Discovery of Affinity-Based Probes for Btk Occupancy Assays

Bruton's tyrosine kinase (Btk) is an attractive target for the treatment of a wide array of B-cell malignancies and autoimmune diseases. Small-molecule covalent irreversible Btk inhibitors targeting Cys481 have been developed for the treatment of such diseases. In clinical trials, probe molecules are required in occupancy studies to measure the level of engagement of the protein by these covalent irreversible inhibitors. The result of this pharmacodynamic (PD) activity provides guidance for appropriate dosage selection to optimize inhibition of the drug target and correlation of target inhibition with disease treatment efficacy. This information is crucial for successful evaluation of drug candidates in clinical trials. Based on the pyridine carboxamide scaffold of a novel solvent-accessible pocket (SAP) series of covalent irreversible Btk inhibitors, we successfully developed a potent and selective affinity-based biotinylated probe 12 (2-[(4-{4-[5-(1-{5-[(3aS,4S,6aR)-2-oxo-hexahydro-1H-thieno[3,4-d]imidazol-4-yl]pentanamido}-3,6,9,12-tetraoxapentadecan-15-amido)pentanoyl]piperazine-1-carbonyl}phenyl)amino]-6-[1-(prop-2-enoyl)piperidin-4-yl]pyridine-3-carboxamide). Compound 12 has been used in Btk occupancy assays for preclinical studies to determine the therapeutic efficacy of Btk inhibition in two mouse lupus models driven by TLR7 activation and type I interferon.     

Colloidal Photonic Crystals Doped with Gold Nanoparticles: Spectroscopy and Optical Switching Properties

Polystyrene artificial opals with few gold nanoparticles (AuNp) embedded in the interstices (doping) are grown by using the meniscus technique starting from a mixed suspension of microspheres and AuNp. Samples having different sphere diameters and nanoparticle loads have been prepared. Their reflectance spectra clearly show a dramatic bathochromic shift of the photonic stop band (up to 1400 cm^–1) and a reduction of its full width half maximum, due to an increase of the effective refractive index of about 8 % with respect to bare opals, which is accounted for by analytical theoretical models. Reflectance spectra do not show any direct evidence of AuNp absorption even at the higher AuNp doping level. Nanosecond transient absorption measurements on these systems indicate that a variation of transmission (optical switching) of about 150 % is observed for AuNp doped opals upon photoexcitation with 9 ns laser pulses at 532 nm. No switching is instead observed for bare opals.     

An improved code density test for the dynamic characterization offlash A/D converters

An improved code density test for flash A/D converters is proposed, revealing some dynamic phenomena (e.g., missing codes) hidden by the conventional approach. Formulas are reported for obtaining, from code density, effective noise estimates fully consistent with those provided by waveform analysis. Finally, it is shown that the variance of noise estimates obtained by time-domain analysis may be unacceptably large if the observation window is not properly chosen     

Semantic annotation of narrative media objects

This paper addresses the annotation of the narrative features of media objects. Based on a relevant narratological and computational background, we introduce an ontology?Cbased model called Drammar, an annotation schema for the narrative features of media objects based on Drammar and a software tool, Cinematic, for annotating these objects and validating the annotation. Annotated media objects can also be automatically edited into sequences, with the twofold goal of testing the validity of the annotation??through the reconstruction of the baseline sequence??and exploring the possibility of alternative sequences. The software tool encodes both the narrative model and the annotation itself in ontological format, and relies on external ontologies for representing world knowledge and limit the arbitrariness of the annotation. The paper opens the way to the design of a general annotation schema for narrative multimedia with the long?Cterm goal of building large corpora of annotated video material and of bridging the gap between the low?Clevel signal analysis and the high?Clevel semantic representation of the narrative content of the media objects. Finally, the paper illustrates a few projects elaborated with the Drammar annotation and the Cinematic tool, with purposes of artistic research and cross?Cmedia analysis, that provide an empirical validation of the annotation process.     

On arginine-based polyurethane-blends specific to vascular prostheses

Polymer blends based on Tecoflex™ and an experimental aliphatic polyurethane (HMDI-PCL-arginine stands for 4,4 (metylene-biscyclohexyl) isocyanate - poly (ε caprolactone) diol, SPUUR stands for segmented poly(urea)urethanes using amino acid of L-Arginine as chain extender) were obtained by solvent casting, and further studied by fourier transform infrared (FTIR) and Raman spectroscopy, differential scanning calorimetry (DSC), thermogravimetric analysis, and X-ray diffraction (XRD). Their biological performances were assessed in terms of hemocompatibility and Human umbilical vein endothelial cell (HUVEC) cytotoxicity. Tensile properties of dumbbell specimens were compared to longitudinal and circumferential tensile properties of tubular vascular graft. FTIR showed that as the SPUUR content increased in the blend, absorptions at 2860 cm⁻¹ increased, carbonyl absorptions at 1724 cm⁻¹ broaden and the small peak at 2796 cm⁻¹, typical of Tecoflex™ disappeared. Raman spectroscopy showed that the low intensity carbonyl absorption at 1724 cm⁻¹ also increased with SPUUR content. DSC allowed detection of PCL soft segment melting (T_m = 50°C) in agreement with X-ray reflections at 21.3° and 23.6°, assigned to SPUUR. However, no improvements in thermal stability were detected by TGA by blending. The addition of SPUUR to Tecoflex™ improved hemocompatibility and HUVEC cytotoxicity. The vascular grafts performance showed that 40% SPUUR blends exhibited the highest force in the longitudinal test whereas 50% SPUUR blends showed the highest circumferential force. Pressure burst strength was higher than 1000 mmHg for all blends. Overall, these blends can be used for high caliber vascular grafts.     

Levothyroxine suppressive therapy for solitary thyroid nodule

In order to evaluate the efficacy of a TSH suppressive dose of levothyroxine to reduce the volume of a single thyroid nodule we studied 55 euthyroid patient: 45 (group A) were suppressed with LT4 (mean 1.7 +/- 0.9 micrograms/Kg/day) for 21.3 +/- 5.3 months, and 10 patients (group B) served as controls. All the nodules were "cold" at scintiscanning, solid at ultrasonography and benign by fine-needle aspiration cytology. As responders were assumed the nodules shrinked at the end of treatment of 50% in volume. Thyroid function values (TSH, T4, FT4, T3, FT3, thyroid peroxidase and thyroglobulin antibodies), clinical and ultrasonographic findings were evaluated initially and at the end of the study. A significant nodular volume decrease occurred in 8 treated patients (17.8%) while 37 (82.2%) amongst the group suppressed and all controls showed no change (A vs B = NS). In two untreated patients new nodules were noted; no new nodules were discovered in the treated group (A vs B p < 005). No side effects occurred in any treated patient, even if at the end of treatment a significant T4 and FT4 (p < 0.01) increase was observed. No one onset parameter can predict the response to the therapy. These results suggest that only a small group of patients affected by a single thyroid nodule seems to respond to a TSH suppressive therapy.     

The Role of Extracellular Vesicles in the Progression of Human Neuroblastoma

The long-underestimated role of extracellular vesicles in cancer is now reconsidered worldwide by basic and clinical scientists, who recently highlighted novel and crucial activities of these moieties. Extracellular vesicles are now considered as king transporters of specific cargoes, including molecular components of parent cells, thus mediating a wide variety of cellular activities both in normal and neoplastic tissues. Here, we discuss the multifunctional activities and underlying mechanisms of extracellular vesicles in neuroblastoma, the most frequent common extra-cranial tumor in childhood. The ability of extracellular vesicles to cross-talk with different cells in the tumor microenvironment and to modulate an anti-tumor immune response, tumorigenesis, tumor growth, metastasis and drug resistance will be pinpointed in detail. The results obtained on the role of extracellular vesicles may represent a panel of suggestions potentially useful in practice, due to their involvement in the response to chemotherapy, and, moreover, their ability to predict resistance to standard therapies—all issues of clinical relevance.     

Gauging food and nutritional care quality in hospitals

ABSTRACT: BACKGROUND: Food and nutritional care quality must be assessed and scored, so as to improve health institution efficacy. This study aimed to detect and compare actions related to food and nutritional care quality in public and private hospitals. METHODS: Investigation of the Hospital Food and Nutrition Service (HFNS) of 37 hospitals by means of structured interviews assessing two quality control corpora, namely nutritional care quality (NCQ) and hospital food service quality (FSQ). HFNS was also evaluated with respect to human resources per hospital bed and per produced meal. RESULTS: Comparison between public and private institutions revealed that there was a statistically significant difference between the number of hospital beds per HFNS staff member (p = 0.02) and per dietitian (p < 0.01). The mean compliance with NCQ criteria in public and private institutions was 51.8% and 41.6%, respectively. The percentage of public and private health institutions in conformity with FSQ criteria was 42.4% and 49.1%, respectively. Most of the actions comprising each corpus, NCQ and FSQ, varied considerably between the two types of institution. NCQ was positively influenced by hospital type (general) and presence of a clinical dietitian. FSQ was affected by institution size: large and medium-sized hospitals were significantly better than small ones. CONCLUSIONS: Food and nutritional care in hospital is still incipient, and actions concerning both nutritional care and food service take place on an irregular basis. It is clear that the design of food and nutritional care in hospital indicators is mandatory, and that guidelines for the development of actions as well as qualification and assessment of nutritional care are urgent.     

Labyrinth 3D. Cultural archetypes for exploring media archives

Since the advent of the World Wide Web, online media archives have changed their audience from a restricted number of professionals and amateurs to the general public. This shift is not without consequences: if, on the one side, it represents an important opportunity for archives to engage in a dialogue with a larger audience, on the other side, it advocates novel forms of access that go beyond the highly specialized models underlying traditional access tools. In this paper, we propose to use 3-D graphics for designing novel tools of exploratory search in cultural heritage archives. Our approach has been deployed as an online virtual environment where the user can navigate the meaning relations over the items in the archive. Targeted at cultural heritage, the application, called Labyrinth 3D, relies on the use of cultural archetypes to inform the conceptualization of the archive and the creation of the virtual environment, with the goal of engaging the user in the exploration of the archive through the creation of personal paths.     

Development and Validation of Europium-Sensitized Luminescence (ESL) Method for the Determination of Tetracycline Residues in Milk

The development of a fast and reliable screening method for the determination of tetracycline residues in milk is described and compared to high-performance liquid chromatography. The method is based on europium-sensitized luminescence: The emissive properties of the lanthanide cation are used as a fingerprint of europium (III) complexation with tetracycline. The optimization of the extraction and purification procedures provided a simple and convenient route to prepare stable tetracycline samples that can safely resist freezing cycles. The method is validated for the first time in milk matrix: The results show that accuracy and precision of the method meet complaints with the criteria of the Commission Decision 2002/657/EC. The proposed method has a false compliant rate (β error) lower than 5%.