Metformin inhibits androgen-induced IGF-IR up-regulation in prostate cancer cells by disrupting membrane-initiated androgen signaling.

We have previously demonstrated that, in prostate cancer cells, androgens up-regulate IGF-I receptor (IGF-IR) by inducing cAMP-response element-binding protein (CREB) activation and CREB-dependent IGF-IR gene transcription through androgen receptor (AR)-dependent membrane-initiated effects. This IGF-IR up-regulation is not blocked by classical antiandrogens and sensitizes cells to IGF-I-induced biological effects. Metformin exerts complex antitumoral functions in various models and may inhibit CREB activation in hepatocytes. We, therefore, evaluated whether metformin may affect androgen-dependent IGF-IR up-regulation. In the AR(+) LNCaP prostate cancer cells, we found that metformin inhibits androgen-induced CRE activity and IGF-IR gene transcription. CRE activity requires the formation of a CREB-CREB binding protein-CREB regulated transcription coactivator 2 (CRTC2) complex, which follows Ser133-CREB phosphorylation. Metformin inhibited Ser133-CREB phosphorylation and induced nuclear exclusion of CREB cofactor CRTC2, thus dissociating the CREB-CREB binding protein-CRTC2 complex and blocking its transcriptional activity. Similarly to metformin action, CRTC2 silencing inhibited IGF-IR promoter activity. Moreover, metformin blocked membrane-initiated signals of AR to the mammalian target of rapamycin/p70S6Kinase pathway by inhibiting AR phosphorylation and its association with c-Src. AMPK signals were also involved to some extent. By inhibiting androgen-dependent IGF-IR up-regulation, metformin reduced IGF-I-mediated proliferation of LNCaP cells. These results indicate that, in prostate cancer cells, metformin inhibits IGF-I-mediated biological effects by disrupting membrane-initiated AR action responsible for IGF-IR up-regulation and suggest that metformin could represent a useful adjunct to the classical antiandrogen therapy

The Challenge of Using an Antigen Test as a Screening Tool for SARS-CoV-2 Infection in an Emergency Department: Experience of a Tertiary Care Hospital in Southern Italy

Background. In emergency hospital settings, rapid diagnosis and isolation of SARS-CoV-2 patients are required. The aim of the study was to evaluate the performance of an antigen chemiluminescence enzymatic immunoassay (CLEIA) and compare it with that of Real-time Reverse transcription-Polymerase Chain Reaction (RT-qPCR), the gold standard assay, to assess its suitability as a rapid diagnostic method for managing patients in the emergency department (ED). Methods. Consecutive patients with no previous history of SARS-CoV-2 infection attending the ED of the Policlinico Hospital of Bari between 23rd October and 4th November 2020 were enrolled. Clinical and demographic data were collected for all patients. Nasopharyngeal swabs collected on admission were subjected both to molecular (RT-qPCR) and antigen (CLEIA) tests for SARS-CoV-2. The performance of the CLEIA antigen test was analyzed using R Studio software and Microsoft Excel. Receiver operating characteristics were also performed. Results. A total of 911 patients were enrolled, of whom 469 (51.5%) were male. Of the whole cohort, 23.7% tested positive for SARS-CoV-2 by RT-qPCR and 24.5% by CLEIA. The overall concordance rate was 96.8%. The sensitivity, specificity, positive predictive value, and negative predictive value of the antigen test were 94.9% (95% CI, 91.9–97.0), 97.4% (95% CI, 96.5–98.1), 91.9% (95% CI, 89.0–94.0), and 98.4% (95% CI, 97.4–99.1), respectively. The area under the curve (AUC) was 0.99. The kappa coefficient was 0.91. The overall positive and negative likelihood ratios were 37 (95% CI 23-58) and 0.05 (95% CI, 0.03–0.09), respectively. Conclusions. Data analysis demonstrated that the antigen test showed very good accuracy for discriminating SARS-CoV-2-infected patients from negative participants. The CLEIA is suitable for rapid clinical diagnosis of patients in hospital settings, particularly in EDs with a high prevalence of symptomatic patients and where a rapid turnaround time is critical. Timely and accurate testing for SARS-CoV-2 plays a crucial role in limiting the spread of the virus

Rapid Spread of the SARS-CoV-2 Variant of Concern 202012/01 in Southern Italy (December 2020–March 2021)

Epidemiological and virological studies have revealed that SARS-CoV-2 variants of concern (VOCs) are emerging globally, including in Europe. The aim of this study was to evaluate the spread of B.1.1.7-lineage SARS-CoV-2 in southern Italy from December 2020–March 2021 through the detection of the S gene target failure (SGTF), which could be considered a robust proxy of VOC B.1.1.7. SGTF was assessed on 3075 samples from week 52/2020 to week 10/2021. A subset of positive samples identified in the Apulia region during the study period was subjected to whole-genome sequencing (WGS). A descriptive and statistical analysis of the demographic and clinical characteristics of cases according to SGTF status was performed. Overall, 20.2% of samples showed SGTF; 155 strains were confirmed as VOC 202012/01 by WGS. The proportion of SGTF-positive samples rapidly increased over time, reaching 69.2% in week 10/2021. SGTF-positive cases were more likely to be symptomatic and to result in hospitalization (p < 0.0001). Despite the implementation of large-scale non-pharmaceutical interventions (NPIs), such as the closure of schools and local lockdowns, a rapid spread of VOC 202012/01 was observed in southern Italy. Strengthened NPIs and rapid vaccine deployment, first among priority groups and then among the general population, are crucial both to contain the spread of VOC 202012/01 and to flatten the curve of the third wav

Update on the Epidemiology of Macrolide-Resistant Mycoplasma pneumoniae in Europe: A Systematic Review

Macrolide-resistant Mycoplasma pneumoniae (MR-MP) infections cause upper and lower respiratory tract infections in both children and adults, and are characterized by a longer duration of symptoms. Here, we undertook a systematic review of studies on MR-MP in Europe. The review meets PRISMA guidelines. The PubMed, Scopus, and Science Direct databases were searched using suitable keywords to identify relevant studies published from 2010 to 2021; 21 studies were included. Overall, a low level of MR-MP spread was reported in Europe. MR-MP spread increased during epidemic waves registered in Europe, particularly in Italy and Scotland, where the highest MR-MP infection rates were registered during the 2010–2011 epidemic. By contrast, no MR-MP infections were reported in Finland and the Netherlands. Continued monitoring of MR-MP in Europe is needed to maintain the low rates of infection. Moreover, a coordinated and structured pan-European surveillance program adequate for public health surveillance is advisable, with the purpose of containing the spread of antimicrobial resistance

Changing Features of COVID-19: Characteristics of Infections with the SARS-CoV-2 Delta (B.1.617.2) and Alpha (B.1.1.7) Variants in Southern Italy

Differences in the demographic and clinical characteristics of patients infected with the Alpha and Delta SARS‐CoV‐2 variants of concern in a large region of Southern Italy were assessed. Two cohorts of positive patients were compared. The Alpha group consisted of 11,135 subjects diagnosed between 21 March and 21 April 2021, and the Delta group consisted of 499 positive subjects diagnosed between 21 July and 21 August 2021. A descriptive and statistical analysis of the demographic and clinical characteristics of the two groups was performed. The proportion of patients with mild and moderate infections was significantly higher in the Delta than in the Alpha group (p < 0.001). In fully vaccinated patients, the proportion of symptomatic individuals was significantly higher in the Delta than in the Alpha group. The Delta group showed odds ratios of 3.08 (95% CI, 2.55–3.72) for symptomatic infection and 2.66 (95% CI, 1.76–3.94) for hospitalization. Improving COVID‐19 vaccination rates is a priority, since infection with the SARS‐CoV‐2 Delta variant has a significant impact on patient outcomes. Additional targeted prevention strategies such as social distancing, the use of masks in indoor settings irrespective of vaccination status, and the use of a sanitary passport could be crucial to contain further spread of SARS‐CoV‐2 infection

A novel role for drebrin in regulating progranulin bioactivity in bladder cancer.

We recently established a critical role for the growth factor progranulin in bladder cancer insofar as progranulin promotes urothelial cancer cell motility and contributes, as an autocrine growth factor, to the transformed phenotype by modulating invasion and anchorage-independent growth. In addition, progranulin expression is upregulated in invasive bladder cancer tissues compared to normal controls. However, the molecular mechanisms of progranulin action in bladder cancer have not been fully elucidated. In this study, we searched for novel progranulin-interacting proteins using pull-down assays with recombinant progranulin and proteomics. We discovered that drebrin, an F-actin binding protein, bound progranulin in urothelial cancer cells. We characterized drebrin function in urothelial cancer cell lines and showed that drebrin is critical for progranulin-dependent activation of the Akt and MAPK pathways and modulates motility, invasion and anchorage-independent growth. In addition, drebrin regulates tumor formation in vivo and its expression is upregulated in bladder cancer tissues compared to normal tissue controls. Our data are translationally relevant as indicate that drebrin exerts an essential functional role in the regulation of progranulin action and may constitute a novel target for therapeutic intervention in bladder tumors. In addition, drebrin may serve as novel biomarker for bladder cancer

Rational steering of insulin binding specificity by intra-chain chemical crosslinking

Insulin is a key hormone of human metabolism with major therapeutic importance for both types of diabetes. New insulin analogues with more physiological profiles and better glycemic control are needed, especially analogues that preferentially bind to the metabolic B-isoform of insulin receptor (IR-B). Here, we aimed to stabilize and modulate the receptor-compatible conformation of insulin by covalent intra-chain crosslinking within its B22-B30 segment, using the Cu I -catalyzed Huisgen 1,3-dipolar cycloaddition reaction of azides and alkynes. This approach resulted in 14 new, systematically crosslinked insulin analogues whose structures and functions were extensively characterized and correlated. One of the analogues, containing a B26-B29 triazole bridge, was highly active in binding to both IR isoforms, with a significant preference for IR-B. Our results demonstrate the potential of chemistry-driven modulation of insulin function, also shedding new light on the functional importance of hormones B-chain C-terminus for its IR-B specificity

La morte della persona umana nell'epoca del trionfo della medicina: considerazioni etiche

Dottorato di ricerca in deontologia ed etica medica. 9. ciclo. A.a. 1993-96Consiglio Nazionale delle Ricerche - Biblioteca Centrale - P.le Aldo Moro, 7, Rome; Biblioteca Nazionale Centrale - P.za Cavalleggeri, 1, Florence / CNR - Consiglio Nazionale delle RichercheSIGLEITItal