Anticancer Activity, Reduction Mechanism and G-Quadruplex DNA Binding of a Redox-Activated Platinum(IV)–Salphen Complex

Aiming at reducing the unselective cytotoxicity of Pt(II) chemotherapeutics, a great deal of effort has been concentrated into the design of metal‐containing drugs with different anticancer mechanisms of action. Inert Pt(IV) prodrugs have been proposed to be a valid alternative as they are activated by reduction directly into the cell releasing active Pt(II) species. On the other hand, a promising strategy for designing metallodrugs is to explore new potential biological targets rather than canonical B‐DNA. G‐quadruplex nucleic acid, obtained by self‐assembly of guanine‐rich nucleic acid sequences, has recently been considered an attractive target for anticancer drug design. Therefore, compounds capable of binding and stabilizing this type of DNA structure would be greatly beneficial in anticancer therapy. Here, computational analysis reports the mechanism of action of a recently synthesized Pt(IV)–salphen complex conjugating the inertness of Pt(IV) prodrugs with the ability to bind G‐quadruplexes of the corresponding Pt(II) complex. The reduction mechanism of the Pt(IV) complex with a biological reducing agent was investigated in depth by means of DFT, whereas classical MD simulations were carried out to shed light into the binding mechanism of the released Pt(II) complex. The results show that the Pt(IV) prodrug may be reduced by both inner‐ and outer‐sphere mechanisms, and the active Pt(II) complex, as a function of its protonation state, stabilizes the G‐quadruplex DNA prevalently, either establishing π‐stacking nteractions with the terminal G‐tetrad or through electrostatic interactions along with H‐bonds formation

Clonal heterogeneity in chronic lymphocytic leukemia cells: superior response to surface IgM cross-linking in CD38, ZAP-70-positive cells.

Background Patients with chronic lymphocytic leukemia whose cells express CD38 and ZAP-70 and utilize unmutated Ig VH region genes have a very poor prognosis. We studied whether cells expressing CD38 and ZAP-70 are more susceptible to stimulation through B-cell receptors than are cells that do not express CD38 and ZAP-70.Design and Methods CD38-positive and CD38-negative leukemic cells were separated from single cases and compared for their response to B-cell receptor cross-linking and ZAP-70 expression. Cohort studies were also carried out by measuring the apoptotic response to surface immunoglobulin M (IgM) cross-linking in 82 patients with chronic lymphocytic leukemia and the protein tyrosine phosphorylation induced by surface IgM in 21 patients.Results CD38-positive cells, isolated from cases of chronic lymphocytic leukemia classified as CD38-positive or CD38-negative, expressed more ZAP-70 than the corresponding CD38-negative cells, exhibited more robust protein tyrosine phosphorylation and had a greater tendency to apoptosis upon B-cell receptor cross-linking. In the cohort studies, surface IgM-induced protein tyrosine phosphorylation correlated significantly with CD38 and ZAP-70 expression and with the absence of Ig VH gene mutations. Apoptosis induced by surface IgM cross-linking correlated significantly only with the proportion of CD38-positive cells. Difficulties in finding more definitive correlations were probably related to imprecision in the in vitro test system and in the definition of cases as positive or negative.Conclusions Collectively, these data indicate that CD38-positive, ZAP-70-positive cells have a greater capacity for signaling through the B-cell receptor and suggest a function for B-cell receptor signaling in promoting chronic lymphocytic leukemia cell expansion, especially within the CD38-positive fraction of the leukemic clone

Hydrogeological Features and Sustainable Use of Geothermal Resources: Selected Case Studies in Italy

Within the framework of the activities aimed at studying current and future exploitation and the related sustainability of geothermal resources, and considering the key role hydrogeology plays in the study of geothermal systems and design of installations, in October 2012 the Working Group IDROGEOTER was set-up within the IAH (International Association of Hydrogeologists) Italian Chapter. The first activity of IDROGEOTER‘s workplan is the analysis of state of the art in current use of low-to high enthalpy geothermal resources in Italy and of the hydrogeological settings resulting from features (e.g.: hydrostratigraphy, hydraulic and hydrodynamic conditions, hydrogeochemistry, …) influencing the availability of the resource and the potential of the systems. Detailed studies supporting the possible optimization of the use of geothermal resources, carried out in different areas (see figure) and under different hydrogeological conditions in Italy, are described in the paper. In the Piedmont Region (NW Italy) several experimental sites have been investigated in order to assess the potential subsurface effects of open-loop Groundwater Heat Pumps (GW-HPs) plants for the cooling and heating of buildings. A comparison between field measures and numerical modelling results reveals that the most important aquifer parameters affecting the developing of the Thermal Affected Zone (TAZ) around the injection wells are those related to advective heat transfer. The Lombardy Region (N Italy) is currently the most populated and industrialized region in Italy and therefore the area where the highest number of GWHP plants (open and closed loop) are installed, from which a representative sample will be selected with the objective of identifying the critical hydrogeological factors contributing both to the geothermal potential and to a sustainable use of the resource. In the Veneto Region (NE Italy), the Euganean Geothermal Field is the most important thermal field in northern Italy (about 250 active wells) and the thermal waters (65-86 °C) are mainly used for spas; recently, a new conceptual model of the Euganean Geothermal System has been proposed and tested in a numerical model; with regard to low enthalpy, studies on sites potentially suitable for closed-loop and open-loop systems, together with data from automated monitoring of several wells, could be used for advanced analysis of different hydrogeothermal systems. Research activities in the Lazio Region (Central Italy) focus also on low enthalpy and are specifically aimed at the mapping of the geothermal potential of aquifers, and at pilot studies of sites characterized by gravel aquifers, alluvial Holocene deposits of the Tevere River and alluvial pre-volcanic Pleistocene deposits. In the Campania Region (S Italy - Mondragone plain), in the framework of the geothermal exploration programme “VIGOR” (Evaluation of Geothermal Potential in Convergence Region), a groundwater balance, verifying the recharge area of thermal springs (temperature 33-54 °C) connected to a large carbonate aquifer, has permitted the identification of the most suitable area in which to drill a geothermal well. In the Apulia Region (SE Italy) the thermal field trends consequent to groundwater advection and the influence of seawater intrusion have been reconstructed for two karstic coastal aquifers (Murgia and Salento) at various elevation between -5 and -100 m amsl. These reconstructions are intended to provide required base knowledge for correctly implementing low enthalpy HP plants in the saturated zones. Further studies and inventory of data and applications will be part of the activities of IDROGEOTER, which will also include the preparation of a proposal of guidelines for hydro-geothermal studies

Flow cytometric immunobead assay for detection of BCR-ABL1 fusion proteins in chronic myleoid leukemia: Comparison with FISH and PCR techniques

Chronic Myeloid Leukemia (CML) is characterized by a balanced translocation juxtaposing the Abelson (ABL) and breakpoint cluster region (BCR) genes. The resulting BCR-ABL1 oncogene leads to increased proliferation and survival of leukemic cells. Successful treatment of CML has been accompanied by steady improvements in our capacity to accurately and sensitively monitor therapy response. Currently, measurement of BCR-ABL1 mRNA transcript levels by real-time quantitative PCR (RQ-PCR) defines critical response endpoints. An antibody-based technique for BCR-ABL1 protein recognition could be an attractive alternative to RQ-PCR. To date, there have been no studies evaluating whether flow-cytometry based assays could be of clinical utility in evaluating residual disease in CML patients. Here we describe a flow-cytometry assay that detects the presence of BCR-ABL1 fusion proteins in CML lysates to determine the applicability, reliability, and specificity of this method for both diagnosis and monitoring of CML patients for initial response to therapy. We show that: i) CML can be properly diagnosed at onset, (ii) follow-up assessments show detectable fusion protein (i.e. relative mean fluorescent intensity, rMFI%>1) when BCR-ABL1IS transcripts are between 1-10%, and (iii) rMFI% levels predict CCyR as defined by FISH analysis. Overall, the FCBA assay is a rapid technique, fully translatable to the routine management of CML patients

Twelve Variants Polygenic Score for Low-Density Lipoprotein Cholesterol Distribution in a Large Cohort of Patients With Clinically Diagnosed Familial Hypercholesterolemia With or Without Causative Mutations

: Background A significant proportion of individuals clinically diagnosed with familial hypercholesterolemia (FH), but without any disease-causing mutation, are likely to have polygenic hypercholesterolemia. We evaluated the distribution of a polygenic risk score, consisting of 12 low-density lipoprotein cholesterol (LDL-C)-raising variants (polygenic LDL-C risk score), in subjects with a clinical diagnosis of FH. Methods and Results Within the Lipid Transport Disorders Italian Genetic Network (LIPIGEN) study, 875 patients who were FH-mutation positive (women, 54.75%; mean age, 42.47±15.00 years) and 644 patients who were FH-mutation negative (women, 54.21%; mean age, 49.73±13.54 years) were evaluated. Patients who were FH-mutation negative had lower mean levels of pretreatment LDL-C than patients who were FH-mutation positive (217.14±55.49 versus 270.52±68.59 mg/dL, P<0.0001). The mean value (±SD) of the polygenic LDL-C risk score was 1.00 (±0.18) in patients who were FH-mutation negative and 0.94 (±0.20) in patients who were FH-mutation positive (P<0.0001). In the receiver operating characteristic analysis, the area under the curve for recognizing subjects characterized by polygenic hypercholesterolemia was 0.59 (95% CI, 0.56-0.62), with sensitivity and specificity being 78% and 36%, respectively, at 0.905 as a cutoff value. Higher mean polygenic LDL-C risk score levels were observed among patients who were FH-mutation negative having pretreatment LDL-C levels in the range of 150 to 350 mg/dL (150-249 mg/dL: 1.01 versus 0.91, P<0.0001; 250-349 mg/dL: 1.02 versus 0.95, P=0.0001). A positive correlation between polygenic LDL-C risk score and pretreatment LDL-C levels was observed among patients with FH independently of the presence of causative mutations. Conclusions This analysis confirms the role of polymorphisms in modulating LDL-C levels, even in patients with genetically confirmed FH. More data are needed to support the use of the polygenic score in routine clinical practice

How do cardiologists select patients for dual antiplatelet therapy continuation beyond 1 year after a myocardial infarction? Insights from the EYESHOT Post-MI Study

Background: Current guidelines suggest to consider dual antiplatelet therapy (DAPT) continuation for longer than 12 months in selected patients with myocardial infarction (MI). Hypothesis: We sought to assess the criteria used by cardiologists in daily practice to select patients with a history of MI eligible for DAPT continuation beyond 1 year. Methods: We analyzed data from the EYESHOT Post-MI, a prospective, observational, nationwide study aimed to evaluate the management of patients presenting to cardiologists 1 to 3 years from the last MI event. Results: Out of the 1633 post-MI patients enrolled in the study between March and December 2017, 557 (34.1%) were on DAPT at the time of enrolment, and 450 (27.6%) were prescribed DAPT after cardiologist assessment. At multivariate analyses, a percutaneous coronary intervention (PCI) with multiple stents and the presence of peripheral artery disease (PAD) resulted as independent predictors of DAPT continuation, while atrial fibrillation was the only independent predictor of DAPT interruption for patients both at the second and the third year from MI at enrolment and the time of discharge/end of the visit. Conclusions: Risk scores recommended by current guidelines for guiding decisions on DAPT duration are underused and misused in clinical practice. A PCI with multiple stents and a history of PAD resulted as the clinical variables more frequently associated with DAPT continuation beyond 1 year from the index MI

A Qualitative Exploration of the Use of Contraband Cell Phones in Secured Facilities

Offenders accepting contraband cell phones in secured facilities violate state corrections law, and the possession of these cell phones is a form of risk taking behavior. When offenders continue this risky behavior, it affects their decision making in other domains where they are challenging authorities; and may impact the length of their incarceration. This qualitative phenomenological study examined the lived experience of ex-offenders who had contraband cell phones in secured correctional facilities in order to better understand their reasons for taking risks with contraband cell phones. The theoretical foundation for this study was Trimpop\u27s risk-homeostasis and risk-motivation theories that suggest an individual\u27s behaviors adapt to negotiate between perceived risk and desired risk in order to achieve satisfaction. The research question explored beliefs and perceptions of ex-offenders who chose to accept the risk of using contraband cell phones during their time in secured facilities. Data were collected anonymously through recorded telephone interviews with 8 male adult ex-offenders and analyzed using thematic content analysis. Findings indicated participants felt empowered by possession of cell phones in prison, and it was an acceptable risk to stay connected to family out of concern for loved ones. The study contributes to social change by providing those justice system administrators, and prison managers responsible for prison cell phone policies with more detailed information about the motivations and perspectives of offenders in respect to using contraband cell phones while imprisoned in secured facilities

Della condizione attuale degli Ebrei in Piemonte

[von] L. Vigna e. V. AlbertiAus: Dizinario di diritto amministrativ

Investigation on Thermal and Fluid Dynamic Behaviors in Mixed Convection in Horizontal Channels with Aluminum Foam and Heated from Below

In this paper, mixed convection in a horizontal channel partially filled with a porous medium and the lower wall heated at uniform heat flux is studied experimentally and numerically. A simplified two-dimensional problem is modelled and solved numerically. The domain is made of a principal channel and two channels with adiabatic walls, one upstream and the other one downstream the principal channel. The heated wall temperature profiles as a function of the Ri values are presented. Average Nusselt numbers are evaluated. The experimental test section is made up of a horizontal wall and a parallel adiabatic wall. The distance between the horizontal walls is equal to 40 mm. The porous medium is an aluminium foam and it is placed over the heated lower wall. The porous plate has a thickness equal to 20 mm. The aluminium foam has 10, 20 and 40 PPI. The experiments are performed with working fluid air. The Reynolds numbers investigated are between 5.0 and 250, these being in the laminar regime. The Richardson number, Ri, holds values in the range 1 2000. Results in terms of wall temperature profiles, local and average Nusselt numbers are presented for different Reynolds and Rayleigh number values. Some comparison between experimental and numerical results are accomplished