molecular docking for the selection of a set of compounds potentially able to exert Hsp90-B-Raf-PDHK1 multi-target activities. The designed compounds were synthesized and experimentally validated in vitro. According to the in vitro assays, compounds 4 a, 4 d and 4 e potently inhibited Hsp90 and moderately inhibited the PDHK1 kinase. Finally, molecular dynamics simulations were performed to provide further insights into the structural basis of their multi-target activity.openPinzi L.; Foschi F.; Christodoulou M.S.; Passarella D.; Rastelli G.Pinzi, L.; Foschi, F.; Christodoulou, M. S.; Passarella, D.; Rastelli, G

Diagnosis and Treatment of Biliary Fistulas in the Laparoscopic Era

Biliary fistulas are rare complications of gallstone. They can affect either the biliary or the gastrointestinal tract and are usually classified as primary or secondary. The primary fistulas are related to the biliary lithiasis, while the secondary ones are related to surgical complications. Laparoscopic surgery is a therapeutic option for the treatment of primary biliary fistulas. However, it could be the first responsible for the development of secondary biliary fistulas. An accurate preoperative diagnosis together with an experienced surgeon on the hepatobiliary surgery is necessary to deal with biliary fistulas. Cholecystectomy with a choledocoplasty is the most frequent treatment of primary fistulas, whereas the bile duct drainage or the endoscopic stenting is the best choice in case of minor iatrogenic bile duct injuries. Roux-en-Y hepaticojejunostomy is the extreme therapeutic option for both conditions. The sepsis, the level of the bile duct damage, and the involvement of the gastrointestinal tract increase the complexity of the operation and affect early and late results

Long-term prognostic significance of three-dimensional echocardiographic parameters of the left ventricle and left atrium

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Doping, European Law and the Implications of Meca-Medina

The ruling of the European Court of Justice in the anti-doping case of Meca Medina v. The Commission has important implications for athletes, domestic governing bodies, international federations and supra-national actors such as WADA and the Court of Arbitration for Sport. Meca-Medina has been criticised as an unwelcome interference by the courts in the legitimate activities of sporting organisations, but after Bosman it was fanciful to argue that those organisations should be ‘above the law’ and the courts should have no jurisdiction over their activities. That said, there is a stark difference between the courts having jurisdiction over sports’ decisions and being willing to overturn them - the courts have been, and remain, willing to defer to the expertise of sporting organisations. However, the ECJ’s ruling in MOTOE confirms that the courts will intervene in appropriate circumstances. In order to avoid sanction on competition law grounds sports organisations must thus be able to justify their provisions on (for example) what is an unacceptable level of nandrolone, show that athletes’ fundamental rights such as the right to a fair hearing have been respected, and ensure that any sanctions imposed upon athletes who fall foul of doping regulations are proportionate to the offence committed

Distorted Copulas: Constructions and Tail Dependence

Given a copula C, we examine under which conditions on an order isomorphism ψ of [0, 1] the distortion C ψ: [0, 1]2 → [0, 1], C ψ(x, y) = ψ{C[ψ−1(x), ψ−1(y)]} is again a copula. In particular, when the copula C is totally positive of order 2, we give a sufficient condition on ψ that ensures that any distortion of C by means of ψ is again a copula. The presented results allow us to introduce in a more flexible way families of copulas exhibiting different behavior in the tails

Definition of a Core Collection and Construction of a Reference Set for Genome-Wide Association Studies from a Large Prunus persica Germplasm Collection

Genome-wide association studies take advantage of the natural variation present in germplasm repositories for identifying genes underlying agronomic traits, through plant molecular and phenotypic characterization. For tree crops, in vivo maintenance and phenotyping are particularly onerous and the reduction of redundancy and duplicates could help lowering management costs. In the frame of the European project FruitBreedomics, a collection of 1580 Prunus accessions from different institutions in Europe and China has been genotyped with the IPSC 9K SNP Array and phenotyped for different agronomic traits and a GWAS analysis with 4271 SNPs on 7 monogenic traits has been carried out (Micheletti et al. 2015). In the present work, the same set of 4271 SNP markers was used to identify a peach core collection by applying the maximization strategy implemented in the software PowerCore v 1.0 (Kim et al. 2007). Out of a total of 1540 a core of 72 (C72) accessions was identified, representing 4.7% sampling size. C72 contains the accessions with higher diversity representing the total allelic coverage with an efficiency index of 0.83 with respect to random sampling. In the view of setting up a genomic tool for GWAS analyses a reference subset of 150 accessions was also developed taking into account allelic and phenotypic traits representativeness through the maximization strategy, population stratification and controlled redundancy required to have enough statistical power. Preliminary PCA analysis shows population structure to explain less than 30% of variability due to the local varieties. Validation of the reference set will also be presented

A sharp condition for scattering of the radial 3d cubic nonlinear Schroedinger equation

We consider the problem of identifying sharp criteria under which radial $H^1$ (finite energy) solutions to the focusing 3d cubic nonlinear Schr\"odinger equation (NLS) $i\partial_t u + \Delta u + |u|^2u=0$ scatter, i.e. approach the solution to a linear Schr\"odinger equation as $t\to \pm \infty$. The criteria is expressed in terms of the scale-invariant quantities $\|u_0\|_{L^2}\|\nabla u_0\|_{L^2}$ and $M[u]E[u]$, where $u_0$ denotes the initial data, and $M[u]$ and $E[u]$ denote the (conserved in time) mass and energy of the corresponding solution $u(t)$. The focusing NLS possesses a soliton solution $e^{it}Q(x)$, where $Q$ is the ground-state solution to a nonlinear elliptic equation, and we prove that if $M[u]E[u]<M[Q]E[Q]$ and $\|u_0\|_{L^2}\|\nabla u_0\|_{L^2} < \|Q\|_{L^2}\|\nabla Q\|_{L^2}$, then the solution $u(t)$ is globally well-posed and scatters. This condition is sharp in the sense that the soliton solution $e^{it}Q(x)$, for which equality in these conditions is obtained, is global but does not scatter. We further show that if $M[u]E[u] \|Q\|_{L^2}\|\nabla Q\|_{L^2}$, then the solution blows-up in finite time. The technique employed is parallel to that employed by Kenig-Merle \cite{KM06a} in their study of the energy-critical NLS

Genetic Dissection of Complex Fruit Quantitative Traits in Peach Progen

Major research efforts in peach are dedicated to the discovery of genomic variants causing phenotypic effects in complex fruit traits such as: maturity date (MD), fruit size (FW), sugar (SSC) and acid content (TA), flesh texture (slow softening, SSf) and resistance to brown rot by Monilinia spp. (BRr). Five segregating progenies showing phenotypic variation for at least one of these traits are available in our experimental fields. For SSC and TA, an already validated approach based on Near-InfraRed spectroscopy (NIR), is being applied to phenotype some segregating progenies. For SSf and BRr instead, trait characterization has been performed, resulting in the identification of co-factor traits and definition of standardized phenotyping tools, which are currently applied in the characterization of segregating material (in the context of FruitBreedomics EU project). High-density linkage maps have been constructed with genotypic data obtained from IPSC Illumina 9K SNP chip (Italian Drupomics and FruitBreedomics frameworks) and Genotyping-by-Sequencing (GBS). Additionally, parents of these progenies have been re-sequenced (30-40x) and genetic variants present along their genomes have been identified. Multiple-QTL models (MQM) coupled with the use of co-factor traits is leading to the discovery of significant QTLs. Genomic variants are explored within QTL intervals on the genomes of progeny parents, in order to identify possible mutations causing phenotypic differences, and develop markers for marker-assisted selection approaches

One-step nucleic acid amplification (OSNA) fits better with lower cost in breast cancer axillary management

Introduction: One-Step Nucleic Acid Amplification (OSNA) has been already validated for Analysis of Sentinel Node (SLN) in breast cancer. We investigated benefits of OSNA beyond accuracy, with a focus on cost-effectiveness. Methods: 253 consecutive breast cancer patients were reviewed: SLN was analyzed by OSNA in 114 cases and by standard histopathology in 139 cases. Nodal involvement detection, reintervention rate, time between surgery and adjuvant therapy were assessed. A cost analysis of OSNA vs. standard histopathology was performed. Results: With OSNA the re-intervention rate significantly decreased (10.79% vs. 0%, p = 0.0003), and adjuvant therapy started earlier (38.5 days vs. 23.8 days, p < 0.0001). Total cost per patient was 5,990.8\u20ac for histopathology vs. 4,308\u20ac with OSNA (p < 0.0001) if positive SLN. In case of negative SLN costs were similar (2,419.6\u20ac vs. 2,425.2\u20ac, p = 0.947). Conclusions: OSNA reduces re-interventions, allows to start earlier adjuvant therapy and is more cost-effective than histopathology

Individualized Prediction of Drug Resistance in People with Post-Stroke Epilepsy: A Retrospective Study

Background: The study aimed to develop a model and build a nomogram to predict the probability of drug resistance in people with post-stroke epilepsy (PSE). Methods: Subjects with epilepsy secondary to ischemic stroke or spontaneous intracerebral hemorrhage were included. The study outcome was the occurrence of drug-resistant epilepsy defined according to International League Against Epilepsy criteria. Results: One hundred and sixty-four subjects with PSE were included and 32 (19.5%) were found to be drug-resistant. Five variables were identified as independent predictors of drug resistance and were included in the nomogram: age at stroke onset (odds ratio (OR): 0.941, 95% confidence interval (CI) 0.907–0.977), intracerebral hemorrhage (OR: 6.292, 95% CI 1.957–20.233), severe stroke (OR: 4.727, 95% CI 1.573–14.203), latency of PSE (&gt;12 months, reference; 7–12 months, OR: 4.509, 95% CI 1.335–15.228; 0–6 months, OR: 99.099, 95% CI 14.873–660.272), and status epilepticus at epilepsy onset (OR: 14.127, 95% CI 2.540–78.564). The area under the receiver operating characteristic curve of the nomogram was 0.893 (95% CI: 0.832–0.956). Conclusions: Great variability exists in the risk of drug resistance in people with PSE. A nomogram based on a set of readily available clinical variables may represent a practical tool for an individualized prediction of drug-resistant PSE