Metodi computazionali per la descrizione dei cristalli molecolari: strategie di utilizzo e sistemi modello

This present thesis work describes a first theoretical investigation on the molecular crystals of indigo and some alkyl derivatives 2,3-thieno(bis)imide (Cn-NT4N, with n = 1, 4, 5, 6 and 8) performed for prepare the ground for more in-depth studies on these systems and to test numerous methods of calculation. The first molecule is very rigid and have polymorphs that differ by packing at solid state while the Cn-NT4N family has different conformations that crystallize with different packings (conformational polymorphs). We used classical methods based on empirical potential modelsq, and quantum ab-initio methods, semi-empirical and based on the theory of functional densities. The various methods have been tested calculating the crystallographic structures and Raman spectra of the various polymorphs, also in order to support the interpretation of experimental results. The combinations of methods chosen in each case was carefully weighed on the features of the system under examination, on the purpose of the calculation, and on its cost. As we have heard in a conference: "a different horse for each race"

Bulk and Surface-Mediated Polymorphs of Bio-Inspired Dyes Organic Semiconductors: The Role of Lattice Phonons in their Investigation

AbstractRaman spectroscopy of organic molecular materials in the low‐wavenumber region gives access to lattice vibrational modes and to the wealth of information on solid state properties that these can provide. In the field of organic electronics a useful application concerns the discrimination of the crystalline forms i. e. polymorphism of the semiconductor. The capability of characterizing and identifying the polymorphs of a compound is in fact the prerequisite for an exhaustive study of the charge transport characteristics which arise from the relationship between molecular, electronic, and crystal structures. Thus, the need is felt of a non‐invasive, non‐destructive tool such as Raman, which probes the crystal phase by detecting the lattice modes which are sensitive even to subtle variations of the packing. Here we review the contribution of the technique to the study of organic pigments displaying promising semiconducting properties and characterized by polymorphism both in their bulk and thin film phases

Near-field propagation of tsunamis from megathrust earthquakes

We investigate controls on tsunami generation and propagation in the near-field of great megathrust earthquakes using a series of numerical simulations of subduction and tsunamigenesis on the Sumatran forearc. The Sunda megathrust here is advanced in its seismic cycle and may be ready for another great earthquake. We calculate the seafloor displacements and tsunami wave heights for about 100 complex earthquake ruptures whose synthesis was informed by reference to geodetic and stress accumulation studies. Remarkably, results show that, for any near-field location: (1) the timing of tsunami inundation is independent of slip-distribution on the earthquake or even of its magnitude, and (2) the maximum wave height is directly proportional to the vertical coseismic displacement experienced at that location. Both observations are explained by the dominance of long wavelength crustal flexure in near-field tsunamigenesis. The results show, for the first time, that a single estimate of vertical coseismic displacement might provide a reliable short-term forecast of the maximum height of tsunami waves

LA LINGUA ITALIANA COME HERITAGE LANGUAGE NELLA COMUNITÀ ITALO-LEVANTINA DI ISTANBUL: UNO STUDIO SUL SOGGETTO POSTVERBALE

Lo studio riporta i risultati di un esperimento riguardante la produzione e la preferenza di soggetti postverbali in italiano da parte di 8 Heritage Speakers adulti dominanti in turco. I partecipanti appartengono all’antica comunità italo-levantina di Istanbul, che da sempre mantiene un repertorio plurilingue comprendente italiano, francese, greco e turco. Secondo l’Interface Hypothesis strutture di interfaccia tra sintassi e discorso risultano particolarmente vulnerabili nelle situazioni di plurilinguismo – compresa l’acquisizione delle Heritage Languages – a causa dell’influenza cross-linguistica della lingua dominante e dei costi cognitivi del plurilinguismo. L’impatto di questi fattori e del ruolo del turco come lingua di istruzione elementare e media è stato valutato confrontando i risultati del gruppo sperimentale e di un gruppo di controllo di 10 nativi monolingui adulti in un test di combinazione di parole e uno di preferenza. I dati appaiono in linea con precedenti studi sulla stessa struttura in diverse situazioni di bilinguismo. Nella produzione di strutture VS gli Heritage Speakers si mostrano significativamente meno accurati rispetto alla controparte monolingue, mentre nella preferenza non emergono differenze significative. La discrepanza si riconduce alla differenza di carico cognitivo impiegato nei due tasks e rappresenta una conferma del ruolo dei fattori cognitivi nelle differenze di comportamento linguistico tra monolingui e plurilingui. Differenze interne al gruppo sperimentale emergono nella produzione secondo una scala di accuratezza che va dal sottogruppo di informanti che non hanno frequentato scuole turche a coloro che le hanno frequentate per otto anni consecutivi (6-14 anni). Il dato conferma il ruolo dell’educazione formale e delle scelte di vita del parlante nel favorire l’acquisizione della heritage language, e spinge ad una riflessione sull’importanza della scolarizzazione per la salvaguardia delle lingue minoritarie.   The Italian language as heritage language in the Italian-Levantine community of Istanbul: a study on the postverbal subject The study reports the results of an experiment targeting the production and interpretation of postverbal subjects in Italian by multilingual Heritage Speakers of Italian whose dominant language is Turkish. All participants belong to the ancient Italian Levantine community of Istanbul, whose members have always maintained a multilingual linguistic repertoire that includes Italian, French and Greek, as well as Turkish. According to the Interface Hypothesis, syntax-discourse interfaces prove to be problematic in different bilingual situations – including the acquisition of Heritage Languages – due to both cross-linguistic influences and cognitive factors related to bilingualism itself. The role of these factors and that of Turkish as the language of primary and secondary education were assessed while comparing the results of the experimental group and a control group of 10 Italian, monolingual natives in a word combination task and a preference task. Data are consistent with previous studies on the same structure in different bilingual situations. When producing VS structures, the Heritage Speakers were found to be significantly less accurate compared to their monolingual counterparts, while with regard to preference there were no significant differences. The discrepancy is explained by the diverse cognitive burdens involved in the two linguistic tasks, thus confirming the role of cognitive factors in differentiating linguistic behaviors between monolinguals and bilinguals. Differences within the experimental group arose in production according to an accuracy pattern that proceeded from the subgroup of informants who had not gone to Turkish schools to those who attended them for eight consecutive years (between the ages of 6-14). Data confirmed the role of formal education and speakers’ life choices in favoring the acquisition of HLs, thus offering food for thought about the importance of schooling in the preservation of minority languages

Clinical significance of ROS1 5' deletions detected by FISH and response to crizotinib

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Inter and intra-population variability of the migratory behaviour of a short-distance partial migrant, the Eurasian Stone-curlew Burhinus oedicnemus (Charadriiformes, Burhinidae)

Migratory behaviour in birds shows a remarkable variability at species, population and individual levels. Short-distance migrants often adopt a partial migratory strategy and tend to have a flexible migration schedule that allows a more effective response to extreme environmental variations. Weather seasonality and environmental heterogeneity have been reported as significant factors in the diversification of migratory behaviour for Mediterranean migrants, but relatively few studies investigated the migration patterns of non-passerine birds migrating within the Mediterranean basin. In this study, we investigated the migratory strategy of 40 Eurasian Stone-curlews Burhinus oedicnemus tagged with geolocators and GPS-GSM tags and belonging to continental and Mediterranean populations of the Italian peninsula. The proportion of migrants was higher in continental populations, but we observed a significant variability also within Mediterranean populations. All birds spent the winter within the Mediterranean basin. Continental Stone-curlews departed earlier in spring and later in autumn and covered longer distances than those from Mediterranean areas. The speed of migration did not change between seasons for continental birds, while Mediterranean individuals migrated faster in spring. The likelihood of departure for autumn migration of GPS-tagged birds increased when temperatures were near or below 0 °C suggesting that Stone-curlews tend to delay departure until weather conditions worsen abruptly. As a consequence of global warming in the Mediterranean, the frequency of migratory birds in the considered populations might decrease in the near future. This could affect the distribution of species throughout the year and should be taken into account when targeting conservation measures

Wide spetcrum mutational analysis of metastatic renal cell cancer : a retrospective next generation sequencing approach

Renal cell cancer (RCC) is characterized by histological and molecular heterogeneity that may account for variable response to targeted therapies. We evaluated retrospectively with a next generation sequencing (NGS) approach using a pre-designed cancer panel the mutation burden of 32 lesions from 22 metastatic RCC patients treated with at least one tyrosine kinase or mTOR inhibitor. We identified mutations in the VHL, PTEN, JAK3, MET, ERBB4, APC, CDKN2A, FGFR3, EGFR, RB1, TP53 genes. Somatic alterations were correlated with response to therapy. Most mutations hit VHL1 (31,8%) followed by PTEN (13,6%), JAK3, FGFR and TP53 (9% each). Eight (36%) patients were wild-type at least for the genes included in the panel. A genotype concordance between primary RCC and its secondary lesion was found in 3/6 cases. Patients were treated with Sorafenib, Sunitinib and Temsirolimus with partial responses in 4 (18,2%) and disease stabilization in 7 (31,8%). Among the 4 partial responders, 1 (25%) was wild-type and 3 (75%) harbored different VHL1 variants. Among the 7 patients with disease stabilization 2 (29%) were wild-type, 2 (29%) PTEN mutated, and single patients (14% each) displayed mutations in VHL1, JAK3 and APC/CDKN2A. Among the 11 non-responders 7 (64%) were wild-type, 2 (18%) were p53 mutated and 2 (18%) VHL1 mutated. No significant associations were found among RCC histotype, mutation variants and response to therapies. In the absence of predictive biomarkers for metastatic RCC treatment, a NGS approach may address single patients to basket clinical trials according to actionable molecular specific alterations.Peer reviewe

ADK-VR2, a cell line derived from a treatment-naïve patient with SDC4-ROS1 fusion-positive primarily crizotinib-resistant NSCLC: a novel preclinical model for new drug development of ROS1- rearranged NSCLC

(NSCLCs). Several tyrosine kinase inhibitors (TKIs) have shown high efficacy in patients whose tumors harbour a ROS1 fusion. However, the limited availability of preclinical models of ROS1-positive NSCLC hinders the discovery of new drugs and the understanding of the mechanisms underlying drug resistance and strategies to overcome it. Methods: The ADK-VR2 cell line was derived from the pleural effusion of a treatment-naïve NSCLC patient bearing SDC4-ROS1 gene fusion. The sensitivity of ADK-VR2 and its crizotinib-resistant clone ADK-VR2 AG143 (selected in 3D culture in the presence of crizotinib) to different TKIs was tested in vitro, in both 2D and 3D conditions. Tumorigenic and metastatic ability was assessed in highly immunodeficient mice. In addition, crizotinib efficacy on ADK-VR2 was evaluated in vivo. Results: 2D-growth of ADK-VR2 cells was partially inhibited by crizotinib. On the contrary, the treatment with other TKIs, such as lorlatinib, entrectinib and DS-6051b, did not result in cell growth inhibition. TKIs showed dramatically different efficacy on ADK-VR2 cells, depending on the cell culture conditions. In 3D culture, ADK-VR2 growth was indeed almost totally inhibited by lorlatinib and DS-6051b. The clone ADK VR2 AG143 showed higher resistance to crizotinib treatment in vitro, compared to its parental cell line, in both 2D and 3D cultures. Similarly to ADK-VR2, ADK-VR2 AG143 growth was strongly inhibited by lorlatinib in 3D conditions. Nevertheless, ADK-VR2 AG143 sphere formation was less affected by TKIs treatment, compared to the parental cell line. In vivo experiments highlighted the high tumorigenic and metastatic ability of ADK-VR2 cell line, which, once injected in immunodeficient mice, gave rise to both spontaneous and experimental lung metastases while the crizotinib-resistant clone ADK-VR2 AG143 showed a slower growth in vivo. In addition, ADK-VR2 tumor growth was significantly reduced but not eradicated by crizotinib treatment. Conclusions: The ADK-VR2 cell line is a promising NSCLC preclinical model for the stud

Phase II study of liposomal doxorubicin, docetaxel and trastuzumab in combination with metformin as neoadjuvant therapy for HER2-positive breast cancer

Background:The aim of this study was to improve activity over single human epidermal growth factor receptor 2 (HER2)-blockade sequential neaodjuvant regimens for HER2-positive breast cancer, by exploiting the concomitant administration of trastuzumab, taxane and anthracycline, while restraining cardiac toxicity with use of liposomal doxorubicin, and by adding metformin, based on preliminary evidence of antitumor activity.Patients and methods:This multi-center, single-arm, two-stage phase II trial, assessed the safety and the activity of a new treatment regimen for HER2-positive, early or locally advanced breast cancer. Patients received six 21-day cycles of non-pegylated liposomal doxorubicin, 50 mg/m(2) intravenously (i.v.) on day 1, docetaxel, 30 mg/m(2) i.v. on days 2 and 9, trastuzumab, 2 mg/kg/week i.v. on days 2, 9, and 16 (with 4 mg/kg loading dose), in association with metformin 1000 mg orally twice daily. The primary endpoint was the rate of pathological complete response (pCR) in the breast and axilla (ypT0/is ypN0). A subgroup of patients performed a 3-deoxy-3-18F-fluorothymidine positron emission tomography (FLT-PET) at baseline and after one cycle.Results:Among 47 evaluable patients, there were 18 pCR [38.3%, 95% confidence interval (CI) 24.5-53.6%]. A negative estrogen-receptor status, high Ki67, and histological grade 3 were related with pCR, although only grade reached statistical significance. FLT-PET maximum standardized uptake value after one cycle was inversely related to pCR in the breast (odds ratio 0.29, 95% CI 0.06-1.30, p = 0.11). Toxicity included grade 3-4 neutropenia in 70% and febrile neutropenia in 4% of patients, grade 1-2 nausea/vomiting in 60%/38%, and grade 3 in 4%/2%, respectively, grade 1-2 diarrhea in 72%, and grade 3 in 6%. There were two cases of reversible grade 2 left-ventricular ejection-fraction decrease, and one case of sharp troponin-T increase.Conclusions:The concomitant administration of trastuzumab, liposomal doxorubicin, docetaxel, and metformin is safe and shows good activity, but does not appear to improve activity over conventional sequential regimens

UV and Hα\alpha HST observations of 6 GASP jellyfish galaxies

Star-forming, H$\alpha$-emitting clumps are found embedded in the gaseous tails of galaxies undergoing intense ram-pressure stripping in galaxy clusters, so-called jellyfish galaxies. These clumps offer a unique opportunity to study star formation under extreme conditions, in the absence of an underlying disk and embedded within the hot intracluster medium. Yet, a comprehensive, high spatial resolution study of these systems is missing. We obtained UVIS/HST data to observe the first statistical sample of clumps in the tails and disks of six jellyfish galaxies from the GASP survey; we used a combination of broad-band filters and a narrow-band H{\alpha} filter. HST observations are needed to study the sizes, stellar masses and ages of the clumps and their clustering hierarchy. These observations will be used to study the clump scaling relations, the universality of the star formation process and verify whether a disk is irrelevant, as hinted by jellyfish galaxy results. This paper presents the observations, data reduction strategy, and some general results based on the preliminary data analysis: the UVIS high spatial resolution gives an unprecedented sharp view of the complex structure of the inner regions of the galaxies and of the substructures in the galaxy disks; we found clear signatures of stripping in regions very close in projection to the galactic disk; the star-forming regions in the stripped tails are extremely bright and compact while we did not detect a significant number of star-forming clumps outside those detected by MUSE. The paper finally presents the development plan for the project.Comment: 17 pages, 7 figures. Accepted for publication in Ap