HDAC inhibition is associated to valproic acid induction of early megakaryocytic markers

Valproic acid (VPA), a histone deacetylase inhibitor, causes differentiation in different cell lines and in a cell-specific manner; yet, its effect on megakaryocytic (MK) differentiation has not been studied. We evaluated whether VPA induces MK differentiation in a UT-7 cell line through histone acetylation in the GpIIIa gene region and activation of the ERK pathway. UT-7 cells, derived from megakaryoblastic leukemia, were treated with VPA at various concentrations, and the expression of differentiation markers as well as the gene expression profile was assessed. Flow cytometry, immunoblot analysis, and RT-PCR demonstrated that VPA induced the expression of the early MK markers GpIIIa (CD61) and GpIIb/IIIa (CD41) in a dose-dependent manner. The VPA-treated cells showed hyperacetylation of the histones H3 and H4; in particular, histone acetylation was found to have been associated with CD61 expression, in that the GpIIIa promoter showed H4 hyperacetylation, as demonstrated by the chromatin immunoprecipitation assay. Furthermore, activation of the ERK pathway was involved in VPA-mediated CD61/CD41 expression and in cell adhesion, as demonstrated by using the MEK/ERK inhibitor U0126. In conclusion, the capacity of VPA to commit UT-7 cells to MK differentiation is mediated by its inhibitory action on HDAC and the long-lived activation of ERK1/2

Key role of MEK/ERK pathway in sustaining tumorigenicity and in vitro radioresistance of embryonal rhabdomyosarcoma stem-like cell population

The identification of signaling pathways that affect the cancer stem-like phenotype may provide insights into therapeutic targets for combating embryonal rhabdomyosarcoma. The aim of this study was to investigate the role of the MEK/ERK pathway in controlling the cancer stem-like phenotype using a model of rhabdospheres derived from the embryonal rhabdomyosarcoma cell line (RD)

Early primary tumor response in metastatic RCC patients treated with immune checkpoint inhibitors-based combinations

Background: 25-30% of renal cell carcinoma presents with metastases (mRCC) at diagnosis. The activity of immune checkpoint inhibitor (ICI)-combinations on the primary tumor (PT) is debated. Patients andMethods: mRCC patients (pts) with PT who received first-line nivolumab plus ipilimumab (N/I) or pembrolizumab plus axitinib (P/A) were included. We investigated the early primary tumor response (EPTR) at the first radiological assessment. Results: 73 pts were included. The median early reduction of the PT longest diameter was 12.4% with P/A versus 6.2% with N/I (p = 0.42). We evaluated if the type of EPTR could affect the metastases response. Among pts with PT stable disease (SD), 8.3% had metastatic disease progression (PD) with P/A and 34.8% with N/I. Early PT partial response (PR) was associated with no metastatic PD with both N/I and P/A. The 2 pts with PT PD had also metastatic PD to P/A. Of the 3 PT with PD to N/I, 1 had metastatic SD and 2 PD. In the overall population, of the 94.1% without PT progression (PR+SD), 47.5% had metastatic PR, 35.6% SD, 16.9% PD. Conclusions: ICIs-combinations achieved an early PT PR in about 10-20%, without any complete responses. Only a small percentage of PT had an early PD, mainly associated with metastatic PD. However, among those PT without an early progression, metastatic PR can be achieved in approximately 50% of cases

Structured reporting for fibrosing lung disease: a model shared by radiologist and pulmonologist

Objectives: To apply the Delphi exercise with iterative involvement of radiologists and pulmonologists with the aim of defining a structured reporting template for high-resolution computed tomography (HRCT) of patients with fibrosing lung disease (FLD). Methods: The writing committee selected the HRCT criteria\ue2\u80\u94the Delphi items\ue2\u80\u94for rating from both radiology panelists (RP) and pulmonology panelists (PP). The Delphi items were first rated by RPs as \ue2\u80\u9cessential\ue2\u80\u9d, \ue2\u80\u9coptional\ue2\u80\u9d, or \ue2\u80\u9cnot relevant\ue2\u80\u9d. The items rated \ue2\u80\u9cessential\ue2\u80\u9d by < 80% of the RP were selected for the PP rating. The format of reporting was rated by both RP and PP. Results: A total of 42 RPs and 12 PPs participated to the survey. In both Delphi round 1 and 2, 10/27 (37.7%) items were rated \ue2\u80\u9cessential\ue2\u80\u9d by more than 80% of RP. The remaining 17/27 (63.3%) items were rated by the PP in round 3, with 2/17 items (11.7%) rated \ue2\u80\u9cessential\ue2\u80\u9d by the PP. PP proposed additional items for conclusion domain, which were rated by RPs in the fourth round. Poor consensus was observed for the format of reporting. Conclusions: This study provides a template for structured report of FLD that features essential items as agreed by expert thoracic radiologists and pulmonologists

Traces of trauma – a multivariate pattern analysis of childhood trauma, brain structure and clinical phenotypes

Background: Childhood trauma (CT) is a major yet elusive psychiatric risk factor, whose multidimensional conceptualization and heterogeneous effects on brain morphology might demand advanced mathematical modeling. Therefore, we present an unsupervised machine learning approach to characterize the clinical and neuroanatomical complexity of CT in a larger, transdiagnostic context. Methods: We used a multicenter European cohort of 1076 female and male individuals (discovery: n = 649; replication: n = 427) comprising young, minimally medicated patients with clinical high-risk states for psychosis; patients with recent-onset depression or psychosis; and healthy volunteers. We employed multivariate sparse partial least squares analysis to detect parsimonious associations between combinations of items from the Childhood Trauma Questionnaire and gray matter volume and tested their generalizability via nested cross-validation as well as via external validation. We investigated the associations of these CT signatures with state (functioning, depressivity, quality of life), trait (personality), and sociodemographic levels. Results: We discovered signatures of age-dependent sexual abuse and sex-dependent physical and sexual abuse, as well as emotional trauma, which projected onto gray matter volume patterns in prefronto-cerebellar, limbic, and sensory networks. These signatures were associated with predominantly impaired clinical state- and trait-level phenotypes, while pointing toward an interaction between sexual abuse, age, urbanicity, and education. We validated the clinical profiles for all three CT signatures in the replication sample. Conclusions: Our results suggest distinct multilayered associations between partially age- and sex-dependent patterns of CT, distributed neuroanatomical networks, and clinical profiles. Hence, our study highlights how machine learning approaches can shape future, more fine-grained CT research

Prompting migrants’ experiential processes of deconstructing and authenticating a host community’s literary text through ELF

This chapter introduces an ELF-mediated on-going research project aimed at involving communities of migrants and refugees hosted in Southern Italy who are encouraged to access and ‘authenticate’ (Widdowson 1979) the Italian theatrical culture according to their own linguacultural and experiential backgrounds. Such an appropriation is assumed to occur by having migrants improvising on the plays (Checkhov 1953; Johnstone 1981), translating and re-writing them (Slembrouck 1999) into their own ELF variations, thus creating parallel texts to the original ones, and then embodying them on an actual stage (Guido 1999). This study specifically presents a case study on migrants’ appropriation and embodiment of Luigi Pirandello’s play Six characters in search of an author, where the original characters’ experiences of displacement and identity loss are filtered, reinterpreted and re-contextualized through the subjects’ different schemata, and then rendered into their own ELF variations at the semantic, syntactic, pragmatic and metaphorical levels (Guido 2008). The objective is to make migrants appreciate the original text by re-textualizing it into a new parallel one where their own personal experience of existential displacement and of being uprooted from their own native countries can find an artistic expression

Italian Registry of Congenital Bleeding Disorders

In Italy, the surveillance of people with bleeding disorders is based on the National Registry of Congenital Coagulopathies (NRCC) managed by the Italian National Institute of Health (Istituto Superiore di Sanità). The NRCC collects epidemiological and therapeutic data from the 54 Hemophilia Treatment Centers, members of the Italian Association of Hemophilia Centres (AICE). The number of people identified with bleeding disorders has increased over the years, with the number rising from approx. 7000 in 2000 to over 11,000 in 2015. The NRCC includes 4020 patients with hemophilia A and 859 patients with hemophilia B. The prevalence of the rare type 3 vWD is 0.20/100,000 inhabitants. Less common congenital bleeding disorders include the following deficiencies: Factor I (fibrinogen), Factor II (prothrombin), Factor V, Factor VII, Factor X, Factor XI and Factor XIII, which affect 1953 patients. Hepatitis C Virus (HCV) infection affects 1561 patients, more than 200 of whom have two infections (HCV + HIV). Estimated hemophilia-related drug consumption in 2015 was approx. 550 million IU of FVIII for hemophilia A patients and approx. 70 million IU of FIX for hemophilia B patients. The NRCC, with its bleeding disorder data set, is a tool that can provide answers to fundamental questions in public health, monitoring care provision and drug treatment, as well as facilitating clinical and epidemiological research

Italian National Survey of Blood Donors: External Quality Assessment (EQA) of Syphilis Testing▿

The detection of syphilis among blood donors may reveal high-risk sexual behavior, which can go unreported at the time of donor selection and compromise the safety of the donated blood. In Italy, blood is collected, tested, and distributed by transfusion services (TSs), which also perform outpatient transfusions. Although the TSs must screen for syphilis by law, there are no indications of the specific type of method to be used, generating discrepancies in the results obtained by the different TSs. To determine the proficiency of the TSs in screening for syphilis, we performed an external quality assessment (EQA). The EQA was based on two shipments of serum panels; 133 and 118 of the 326 existing TSs participated in the first and second shipments, respectively. Each panel consisted of both positive and negative serum samples. The results confirmed that the use of a single nontreponemal test (the Venereal Disease Research Laboratory [VDRL] and the rapid plasma reagin [RPR] tests) is the least sensitive means of identifying samples that are positive for syphilis antibodies. We also found that the interpretation of the results of manual techniques, such as the RPR test, the VDRL test, the Treponema pallidum hemagglutination (TPHA) assay, and the T. pallidum particle agglutination (TPPA) assay, can vary greatly among different TSs and operators. Total Ig enzyme immunoassays (EIAs) are the most sensitive. However, the determination of syphilis on the basis of the results of a single test is not sufficient for an accurate screening; and all blood units should thus be assessed by two distinct treponemal tests, that is, a total Ig EIA and the TPHA or the TPPA assay