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Glioblastoma Multiforme (GBM) is the most common of malignant gliomas in adults with an exiguous life expectancy. Standard treatments are not curative and the resistance to both chemotherapy and conventional radiotherapy (RT) plans is the main cause of GBM care failures. Proton therapy (PT) shows a ballistic precision and a higher dose conformity than conventional RT. In this study we investigated the radiosensitive effects of a new targeted compound, SRC inhibitor, named Si306, in combination with PT on the U87 glioblastoma cell line. Clonogenic survival assay, dose modifying factor calculation and linear-quadratic model were performed to evaluate radiosensitizing effects mediated by combination of the Si306 with PT. Gene expression profiling by microarray was also conducted after PT treatments alone or combined, to identify gene signatures as biomarkers of response to treatments. Our results indicate that the Si306 compound exhibits a radiosensitizing action on the U87 cells causing a synergic cytotoxic effect with PT. In addition, microarray data confirm the SRC role as the main Si306 target and highlights new genes modulated by the combined action of Si306 and PT. We suggest, the Si306 as a new candidate to treat GBM in combination with PT, overcoming resistance to conventional treatments.

The present contribution proposes three projects and relative speculative reflections, elaborated by the writers, concerning the important theme of the wooden roof construction, showing the results of the three competitions organized by the Terres de Hetre® consortium, entitled: “L’architecture au service de construction en bois de hetre des vosges”. The three projects, object of the paper (awarded with the third placement during the first edition and with the second placement during the third edition), describe an effort to demonstrate new applications, characteristics, shapes and unexpected unexpressed potentials of this traditional material for a new contemporary design; they are architectures that have the common characteristic of being all a great challenge to the intrinsic limits of the wooden material: in all the outcomes results the research of geometric complexity and the limit of the static-mechanical resistance of the elements is evident. The architectural forms are developed starting from a series of geometric and topological variations on the theme of the wood-frame roof: the first with powerful overhangs on the model of the gull-wing structure, the second on the tree-shape model and the third on the shell-ruled–surface model.

Aim: Inhibition of P53-mdm2 interaction will lead to cancer cell apoptosis. This strategy was achieved by reported spiro-oxindole derivatives. Materials & methods: Spiro(indoline-3,4′-pyrazolo[3,4-b]pyridine)-5′-carbonitrile derivatives (4a–i and 9a, b) were synthesized and screened for their in vitro anticancer activity. The most active compounds were subjected to P53-MDM2 inhibitory activity, apoptotic and molecular docking studies. Results & discussion: Compound 4d exhibited potent and broad spectrum of antiproliferative activity with full panel GI50 (MG-MID) value of 3.97 μM. Compounds 4d and 4i inhibited p53-MDM2 protein–protein interaction with IC50 = 52.1 and 95.2 nM, respectively. Compound 4d inhibits the expression of wild p53 in MCF-7 more than mutant p53 in MDA-MB231 at the molecular level. Molecular docking studies illustrated the possible interaction of the target spiro-oxindoles with the p53 binding site on MDM2.

Mater[i]a inaugura la stagione dei New Fundamentals Research Books, la collana editoriale del gruppo di ricerca omonimo, che raccoglierà la propria produzione scientifica elaborata sia all'interno del dipartimento Dicar del Politecnico di Bari, sia in altre sedi universitarie. Le attività del gruppo di ricerca intendono strutturarsi su tre assi portanti: ricerca, didattica e progetto, contribuendo allo sviluppo delle odierne tematiche sulla progettazione architettonica contemporanea, in continuità evolutiva con il sapere storico, studiando, analizzando e promuovendo il dibattito odierno sull'argomento. In particolare, il presente libro è un contributo libero all'attuale dibattito sulla città di Matera, designata Capitale Europea della Cultura per l'anno 2019, di cui si tracciano alcune strade progettuali potenzialmente percorribili nell'ottica del potenziamento museale e culturale della città, sviluppate dopo un'analisi del contesto urbano e paesaggistico della città e del panorama museale e culturale della Regione.

The paper aims to investigate the experiential learning approach applied to the teaching of architectural design in university courses. The introduction of IT tools in architecture in the last decades, has introduced new questions in how to teach the computer-aided architectural design to students and how to use these tools properly. Among these themes, parametric design tools have become relevant for many researchers and designers around the world. This paper aims to describe how to provide students the critical tools to use the new parametric design softwares consciously, showing also the results of the students’ research projects for the 3rd year Architectural Design Course. As mentioned before, the course is set on learning by doing and experiential learning didactic paradigms. In the first semester, the students were asked to imagine new complex stereotomic vaulted systems using parametric softwares. In the second semester, following the latest developments in sustainable architecture, the students were asked to imagine and fabricate reactive devices in order to design smart building envelopes, through dynamic sunlight filtering. At the end of the year, the students were able to use the skills developed during the whole year, designing a more complex architecture, like an innovative high school.

A series of compounds containing the N-hydroxyoxindole scaffold were synthesized and evaluated for antitumor activity. The compounds showed potent antiproliferative activity against the wild-type p53 IGROV-1 ovarian carcinoma cell line and considerably lower efficacy against the mutant IGROV-1/Pt1 subline that lacks p53 function. The differential response of ovarian carcinoma cells depending on p53 status was also reflected in the varied susceptibility to apoptosis of the treated cell lines. These results support a role for the p53 transcription factor as a determinant of cytotoxicity. The therapeutic potential of the most promising compound of the series was evaluated in the treatment of an IGROV-1 xenograft growing as ascitic tumor in mice. Using intraperitoneal administration, daily treatment with the compound for four weeks produced a significant delay in the onset of ascites.

An innovative lyophilized dry powder formulation consisting of urea-crosslinked hyaluronic acid (HA-CL) and sodium ascorbyl phosphate (SAP) – LYO HA-CL – SAP- was prepared and characterized in vitro for physico-chemical and biological properties. The aim was to understand if LYO HA-CL – SAP could be used as adjuvant treatment for nasal inflammatory diseases. LYO HA-CL – SAP was suitable for nasal delivery and showed to be not toxic on human nasal septum carcinoma-derived cells (RPMI 2650 cells) at the investigated concentrations. It displayed porous, polygonal particles with unimodal, narrow size distribution, mean geometric diameter of 328.3 ± 27.5 µm, that is appropriate for nasal deposition with no respirable fraction and 88.7% of particles with aerodynamic diameter >14.1 µm. Additionally, the formulation showed wound healing ability on RPMI 2650 cells, and reduced interleukin-8 (IL-8) level in primary nasal epithelial cells pre-induced with lipopolysaccharide (LPS). Transport study across RPMI 2650 cells showed that HA-CL could act not only as carrier for SAP and active ingredient itself, but potentially also as mucoadhesive agent. In conclusion, these results suggest that HA-CL and SAP had anti-inflammatory activity and acted in combination to accelerate wound healing. Therefore, LYO HA-CL – SAP could be a potential adjuvant in nasal anti-inflammatory formulations.

Since its first isolation in 1934, hyaluronic acid (HA) has been studied across a variety of research areas. This unbranched glycosaminoglycan consisting of repeating disaccharide units of N-acetyl-D-glucosamine and D-glucuronic acid is almost ubiquitary in humans and in other vertebrates. HA is involved in many key processes -including cell signaling, wound reparation, tissue regeneration, morphogenesis, matrix organization and pathobiology-, and has unique physico-chemical properties -such as biocompatibility, biodegradability, mucoadhesivity, hygroscopicity and viscoelasticity. For these reasons, exogenous HA has been investigated as drug delivery system and treatment in cancer, ophthalmology, arthrology, pneumology, rhinology, urology, aesthetic medicine and cosmetic. To improve and customize its properties and applications, HA can be subjected to chemical modifications: conjugation and crosslinking. The present review gives an overview regarding HA, describing its history, physico-chemical, structural and hydrodynamic properties, and biology –occurrence, biosynthesis (by hyaluronan synthases), degradation (by hyaluronidases and oxidative stress), roles, mechanisms of action and receptors. Furthermore, both conventional and recently emerging methods developed for the industrial production of HA and its chemical derivatization are presented. Finally, the medical, pharmaceutical and cosmetic applications of HA and its derivatives are reviewed, reporting examples of HA-based products which currently are on the market or are undergoing further investigations.

Since its first isolation in 1934, hyaluronic acid (HA) has been studied across a variety of research areas. This unbranched glycosaminoglycan consisting of repeating disaccharide units of N-acetyl-D-glucosamine and D-glucuronic acid is almost ubiquitary in humans and in other vertebrates. HA is involved in many key processes -including cell signaling, wound reparation, tissue regeneration, morphogenesis, matrix organization and pathobiology-, and has unique physico-chemical properties -such as biocompatibility, biodegradability, mucoadhesivity, hygroscopicity and viscoelasticity. For these reasons, exogenous HA has been investigated as drug delivery system and treatment in cancer, ophthalmology, arthrology, pneumology, rhinology, urology, aesthetic medicine and cosmetic. To improve and customize its properties and applications, HA can be subjected to chemical modifications: conjugation and crosslinking. The present review gives an overview regarding HA, describing its history, physico-chemical, structural and hydrodynamic properties, and biology –occurrence, biosynthesis (by hyaluronan synthases), degradation (by hyaluronidases and oxidative stress), roles, mechanisms of action and receptors. Furthermore, both conventional and recently emerging methods developed for the industrial production of HA and its chemical derivatization are presented. Finally, the medical, pharmaceutical and cosmetic applications of HA and its derivatives are reviewed, reporting examples of HA-based products which currently are on the market or are undergoing further investigations.

The limited treatment options against influenza virus along with the growing public health concerns regarding the continuous emergence of drug-resistant viruses make essential the development of new anti-flu agents with novel mechanisms of action. One of the most attractive targets is the interaction between two subunits of the RNA-dependent RNA polymerase, PA and PB1. Herein we report the rational design of hybrid compounds starting from a 3-cyano-4,6-diphenylpyridine scaffold recently identified as disruptor of PA-PB1 interactions. Guided by the previously reported SAR data, a library of amino acid derivatives was synthesized. The biological evaluation led to the identification of new PA-PB1 inhibitors, that do not show appreciable toxicity. Molecular modeling shed further lights on the inhibition mechanism of these compounds.

Semiclassical techniques constitute a promising route to approximate quantum dynamics based on classical trajectories starting from a quantum-mechanically correct distribution. One of their main drawbacks is the so-called zero-point energy (ZPE) leakage, that is artificial redistribution of energy from the modes with high frequency and thus high ZPE to that with low frequency and ZPE due to classical equipartition. Here, we show that an elaborate semiclassical formalism based on the Herman-Kluk propagator is free from the ZPE leakage despite utilizing purely classical propagation. This finding opens the road to correct dynamical simulations of systems with a multitude of degrees of freedom that cannot be treated fully quantum-mechanically due to the exponential increase of the numerical effort., Comment: 6 pages 2 figures

Objective: To assess the impact of electronic health record (EHR) on healthcare quality, we hence carried out a systematic review and meta-analysis of published studies on this topic. Methods: PubMed, Web of Knowledge, Scopus and Cochrane Library databases were searched to identify studies that investigated the association between the EHR implementation and process or outcome indicators. Two reviewers screened identified citations and extracted data according to the PRISMA guidelines. Meta-analysis was performed using the random effects model for each indicator. Heterogeneity was quantified using the Cochran Q test and I2 statistics, and publication bias was assessed using the Egger’s test. Results: Of the 23 398 citations identified, 47 articles were included in the analysis. Meta-analysis showed an association between EHR use and a reduced documentation time with a difference in mean of −22.4% [95% confidence interval (CI) = −38.8 to −6.0%; P < 0.007]. EHR resulted also associated with a higher guideline adherence with a risk ratio (RR) of 1.33 (95% CI = 1.01 to 1.76; P = 0.049) and a lower number of medication errors with an overall RR of 0.46 (95% CI = 0.38 to 0.55; P < 0.001), and adverse drug effects (ADEs) with an overall RR of 0.66 (95% CI = 0.44 to 0.99; P = 0.045). No association with mortality was evident ( P = 0.936). High heterogeneity among the studies was evident. Publication bias was not evident. Conclusions: EHR system, when properly implemented, can improve the quality of healthcare, increasing time efficiency and guideline adherence and reducing medication errors and ADEs. Strategies for EHR implementation should be therefore recommended and promoted.

The paper describes the students’ works, which included posters and physical models, were the partial outcomes of the current 3rd year design studio, led by Prof Giuseppe Fallacara and taught with the support of Maurizio Barberio and Micaela Colella, both Ph.D. students at the Polytechnic of Bari. The text illustrate an experimental teaching/learning approach which Giuseppe tested during the design studio. This approach was inspired by the concepts of ‘Experiential Learning’ and ‘Flipped Classroom’, consisting in a series of “cooperative classes”, where tutors and students interacted and discussed in an absolute spirit of intellectual equality. The goal was to simulate the activity of a large architecture practice, involved in the design of a public building, which generally requires the contribution of a large number of architects and designers. The students were given a brief for a new museum and multipurpose centre in Matera, Italy, which was recently nominated European Capital of Culture 2019. They had to deliver a design proposal, a rapid prototyped model and a short video.

The research aims to investigate the architectural uses of free-form panels made of natural stone, reinforced through the use of carbon fiber (or glass fiber) sheets on the back, in order to build lightweight shells in granite or marble. The combination of these two materials allows reducing the thickness of the stone components up to few millimetres and the achievement of a great structural performance. The project is a collaboration between the authors (from Polytechnic University of Bari) and the Ticino-based company, Generelli SA.

The paper describes the students’ works, which included posters and physical models, were the partial outcomes of the current 3rd year design studio, led by Prof Giuseppe Fallacara and taught with the support of Maurizio Barberio and Micaela Colella, both Ph.D. students at the Polytechnic of Bari. The goal was to simulate the activity of a large architecture practice, involved in the design of a public building, which generally requires the contribution of a large number of architects and designers. The students were given a brief for a new museum and multipurpose centre in Matera, Italy, which was recently nominated European Capital of Culture 2019. They had to deliver a design proposal, a rapid prototyped model and a short video.

La ricerca indaga le possibilità di utilizzo in architettura e design di pannelli in granito, marmo o pietra naturale a dop-pia o singola curvatura, rinforzati attraverso l'utilizzo di strati di fibra di carbonio o fibra di vetro, per la costituzione di gusci lapidei ultraleggeri. La combinazione tra questi due materiali consente la riduzione dello spessore delle com-ponenti lapidee fino a pochi millimetri e il raggiungimento di grandi performance di resistenza statica del nuovo ma-teriale. Il progetto è frutto di una collaborazione tra gli scri-venti (Politecnico di Bari) e l'azienda ticinese di lavorazione del marmo e del granito Generelli SA.

Mater[i]a inaugura la stagione dei New Fundamentals Research Books, la collana editoriale del gruppo di ricerca omonimo, che raccoglierà la propria produzione scientifica elaborata sia all'interno del dipartimento Dicar del Politecnico di Bari, sia in altre sedi universitarie. Le attività del gruppo di ricerca intendono strutturarsi su tre assi portanti: ricerca, didattica e progetto, contribuendo allo sviluppo delle odierne tematiche sulla progettazione architettonica contemporanea, in continuità evolutiva con il sapere storico, studiando, analizzando e promuovendo il dibattito odierno sull'argomento. In particolare, il presente libro è un contributo libero all'attuale dibattito sulla città di Matera, designata Capitale Europea della Cultura per l'anno 2019, di cui si tracciano alcune strade progettuali potenzialmente percorribili nell'ottica del potenziamento museale e culturale della città, sviluppate dopo un'analisi del contesto urbano e paesaggistico della città e del panorama museale e culturale della Regione.

Btk is a tyrosine kinase dysregulated in several B-cell malignancies and autoimmune diseases, and this has given rise to a search for Btk inhibitors. Nevertheless, only one Btk inhibitor, ibrutinib, has been approved to date, although other compounds are currently being evaluated in clinical trials or in preclinal stages. Area covered: This review, after a brief introduction on Btk and its inhibitors already in clinical trials, focusses on pyrrolo[2,3-d]pyrimidine derivatives patented in the last five years as Btk inhibitors. Indeed, the pyrrolo[2,3-d]pyrimidine scaffold, being a deaza-isostere of adenine, the nitrogenous base of ATP, is an actively pursued target for Btk inhibitors. The patent literature since 2012 have been extensively investigated, pointing out the general features of the patented compounds and, when it is possible, their mechanism of action. Expert opinion: The recently patented pyrrolo[2,3-d]pyrimidines, acting as reversible or irreversible inhibitors, showed a very interesting in vitro activity. For this reason, the development of compounds endowed with this scaffold could afford a significant impact in the search for drug candidates for the treatment of immune diseases or B-cell malignancies.

Transcriptomic phenotypes defined for melanoma have been reported to correlate with sensitivity to various drugs. In this study, we aimed to define a minimal signature that could be used to distinguish melanoma sub-types in vitro, and to determine suitable drugs by which these sub-types can be targeted. By using primary melanoma cell lines, as well as commercially available melanoma cell lines, we find that the evaluation of MLANA and INHBA expression is as capable as one based on a combined analysis performed with genes for stemness, EMT and invasion/proliferation, in identifying melanoma subtypes that differ in their sensitivity to molecularly targeted drugs. Using this approach, we find that 75% of melanoma cell lines can be treated with either the MEK inhibitor AZD6244 or the HSP90 inhibitor 17AAG.

Pyrazolo[3,4-d]pyrimidines are potent protein kinase inhibitors with promising antitumor activity but suboptimal aqueous solubility, consequently worth being further optimized. Herein, we present the one-pot two-step procedure for the synthesis of a set of pyrazolo[3,4-d]pyrimidine prodrugs (1a-8a and 9a-e) with higher aqueous solubility and enhanced pharmacokinetic and therapeutic properties. ADME studies demonstrated for the most promising prodrugs a better aqueous solubility, a favorable hydrolysis in human and murine serum, and an increased ability to cross cell membranes with respect to the parental drugs, explaining their better 24 h in vitro cytotoxicity against human glioblastoma U87 cell line. Finally, the 4-4a couple of drug/prodrug was also evaluated in vivo, revealing a profitable pharmacokinetic profile of the prodrug associated with a good efficacy. The application of the prodrug approach demonstrated to be a successful strategy for improving aqueous solubility of the parental drugs, determining a positive impact also in their biological efficacy.