Supercritical Antisolvent Precipitation of Quercetin Systems: Preliminary Experiments

Flavonoids have attracted a lot of attention due to their antioxidant, antitumor and antibacterial activities. Quercetin (3,5,7,3,4-pentahydroxyflavone) is a polyphenolic flavonoid that shows several biological effects including a strong inhibitory effect on the growth of several human and animal cancer cell lines and enhances the antiproliferative effect of cisplatin both in-vitro and in-vivo. In spite of a variety of its biological effects. Quercetin is very poorly soluble in water, which has limited its absorption upon oral administration. As known, the solubility of drug is often due to the increase of the surface/volume ratio which implies the increase of the number of surface atoms (or molecules) with respect to the number of bulk atoms (or molecules). With this aim, we investigated the use of supercritical antisolvent (SAS) technique for Quercetin microparticles generation finding the best operative conditions through the Peng Robinson’s Equation of State. The obtained simulation behaviors were confirmed by experimental precipitation: the physicochemical characterizations of the samples were also performe

The WNK-regulated SPAK/OSR1 kinases directly phosphorylate and inhibit the K+-Cl- co-transporters

This is the final version of the article. Available from Portland Press via the DOI in this record.There is another ORE record for this publication: http://hdl.handle.net/10871/32310Precise homoeostasis of the intracellular concentration of Cl- is achieved via the co-ordinated activities of the Cl- influx and efflux. We demonstrate that the WNK (WNK lysine-deficient protein kinase)-activated SPAK (SPS1-related proline/alanine-rich kinase)/OSR1 (oxidative stress-responsive kinase 1) known to directly phosphorylate and stimulate the N[K]CCs (Na+-K+ ion co-transporters), also promote inhibition of the KCCs (K+-Cl- co-transporters) by directly phosphorylating a recently described C-terminal threonine residue conserved in all KCC isoforms [Site-2 (Thr1048)]. First, we demonstrate that SPAK and OSR1, in the presence of the MO25 regulatory subunit, robustly phosphorylates all KCC isoforms at Site-2 in vitro. Secondly, STOCK1S-50699, a WNK pathway inhibitor, suppresses SPAK/OSR1 activation and KCC3A Site-2 phosphorylation with similar efficiency. Thirdly, in ES (embryonic stem) cells lacking SPAK/OSR1 activity, endogenous phosphorylation of KCC isoforms at Site-2 is abolished and these cells display elevated basal activity of 86Rb+ uptake that was not markedly stimulated further by hypotonic high K+ conditions, consistent with KCC3A activation. Fourthly, a tight correlation exists between SPAK/OSR1 activity and the magnitude of KCC3A Site-2 phosphorylation. Lastly, a Site-2 alanine KCC3A mutant preventing SPAK/OSR1 phosphorylation exhibits increased activity. We also observe that KCCs are directly phosphorylated by SPAK/OSR1, at a novel Site-3 (Thr5 in KCC1/KCC3 and Thr6 in KCC2/KCC4), and a previously recognized KCC3-specific residue, Site-4 (Ser96). These data demonstrate that the WNK-regulated SPAK/OSR1 kinases directly phosphorylate the N[K]CCs and KCCs, promoting their stimulation and inhibition respectively. Given these reciprocal actions with anticipated net effects of increasing Cl- influx, we propose that the targeting of WNK-SPAK/OSR1 with kinase inhibitors might be a novel potent strategy to enhance cellular Cl- extrusion, with potential implications for the therapeutic modulation of epithelial and neuronal ion transport in human disease states.This work was supported by the Medical Research Council and the Wellcome Trust [grant number 091415] as well as the pharmaceutical companies supporting the Division of Signal Transduction Therapy Unit (AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck KgaA, Janssen Pharmaceutica and Pfizer). K.T.K. is supported by the Manton Center for Orphan Diseases at Children's Hospital Boston at Harvard Medical School, and the Harvard/MIT Joint Research Grants Program in Basic Neuroscience

v-P 2 O 5 micro-clustering in P-doped silica studied by a first-principles Raman investigation

Synthetic vitreous silica is currently the preferred material for the production of optical fibres because of the several excellent properties of this glass, e.g. high transmission in the visible and IR domains, high mechanical strength, chemical durability, and ease of doping with various materials. For instance, fiber lasers and amplifiers exploit the light amplification properties provided by rare-earth ions employed as dopants in the core of silica-based optical fibers. The structure and composition of the nearest neighbor shell surrounding rare-earth ions in silica-based optical fibers and amplifiers have been intensively debated in the last decade. To reduce aggregation effects between rare-earth ions, co-dopants such as phosphorus and aluminium are added as structural modifiers; phosphorus-doping, in particular, has proved to be very efficient in dissolving rare-earth ions. In this work, we provide further insights concerning the embedding of P atoms into the silica network, which may be relevant for explaining the ease of formation of a phosphorus pentoxide nearest-neighbor shell around a rare-earth dopant. In particular, by means of first-principles calculations, we discuss alternative models for an irradiation (UV, x\u2013, \u3b3-rays) induced paramagnetic center, i.e. the so called room-temperature phosphorus-oxygen-hole center, and its precursors. We report that the most likely precursor of a room-temperature phosphorus-oxygen-hole center comprises of a micro-cluster of a few (at least two) neighboring phosphate tetrahedra, and correspondingly that the occurrence of isolated [(O-) 2 P(=O) 2 ] 12 units is unlikely even at low P-doping concentrations. In fact, this work predicts that the symmetric stretching of P=O bonds in isolated [(O-) 2 P(=O) 2 ] 12 units appears as a Raman band at a frequency of ~1110 cm 121 , and only by including at least another corner-sharing phosphate tetrahedron, it is shown to shift to higher frequencies (up to ~40 cm 121 ) due to the shortening of P=O bonds, thereby leading to an improved agreement with the observed Raman band located at ~1145 cm 121

In-bore MRI targeted biopsy

Clinical suspicion of Prostate Cancer (PCa) is largely based on increased prostate specific antigen (PSA) level and/or abnormal digital rectal examination (DRE) and/or positive imaging and, up today, biopsy is mandatory to confirm the diagnosis. The old model consisted of Standard Biopsy (SBx), that is random sampling of the prostate gland under ultrasound guidance (TRUS), in subjects with clinical suspicion of PCa. This involves the risk of not diagnosing a high percentage of tumors (up to 30%) and of an incorrect risk stratification. Multiparametric Magnetic Resonance Imaging (mpMRI) has transformed the diagnostic pathway of PCa, not only as an imaging method for detecting suspicious lesions, but also as an intraprocedural guidance for Target Biopsy (MRI-TBx), thus bridging the diagnostic gap. Several single and multicenter randomized trials, such as PROMIS, MRI first, PRECISION and that reported by Van der Leest et al. have confirmed the superiority of the "MRI pathway", consisting of mpMRI and MRI-TBx of suspicious lesions, over the "standard pathway" of SBx in all patients with elevated PSA and/or positive DRE. MRI-TBx appears to be advantageous in reducing the overall number of biopsies performed, as well as in reducing the diagnosis of clinically insignificant disease while maintaining or improving the diagnosis of clinically significant PCa (cs-PCa). Moreover, it shows a reduction in the diagnosis of ins-PCa, and therefore, of overdiagnosis, when using MRI-TBx without sacrificing performance in the diagnosis of cs-PCa

Contrast-enhanced ultrasound sonography optimises the assessment of lymph nodes in oncology

Ultrasound sonography (US) plays an important role in the assessment of lymph nodes in oncology. However, ultrasound findings are often equivocal in not allowing the differentiation of reactive from metastatic lymph nodes. Here, we present the successful use of contrast-enhanced US in the assessment of a metastatic lymph node, improving the performance of conventional US and optimising the US-guided percutaneous biopsy

A Toolchain Architecture for Condition Monitoring Using the Eclipse Arrowhead Framework

Condition Monitoring is one of the most critical applications of the Internet of Things (IoT) within the context of Industry 4.0. Current deployments typically present interoperability and management issues, requiring human intervention along the engineering process of the systems; in addition, the fragmentation of the IoT landscape, and the adoption of poor architectural solutions often make it difficult to integrate third-party devices in a seamless way. In this paper, we tackle these issues by proposing a tool-driven architecture that supports heterogeneous sensor management through well-established interoperability solutions for the IoT domain, i.e. the Eclipse Arrowhead framework and the recent Web of Things (WoT) standard released by the W3C working group. We deploy the architecture in a real Structural Health Monitoring (SHM) scenario, which validates each developed tool and demonstrates the increased automation derived from their combined usage

Synergistic Effects of Hypofibrinolysis and Genetic and Acquired Risk Factors on the Risk of a First Venous Thrombosis

Frits Rosendaal and colleagues show that the combination of hypofibrinolysis with oral contraceptive use, immobilization, or factor V Leiden results in a risk of venous thrombosis that exceeds the sum of the individual risks