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

Ruthenium-Catalyzed Decarboxylative Rearrangement of 4-Alkenyl-isoxazol-5-ones to Pyrrole Derivatives

Easily accessible isoxazol-5(4H)-ones are useful precursors of heterocycles. In this context, we report the ruthenium-catalyzed transformation of 4-alkenyl-substituted isoxazol-5-ones to afford 1H-pyrrole derivatives. The operative conditions were proven to be effective also on cyclohexane-fused isoxazolones giving 4,5,6,7-tetrahydroindoles. The reactions, which allow for access to tri-and tetra-substituted pyrroles in moderate to high yields, occur through decarboxylative ring-opening/ring-closure involving C-H functionalization of the alkenyl moiety

Acute stroke-like deficits associated with nonketotic hyperglycemic hyperosmolar state: an illustrative case and systematic review of literature

INTRODUCTION: Nonketotic hyperglycemic hyperosmolar state (NKHHS) is associated with a wide spectrum of neurological syndromes including acute stroke-like deficits. Clinical features and etiology have not been established yet. METHODS: Here we provide a case illustration and systematic review on non-epileptic acute neurological deficits in NKHSS. The systematic literature search followed PRISMA guidelines and a predefined protocol, including cases of NKHSS with acute stroke-like presentation. RESULTS: The database search yielded 18 cases. Hemianopia was the most common clinical presentation (73%), followed by partial or total anterior circulation syndrome (26%). Patients with symptoms of acute anterior circulation infarct were significantly older (69.5 ± 5.1 vs. 52.2 ± 13.9 years; p = 0.03) and showed higher mean glucose levels at the admission vs. those with hemianopia (674.8 ± 197.2 vs. 529.4 ± 190.8 mg/dL; p = 0.16). Brain MRI was performed in 89% of patients, resulting abnormal in 71% of them, especially hemianopic (91%). Subcortical hypointensities in T2-FLAIR MR sequences were present in all the analyzed cases. Cortical DWI hyperintensities were also common (64%). EEG showed diffuse or focal slow wave activity in 68% of patients, especially with visual hallucinations (85%). Neurological symptoms completely resolved in 78% of patients within 6 (IQR 3-10) days, following aggressive treatment and glucose normalization. CONCLUSIONS: Our results suggest neuronal dysfunction on a metabolic basis as the leading cause of acute neurological deficits in NKHHS. Despite the generally favorable prognosis, prompt identification and aggressive treatment are crucial to avoid irreversible damage. Larger cohort studies are needed to confirm our findings

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

n/

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

A Self-Powered Wireless Water Quality Sensing Network Enabling Smart Monitoring of Biological and Chemical Stability in Supply Systems

A smart, safe, and efficient management of water is fundamental for both developed and developing countries. Several wireless sensor networks have been proposed for real-time monitoring of drinking water quantity and quality, both in the environment and in pipelines. However, surface fouling significantly affects the long-term reliability of pipes and sensors installed in-line. To address this relevant issue, we presented a multi-parameter sensing node embedding a miniaturized slime monitor able to estimate the micrometric thickness and type of slime. The measurement of thin deposits in pipes is descriptive of water biological and chemical stability and enables early warning functions, predictive maintenance, and more efficient management processes. After the description of the sensing node, the related electronics, and the data processing strategies, we presented the results of a two-month validation in the field of a three-node pilot network. Furthermore, self-powering by means of direct energy harvesting from the water flowing through the sensing node was also demonstrated. The robustness and low cost of this solution enable its upscaling to larger monitoring networks, paving the way to water monitoring with unprecedented spatio-temporal resolution. Document type: Articl

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

Quality of care indicators for head and neck cancers : the experience of the European project RARECAREnet

Background: Monitoring and improving quality of cancer care has become pivotal today. This is especially relevant for head and neck cancers since the disease is complex, it needs multi therapy, patients tend to be older, they tend to have comorbidities and limited social support. However, information on quality of care for head and neck cancers is scarce. In the context of the project "Information Network on Rare Cancers" we aimed to identify indicators of quality of care specific for the head and neck cancers management and to measure the quality of care for head and neck cancers in different EU Member States. Methods: We defined indicators of quality of care for head and neck cancers based on a multidisciplinary and expert-based consensus process at a European level. To test the proposed indicators, we performed an observational population-based retrospective study in four countries (Ireland, Italy, Netherlands, and Slovenia) in the years 2009-2011. Results: The main quality indicators identified are: availability of formalized multidisciplinary team, participation in clinical and translational research; timeliness of care, high quality of surgery and radiotherapy, and of pathological reporting. For head and neck cancers, the quality of care did not reach the optimal standards in most of the countries analyzed. A high proportion of patients was diagnosed at an advanced disease stage, showed delays in starting treatment (especially for radiotherapy), and there was only a very limited use of multi therapy. Conclusions: According to the achieved consensus, indicators of quality of care for head and neck cancers have to cover the patient journey (i.e., diagnosis and treatment). Our results, showed suboptimal quality of care across countries and call for solutions for ensuring good quality of care for head and neck cancer patients in all EU countries. One possible option might be to refer head and neck cancer patients to specialized centers or to networks including specialized centers

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

Diversity of vaginal microbiome and metabolome during genital infections

We characterized the vaginal ecosystem during common infections of the female genital tract, as vulvovaginal candidiasis (VVC, n\u2009=\u200918) and Chlamydia trachomatis infection (CT, n\u2009=\u200920), recruiting healthy (HC, n\u2009=\u200921) and bacterial vaginosis-affected (BV, n\u2009=\u200920) women as references of eubiosis and dysbiosis. The profiles of the vaginal microbiome and metabolome were studied in 79 reproductive-aged women, by means of next generation sequencing and proton based-nuclear magnetic resonance spectroscopy. Lactobacillus genus was profoundly depleted in all the genital infections herein considered, and species-level analysis revealed that healthy vaginal microbiome was dominated by L. crispatus. In the shift from HC to CT, VVC, and BV, L. crispatus was progressively replaced by L. iners. CT infection and VVC, as well as BV condition, were mainly characterised by anaerobe genera, e.g. Gardnerella, Prevotella, Megasphaera, Roseburia and Atopobium. The changes in the bacterial communities occurring during the genital infections resulted in significant alterations in the vaginal metabolites composition, being the decrease of lactate a common marker of all the pathological conditions. In conclusion, according to the taxonomic and metabolomics analysis, we found that each of the four conditions is characterized by a peculiar vaginal microbiome/metabolome fingerprint