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In this paper we present a quantum-classical hybrid model based on the hydrodynamic equations in steady state form. The approach presented here, which has already been proposed in previous works, consists in considering an intrinsically hybrid version of the Bohm potential, which acts only in the region of the domain where quantum effects play an important role, while it disappears where the quantum contribution is essentially negligible and the operation of the device can be well described by using a classical model. Compared to previous results from the same line of research, here we assume that the device at the boundaries of the domain behaves classically, while quantum effects are localised in the central part of it. This is the case of greatest scientific interest, since, in real devices, quantum effects are generally localized in a small area within the device itself. The well posedness of the problem is ensured by adding a viscous term necessary for the convergence of the hybrid limit to an appropriate weak solution. Some numerical tests are also performed for different values of the viscous coefficient, in order to evaluate the effects of the viscosity, especially on the boundaries of the device.

IntroductionPancreatic Ductal Adenocarcinoma (PDA) is one of the most aggressive malignancies with a 5-year survival rate of 13%. Less than 20% of patients have a resectable tumor at diagnosis due to the lack of distinctive symptoms and reliable biomarkers. PDA is resistant to chemotherapy (CT) and understanding how to gain an anti-tumor effector response following stimulation is, therefore, critical for setting up an effective immunotherapy.MethodsProliferation, and cytokine release and TCRB repertoire of from PDA patient peripheral T lymphocytes, before and after CT, were analyzed in vitro in response to four tumor-associated antigens (TAA), namely ENO1, FUBP1, GAPDH and K2C8. Transcriptional state of PDA patient PBMC was investigated using RNA-Seq before and after CT.ResultsCT increased the number of TAA recognized by T lymphocytes, which positively correlated with patient survival, and high IFN-γ production TAA-induced responses were significantly increased after CT. We found that some ENO1-stimulated T cell clonotypes from CT-treated patients were expanded or de-novo induced, and that some clonotypes were reduced or even disappeared after CT. Patients that showed a higher number of effector responses to TAA (high IFN-γ/IL-10 ratio) after CT expressed increased fatty acid-related transcriptional signature. Conversely, patients that showed a higher number of regulatory responses to TAA (low IFN-γ/IL-10 ratio) after CT significantly expressed an increased IRAK1/IL1R axis-related transcriptional signature.ConclusionThese data suggest that the expression of fatty acid or IRAK1/IL1Rrelated genes predicts T lymphocyte effector or regulatory responses to TAA in patients that undergo CT. These findings are a springboard to set up precision immunotherapies in PDA based on the TAA vaccination in combination with CT.

Abstract Background The NAPOLI‐I trial showed better outcome of nanoliposomal irinotecan (nal‐IRI) plus 5‐fluorouracil/leucovorin (5‐FU/LV) compared to 5‐FU/LV in patients with advanced pancreatic ductal adenocarcinoma cancer (advPDAC) progressed to gemcitabine‐based therapy. This study aims to explore the real‐world efficacy and safety of 5‐FU/LV‐nal‐IRI. Methods This is a retrospective multicenter analysis including advPDAC patients receiving 5‐FU/LV‐nal‐IRI after failure of gemcitabine‐based therapy. Survival analyses were performed using Kaplan–Meier method, univariate and multivariate analyses by Cox regression. Results A total of 296 patients (median age 64.4 years, ECOG PS ≥1 in 56% of cases) were treated at 11 Italian institutions between 2016 and 2018. 34% of them underwent primary tumor resection, and 79% received gemcitabine‐nabpaclitaxel as first line. 5‐FU/LV‐nal‐IRI was administered as second‐line in 73% of cases. Objective response and disease control rate were 12% and 41%, respectively. Treatment was well tolerated with dose reductions in 50% of patients but no one permanent discontinuation; the commonest grade ≥3 toxicities were neutropenia (14%) and diarrhea (12%). Median PFS and OS from 5‐FU/LV‐nal‐IRI initiation was 3.2 and 7.1 months, respectively. Conclusions These real‐world data confirm the 5‐FU/LV‐nal‐IRI efficacy and safety in advPDAC patients progressed to gemcitabine‐based therapy, with outcomes comparable to NAPOLI‐1, even in a less‐selected population and with more modern therapeutic algorithm.

Background: Prolactinoma, the most common pituitary adenoma, is usually treated with dopamine agonist (DA) therapy like cabergoline. Surgery is second-line therapy, and radiotherapy is used if surgical treatment fails or in relapsing macroprolactinoma. Objective: This study aimed to provide economic evidence for the management of prolactinoma in Italy, using a cost-of-illness and cost-utility analysis that considered various treatment options, including cabergoline, bromocriptine, temozolomide, radiation therapy, and surgical strategies. Methods: The researchers conducted a systematic literature review for each research question on scientific databases and surveyed a panel of experts for each therapeutic procedure’s specific drivers that contributed to its total cost. Results: The average cost of the first year of treatment was €2,558.91 and €3,287.40 for subjects with microprolactinoma and macroprolactinoma, respectively. Follow-up costs from the second to the fifth year after initial treatment were €798.13 and €1,084.59 per year in both groups. Cabergoline had an adequate cost-utility profile, with an incremental cost-effectiveness ratio (ICER) of €3,201.15 compared to bromocriptine, based on a willingness-to-pay of €40,000 per quality-adjusted life year (QALY) in the reference economy. Endoscopic surgery was more cost-effective than cabergoline, with an ICER of €44,846.64. Considering a willingness-to-pay of €40,000/QALY, the baseline findings show cabergoline to have high cost utility and endoscopic surgery just a tad above that. Conclusions: Due to the favorable cost-utility profile and safety of surgical treatment, pituitary surgery should be considered more frequently as the initial therapeutic approach. This management choice could lead to better outcomes and an appropriate allocation of healthcare resources.

The phytochemical profiles of extracts from closed, semi-opened and opened leaf buds and the summer leaves of Ginkgo biloba were studied. The extraction and purification of bilobalide and ginkgolides, using andrographolide as an internal standard, were optimised. The terpene trilactone concentrations increased with bud development, from 1.07 mg/g dry wt in closed buds to a maximum of 3.75 mg/g dry wt in summer leaves. The major terpene trilactone was bilobalide at all developmental stages. The concentration of flavonol aglycones in hydrolysed extracts was also analysed. The flavonol glycoside concentration increased from the closed bud stage (0.21 ± 0.01% dry wt) to the summer leaf stage (1.15 ± 0.01% dry wt). A linear correlation was observed between the terpene trilactone and flavonoid content during gingko leaf development.

Abstract Background Metabolic reprogramming is an important issue in tumor biology. A recently-identified actor in this regard is the molecular chaperone TRAP1, that is considered an oncogene in several cancers for its high expression but an oncosuppressor in others with predominant oxidative metabolism. TRAP1 is mainly localized in mitochondria, where it interacts with respiratory complexes, although alternative localizations have been described, particularly on the endoplasmic reticulum, where it interacts with the translational machinery with relevant roles in protein synthesis regulation. Results Herein we show that, inside mitochondria, TRAP1 binds the complex III core component UQCRC2 and regulates complex III activity. This decreases respiration rate during basal conditions but allows sustained oxidative phosphorylation when glucose is limiting, a condition in which the direct TRAP1-UQCRC2 binding is disrupted, but not TRAP1-complex III binding. Interestingly, several complex III components and assembly factors show an inverse correlation with survival and response to platinum-based therapy in high grade serous ovarian cancers, where TRAP1 inversely correlates with stage and grade and directly correlates with survival. Accordingly, drug-resistant ovarian cancer cells show high levels of complex III components and high sensitivity to complex III inhibitory drug antimycin A. Conclusions These results shed new light on the molecular mechanisms involved in TRAP1-dependent regulation of cancer cell metabolism and point out a potential novel target for metabolic therapy in ovarian cancer.

Abstract Leucojum aestivum is known for its ability to biosynthesize alkaloids with therapeutic properties, among which galanthamine used for the treatment of Alzheimer's disease. New sources of this alkaloid are still being explored. In this study, a novel strain PLV of endophytic bacterium Paenibacillus lautus was isolated from in vitro L. aestivum plants. We report the whole genome sequence of that strain and its capacity to produce alkaloids and growth regulators. The effect of elicitation with autoclaved bacteria on the production of alkaloids was examined. Ten alkaloids were identified in bacteria extracts: galanthamine, lycorine, ismine, lycoramine, haemanthamine, tazettine, galanthine, homolycorine, 1,2-dihydrochlidanthine, and hippeastrine. The mean contents of galanthamine and lycorine were 37.51 µg/g of dry weight (DW) and 129.93 µg/g of DW, respectively. Moreover, isolated P. lautus strain synthesized: indole-3-acetic acid, t-zeatin, c-zeatin, kinetin, gibberellin A1, abscisic acid, salicylic acid, benzoic acid. In vitro elicitation of cultures with P. lautus increased dry biomass, stimulated galanthamine and lycorine production, contributed to 8,9-desmethylenebis (oxy)-7,9 dimethoxy-crinan biosynthesis, change pigments content, and antioxidant enzymes activities. Our findings for the first time point out that galanthamine can be synthesized by an microorganism. Moreover isolated strain can be used as a new elictor of Amaryllidaceae alkaloids biosynthesis.

Abstract Background The metabolic phenotype of stem cells is increasingly recognized as a hallmark of their pluripotency with mitochondrial and oxygen-related metabolism playing a not completely defined role in this context. In a previous study, we reported the ectopic expression of myoglobin (MB) in bone marrow-derived hematopoietic stem/progenitor cells. Here, we have extended the analysis to mesenchymal stem cells (MSCs) isolated from different tissues. Methods MSCs were isolated from human placental membrane, mammary adipose tissue and dental pulp and subjected to RT-PCR, Western blotting and mass spectrometry to investigate the expression of MB. A combination of metabolic flux analysis and cyto-imaging was used to profile the metabolic phenotype and the mitochondria dynamics in the different MSCs. Results As for the hematopoietic stem/progenitor cells, the expression of Mb was largely driven by an alternative transcript with the protein occurring both in the monomer and in the dimer forms as confirmed by mass spectrometry analysis. Comparing the metabolic fluxes between neonatal placental membrane-derived and adult mammary adipose tissue-derived MSCs, we showed a significantly more active bioenergetics profile in the former that correlated with a larger co-localization of myoglobin with the mitochondrial compartment. Differences in the structure of the mitochondrial network as well as in the expression of factors controlling the organelle dynamics were also observed between neonatal and adult mesenchymal stem cells. Finally, the expression of myoglobin was found to be strongly reduced following osteogenic differentiation of dental pulp-derived MSCs, while it was upregulated following reprogramming of human fibroblasts to induce pluripotent stem cells. Conclusions Ectopic expression of myoglobin in tissues other than muscle raises the question of understanding its function therein. Properties in addition to the canonical oxygen storage/delivery have been uncovered. Finding of Mb expressed via an alternative gene transcript in the context of different stem cells with metabolic phenotypes, its loss during differentiation and recovery in iPSCs suggest a hitherto unappreciated role of Mb in controlling the balance between aerobic metabolism and pluripotency. Understanding how Mb contributes through modulation of the mitochondrial physiology to the stem cell biology paves the way to novel perspectives in regenerative medicine as well as in cancer stem cell therapy. Graphical abstract

Patients suffering from inflammatory chronic diseases are classically treated with anti-inflammatory drugs but unfortunately are highly susceptible to becoming resistant to their treatment. Finding new drugs is therefore crucial and urgent and research on endophytic fungi is a promising way forward. Endophytic fungi are microorganisms that colonize healthy plants and live within their intercellular tissues. They are able to produce a large variety of secondary metabolites while allowing their host to stay healthy. A number of these molecules are endowed with antioxidant or antimicrobial as well as cytotoxic properties, making them very interesting/promising in the field of human therapy. The aim of our study was to investigate whether extracts from five endophytic fungi isolated from plants are endowed with anti-inflammatory activity. Extracts of the endophytic fungi Alternaria alternata from Calotropis procera leaves and Aspergillus terreus from Trigonella foenum-graecum seeds were able to counteract the lipopolysaccharide (LPS) pro-inflammatory effect on THP-1 cells differentiated into macrophages. Moreover, they were able to induce an anti-inflammatory state, rendering them less sensitive to the LPS pro-inflammatory stimulus. Taken together, these results show that these both endophytic fungi could be interesting alternatives to conventional anti-inflammatory drugs. To gain more detailed knowledge of their chemical richness, phytochemical analysis of the ethyl acetate extracts of the five endophytic fungi studied was performed using HPTLC, GC-MS and LC-MS with the Global Natural Products Social (GNPS) platform and the MolNetEnhancer tool. A large family of metabolites (carboxylic acids and derivatives, steroid derivatives, alkaloids, hydroxyanthraquinones, valerolactones and perylenequinones) were detected. The purification of endophytic fungus extract of Alternaria alternate, which diminished TNF-α production of 66% at 20 µg/mL, incubated one hour before LPS addition, led to the characterization of eight pure compounds. These molecules are altertoxins I, II, III, tricycloalternarenes 3a, 1b, 2b, anthranilic acid, and o-acetamidobenzoic acid. In the future, all these pure compounds will be evaluated for their anti-inflammatory activity, while altertoxin II has been shown in the literature as the most active mycotoxin in terms of anti-inflammatory activity.

Abstract Background The net health benefit of using antipsychotics in children and adolescents with ASD is unclear. This review was performed to provide the evidence necessary to inform the Italian national guidelines for the management of ASD. Methods We performed a systematic review of randomized controlled trials (RCTs) comparing antipsychotics versus placebo for the treatment of ASD in children and adolescents. For efficacy, acceptability and safety we considered outcomes evaluated by the guideline panel critical and important for decision-making. Continuous outcomes were analyzed by using standardized mean difference (SMD), and dichotomous outcomes by calculating the risk ratio (RR), with their 95% confidence interval (95% CI). Data were analyzed using a random effects model. We used the Cochrane tool to assess risk of bias of included studies. Certainty in the evidence of effects was assessed according to the GRADE approach. Results We included 21 RCTs with 1,309 participants, comparing antipsychotics to placebo. Antipsychotics were found effective on “restricted and repetitive interests and behaviors” (SMD − 0.21, 95% CI − 0.35 to − 0.07, moderate certainty), “hyperactivity, inattention, oppositional, disruptive behavior” (SMD − 0.67, 95% CI − 0.92 to − 0.42, moderate certainty), “social communication, social interaction” (SMD − 0.38, 95% CI − 0.59 to − 0.16, moderate certainty), “emotional dysregulation/irritability” (SMD − 0.71, 95% CI − 0.98 to − 0.43, low certainty), “global functioning, global improvement” (SMD − 0.64, 95% CI − 0.96 to − 0.33, low certainty), “obsessions, compulsions” (SMD − 0.30, 95% CI − 0.55 to − 0.06, moderate certainty). Antipsychotics were not effective on “self-harm” (SMD − 0.14, 95% CI − 0.58 to 0.30, very low certainty), “anxiety” (SMD − 0.38, 95% CI − 0.82 to 0.07, very low certainty). Antipsychotics were more acceptable in terms of dropout due to any cause (RR 0.61, 95% CI 0.48 to 0.78, moderate certainty), but were less safe in terms of patients experiencing adverse events (RR 1.19, 95% CI 1.07 to 1.32, moderate certainty), and serious adverse events (RR 1.07, 95% CI 0.48 to 2.43, low certainty). Conclusions Our systematic review and meta-analysis found antipsychotics for children and adolescents with ASD more efficacious than placebo in reducing stereotypies, hyperactivity, irritability and obsessions, compulsions, and in increasing social communication and global functioning. Antipsychotics were also found to be more acceptable, but less safe than placebo.

Abstract Background Molecular assessment and treatment of metastatic colorectal cancer (mCRC) quickly evolved during the last decades, hampering longitudinal evaluation of prognostic markers. The aim of this study was to evaluate prognostic predictors of long-term survival in a retrospective series of mCRC, treated prior to the expanded RAS assessment era. Methods mCRC cases treated at the Città della Salute e della Scienza University Hospital (Turin, Italy) between January 2004 and December 2012 were evaluated, including cases with ≥ 5-year follow-up only. Long-term survival was defined as an overall survival (OS) ≥ 4 years based on the observed OS interquartile range values. Univariate/multivariate Cox proportional hazards regression models were performed to assess the prognostic significance of the clinical/biological features, while binary logistic regression models were used to verify their associations with long-term survival. Results Two hundred and forty-eight mCRC cases were included and analyzed. Sixty out of two hundred and forty-eight (24%) patients were long-term survivors. Univariate binary logistic regression analysis demonstrated a significant association between long-term survival and age at diagnosis < 65 (OR = 2.28, p = 0.007), single metastatic site (OR = 1.89, p = 0.039), surgical resection of metastases (OR = 5.30, p < 0.001), local non-surgical treatment of metastases (OR = 4.74, p < 0.001), and a bevacizumab-including first-line treatment schedule (OR = 2.19, p = 0.024). Multivariate binary logistic regression analysis confirmed the prognostic significance of surgical resection of metastases (OR = 3.96, p < 0.001), local non-surgical treatment of metastases (OR = 3.32, p = 0.001), and of bevacizumab-including first-line treatment schedule (OR = 2.49, p = 0.024). Conclusion Long-term survival could be achieved in a significant rate of patients with mCRC even in an era of limited molecular characterization. Local treatment of metastases proved to be a significant predictor of long-term survival.

Abstract Background Recent randomized controlled trials (RCTs) claimed PUFAs to be effective for autism spectrum disorder (ASD) but international guidelines have not considered yet this body of evidence. Our aim was to assess the effectiveness of PUFAs in children and adolescents with ASD, for the Italian national guidelines on the management of ASD in children and adolescents. Methods We performed a systematic review and meta-analysis of RCTs comparing PUFAs versus placebo or a healthy diet for the treatment of ASD in children and adolescents. The outcomes considered were deemed by the guideline panel to be highly relevant to children and adolescents with ASD and to their caregivers. The outcomes included hyperactivity, quality of sleep, self-harm, aggression, irritability, anxiety, attention, adaptive functioning, social interaction, restricted and repetitive interests and behavior, communication, hyperactivity and disruptive behaviors coexistent with core symptoms. The risk of bias of the included studies was assessed with the Cochrane tool, and the rating of the confidence in the effect estimates according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Results We included 9 studies with 405 participants. The strength of evidence ranged from low to very low. Six studies included preschoolers and school-age children, three studies included both children and adolescents. The majority of participants were males (83.8%), with a mean age of 6.7 years. PUFAs were superior compared to placebo in reducing anxiety in individuals with ASD (SMD -1.01, 95% CI − 1.86 to − 0.17; very low certainty of evidence). Moreover, PUFAs worsened quality of sleep compared to a healthy diet (SMD 1.11, 95% CI 0.21 to 2.00; very low certainty of evidence). PUFAs were not better than placebo in reducing aggression, hyperactivity, adaptive functioning, irritability, restricted and repetitive interests and behaviors and communication. Effects on some critical outcomes such as sleep, self-harm and disruptive behavior are currently unknown. The main limitations were the small number of participants included in the RCTs and the dosage which varied greatly (from 200 mg/day to 1540 mg/day), making it difficult to address causal inference. Conclusions PUFAs did not show evidence of effect in children and adolescents with ASD and the certainty of evidence as measured with the GRADE was low to very low. Further research is needed on this topic because the available evidence is inconclusive.

BackgroundEmerging evidence shows that both adults and children may develop post-acute sequelae of SARS-CoV-2 infection (PASC). The aim of this study is to characterise and compare long-term post-SARS-CoV-2 infection outcomes in adults and children in a defined region in Italy.MethodsA prospective cohort study including children (≤18 years old) with PCR-confirmed SARS-CoV-2 infection and their household members. Participants were assessed via telephone and face-to-face visits up to 12 months post-SARS-CoV-2 diagnosis of household index case, using the ISARIC COVID-19 follow-up survey.ResultsOf 507 participants from 201 households, 56.4% (286/507) were children, 43.6% (221/507) adults. SARS-CoV-2 positivity was 87% (249/286) in children, and 78% (172/221) in adults. The mean age of PCR positive children was 10.4 (SD = 4.5) and of PCR positive adults was 44.5 years (SD = 9.5), similar to the PCR negative control groups [children 10.5 years (SD = 3.24), adults 42.3 years (SD = 9.06)]. Median follow-up post-SARS-CoV-2 diagnosis was 77 days (IQR 47–169). A significantly higher proportion of adults compared to children reported at least one persistent symptom (67%, 68/101 vs. 32%, 57/179, p < 0.001) at the first follow up. Adults had more frequently coexistence of several symptom categories at both follow-up time-points. Female gender was identified as a risk factor for PASC in adults (p 0.02 at 1–3 months and p 0.01 at 6–9 months follow up), but not in children. We found no significant correlation between adults and children symptoms. In the paediatric group, there was a significant difference in persisting symptoms between those with confirmed SARS-CoV-2 infection compared to controls at 1–3 months follow up, but not at 6–9 months. Conversely, positive adults had a higher frequency of persisting symptoms at both follow-up assessments.ConclusionOur data highlights that children can experience persistent multisystemic symptoms months after diagnosis of mild acute SARS-CoV-2 infection, although less frequently and less severely than co-habitant adults. There was no correlation between symptoms experienced by adults and children living in the same household. Our data highlights an urgent need for studies to characterise PASC in whole populations and the wider impact on families.

Light-emitting diodes (LEDs) have emerged as efficient light sources for promoting in vitro plant growth and primary and secondary metabolite biosynthesis. This study investigated the effects of blue, red, and white-red LED lights on plant biomass growth, photosynthetic pigments, soluble sugars, phenolic compounds, the production of Amaryllidaceae alkaloids, and the activities of antioxidant enzymes in Leucojum aestivum L. cultures. A white fluorescent light was used as a control. The plants that were grown under white-red and red light showed the highest fresh biomass increments. The blue light stimulated chlorophyll a, carotenoid, and flavonoid production. The white-red and blue lights were favourable for phenolic acid biosynthesis. Chlorogenic, p-hydroxybenzoic, caffeic, syringic, p-coumaric, ferulic, sinapic, and benzoic acids were identified in plant materials, with ferulic acid dominating. The blue light had a significant beneficial effect both on galanthamine (4.67 µg/g of dry weight (DW)) and lycorine (115 µg/g DW) biosynthesis. Red light treatment increased catalase and superoxide dismutase activities, and high catalase activity was also observed in plants treated with white-red and blue light. This is the first report to provide evidence of the effects of LED light on the biosynthesis of phenolic acid and Amaryllidaceae alkaloids in L. aestivum cultures, which is of pharmacological importance and can propose new strategies for their production.

OBIETTIVO Ottimizzazione di un protocollo a bassa dose con tecnica Tomosintesi per lo studio delle mammelle con protesi, nel percorso di screening. INTRODUZIONE ALLO STUDIO le linee guida in Italia, in UK e negli Stati Uniti concordano che la mammografia 2D, in presenza di protesi, non offra una diagnosi affidabile e pertanto invitano ad effettuare anche la manovra di Eklund. A causa della tipica radiopacità delle protesi, la Tomosintesi, attualmente, non rappresenta la tecnica di elezione per lo screening di questo tipo di mammelle. Abbiamo voluto sperimentare un protocollo in cui sia possibile utilizzare la Tomosintesi per dare maggiori informazioni diagnostiche anche in presenza di protesi mammarie, conciliando l’aspetto tecnico, metodologico e dosimetrico. MATERIALI E METODI Sono state arruolate in totale 53 donne che hanno aderito al programma di screening della mammella, riservato a donne con protesi di età compresa tra i 50 ed i 74 anni, nella ASL Roma 1. A queste donne è stato chiesto il consenso di acquisire le immagini anche con la Tomosintesi. In un primo gruppo di 15 donne, utilizzando una configurazione standard per l’algoritmo di controllo automatico dell’esposizione (AEC) presente sul mammografo IMS Giotto Class, sono state acquisite otto proiezioni, di cui quattro con mammografia digitale con protesi inclusa, e quattro in Tomosintesi con manovra di Eklund. In un secondo gruppo di 38 donne si è attivata una configurazione a bassa dose dell’AEC. L’età media delle donne che hanno fatto parte dello studio è compresa tra i 50 ed i 65 anni. Una donna rientrava nel programma di screening dopo 10 anni dall’intervento di quadrantectomia. RISULTATI Dall’analisi e dal confronto dei dati acquisiti nelle diverse modalità di studio è emerso che allo studio in modalità Mammografia, con le sole quattro proiezioni a protesi inclusa, con esposimetro standard, è associata una dose media ghiandolare di 7.5 mGy. Se si effettua anche la manovra di Eklund in modalità Tomosintesi si espone la donna ad una media di 11 mGy totali. Ad una configurazione a bassa dose dell’AEC, per le otto proiezioni, acquisite anche in tomosintesi, è associata una dose media ghiandolare pari a 9,2 mGy totali. Questa configurazione dedicata consente di abbassare la dose del 15%, mantenendo adeguata la qualità delle immagini. DISCUSSIONE Al momento attuale la Tomosintesi per lo studio delle mammelle con protesi non è ancora considerata un valido test diagnostico, principalmente a causa dell’ingombro della protesi; tuttavia, i risultati di questo test sembrano rendere ipotizzabile un suo efficace utilizzo. CONCLUSIONI La metodica di studio sperimentata è basata sulle migliori pratiche e sulle più innovative tecnologie appositamente progettate per la mammografia. Si è dimostrata in grado di migliorare l’accuratezza dei test di screening, ha garantito una dose ghiandolare controllata ed un risultato iconografico adeguato. Diffondendo tale metodologia potremmo essere in grado di aumentare il livello qualitativo delle prestazioni nel target identificato.

Background: Standard of Care (SoC) has been used with different significance across Randomized Clinical Trials (RCTs) on the treatment of Covid-19. In the context of a living systematic review on pharmacological interventions for COVID-19, we assessed the characteristics of the SoC adopted in the published RCTs.Methods: We performed a systematic review searching Medline, Pubmed, Embase, Cochrane Covid-19 register, international trial registers, medRxiv, bioRxiv, and arXiv up to April 10, 2021. We included all RCTs comparing any pharmacological intervention for Covid-19 against any drugs, placebo, or SoC. All trials selected have been classified as studies with SoC including treatments under investigation for COVID-19 (SoC+); studies with SoC without specifications regarding the potential therapies allowed (SoC-); studies including as control groups Placebo (P) or active controls (A+).Results: We included in our analysis 144 RCTs, comprising 78,319 patients. Most of these trials included SoC (108; 75.0%); some in all arms of the study (69.7%) or just as independent comparators (30.3%). Treatments under investigation for COVID-19 in other trials were included in the SoC (SoC+) in 67 cases (62.0%), Thirty-one different therapeutic agents (alone or in combination) were counted within the studies with SoC+: mostly hydroxychloroquine or chloroquine (28), lopinavir/ritonavir (20) or azithromycin (16). No specification was given regarding treatment allowed in the control groups (SoC-) in 41 studies (38.0%).Conclusion: Our analysis shows that the findings emerging from several clinical trials regarding the efficacy and safety of pharmacological intervention for COVID-19 might be jeopardized by the quality of control arms.

Leucojum aestivum is a medicinal plant belonging to the Amaryllidaceae family well known as a producer of alkaloids such as galanthamine and lycorine. However, the endophytic microbes that colonize different plant tissues without causing any damage have not been reported in this plant. Here, we explored the different endophytic bacterial communities isolated from different surface disinfected tissues of L. aestivum ‘Gravety giant’ and screened bacterial isolates producing alkaloids and their potential use as biocontrol agent against wheat pathogens. For that purpose, endophytic bacteria were isolated from bulbs, roots and shoots of L. aestivum. After taxonomical characterization, these microorganisms were screened for their ability to produce alkaloids using high-performance thin-layer chromatography (HPTLC) and untargeted liquid chromatography-Mass Spectrometry/Mass Spectrometry (LC-MS/MS) strategies. We isolated 138 bacteria belonging to four phyla and 42 genera, mainly from roots and shoots. The most abundant genera were Rahnella in shoot, Patulibacter in bulb and Bacillus in roots. Among the different bacterial isolates, the methanolic extracts of Luteibacter rhizovicinus (LaBFB3301) and Commamonas denitrificans (LaBFS2103) slightly delayed the growth of F. graminearum colonies in in vitro dual tests against F. graminearum and M. nivale strains with 15.5% and 19.9% inhibition rates, respectively. These isolates are able to produce an indolic alkaloid tryptophol (C10H11NO, [M + H]+ 162.0913). These endophytic bacteria might be investigated to characterize the plant protection effect and the plant growth promotion effect.

Background: Several pharmacological interventions are now under investigation for the treatment of Covid-19, and the evidence is evolving rapidly. Our aim is to assess the comparative efficacy and safety of these drugs.Methods and Findings: We performed a systematic review and network meta-analysis searching Medline, Pubmed, Embase, Cochrane Covid-19 register, international trial registers, medRxiv, bioRxiv, and arXiv up to December 10, 2020. We included all randomised controlled trials (RCTs) comparing any pharmacological intervention for Covid-19 against any drugs, placebo or standard care (SC). Data extracted from published reports were assessed for risk of bias in accordance with the Cochrane tool, and using the GRADE framework. Primary outcomes were all-cause mortality, adverse events (AEs) and serious adverse events (SAEs). We estimated summary risk ratio (RR) using pairwise and network meta-analysis with random effects (Prospero, number CRD42020176914). We performed a systematic review and network meta-analysis searching Medline, Pubmed, Embase, Cochrane Covid-19 register, international trial registers, medRxiv, bioRxiv, and arXiv up to December 10, 2020. We included all randomised controlled trials (RCTs) comparing any pharmacological intervention for Covid-19 against any drugs, placebo or standard care (SC). Data extracted from published reports were assessed for risk of bias in accordance with the Cochrane tool, and using the GRADE framework. Primary outcomes were all-cause mortality, adverse events (AEs) and serious adverse events (SAEs). We estimated summary risk ratio (RR) using pairwise and network meta-analysis with random effects (Prospero, number CRD42020176914). We included 96 RCTs, comprising of 34,501 patients. The network meta-analysis showed in terms of all-cause mortality, when compared to SC or placebo, only corticosteroids significantly reduced the mortality rate (RR 0.90, 95%CI 0.83, 0.97; moderate certainty of evidence). Corticosteroids significantly reduced the mortality rate also when compared to hydroxychloroquine (RR 0.83, 95%CI 0.74, 0.94; moderate certainty of evidence). Remdesivir proved to be better in terms of SAEs when compared to SC or placebo (RR 0.75, 95%CI 0.63, 0.89; high certainty of evidence) and plasma (RR 0.57, 95%CI 0.34, 0.94; high certainty of evidence). The combination of lopinavir and ritonavir proved to reduce SAEs when compared to plasma (RR 0.49, 95%CI 0.25, 0.95; high certainty of evidence). Most of the RCTs were at unclear risk of bias (42 of 96), one third were at high risk of bias (34 of 96) and 20 were at low risk of bias. Certainty of evidence ranged from high to very low.Conclusion: At present, corticosteroids reduced all-cause mortality in patients with Covid-19, with a moderate certainty of evidence. Remdesivir appeared to be a safer option than SC or placebo, while plasma was associated with safety concerns. These preliminary evidence-based observations should guide clinical practice until more data are made public.

Objective The proportion and characteristics of Italian patients affected by venous thromboembolism (VTE) treated with direct oral anticoagulants (DOACs) or vitamin K antagonists (VKAs), and complications occurring during follow-up.Design A prospective cohort of 2728 VTE patients included in the Survey on anticoagulaTed pAtients RegisTer (START2-Register) from January 2014 to June 2018 was investigated. Characteristics of patients, type of treatment and complications occurring during 2962 years of follow-up were analysed.Setting About 60 Italian anticoagulation and thrombosis centres participated in the observational START2-RegisterParticipants 2728 adult patients with VTE of a lower limb and/or pulmonary embolism (PE), with a follow-up after the initial phase treatment.Interventions Patients could receive DOACs or VKAs; both prescribed by the National and Regional Health Systems for patients with VTE.Outcomes measures Efficacy: rate of VTE recurrence (all thrombotic complications were also recorded). Safety: the rate of major and clinically relevant non-major bleeding events.Results Almost 80% of patients were treated with DOACs. The prevalence of symptomatic PE and impaired renal function was higher in patients receiving VKAs. Duration of anticoagulation was >180 days in approximately 70% of patients. Bleeding events were similar in both treatment groups. The overall eventuality of recurrence was significantly higher in DOAC cohorts versus VKA cohorts (HR 2.15 (1.14–4.06), p=0.018); the difference was almost completely due to recurrences occurring during extended treatment (2.73% DOAC vs 0.49% VKA, p

Background Pancreatic ductal adenocarcinoma (PDA) is an almost incurable tumor that is mostly resistant to chemotherapy (CT). Adaptive immune responses to tumor-associated antigens (TAA) have been reported, but immunotherapy (IT) clinical trials have not yet achieved any significant increase in survival, confirming the suppressive environment of PDA. As CT has immune-modulating properties, we investigated the effect of gemcitabine (GEM) in antitumor effector responses to TAA in patients with PDA.Methods The IgG antibody repertoire in patients with PDA before and after CT was profiled by serological proteome analysis and ELISA and their ability to activate complement-dependent cytotoxicity (CDC) was measured. Peripheral T cells were stimulated in vitro with recombinant TAA, and specific proliferation, IFN-γ/IL-10 and CD8+/Treg ratios were measured. Mice that spontaneously developed PDA were treated with GEM and inoculated with an ENO1 (α−Enolase) DNA vaccine. In some experimental groups, the effect of depleting CD4, CD8 and B cells by specific antibodies was also evaluated.Results CT increased the number of TAA recognized by IgG and their ability to activate CDC. Evaluation of the IFN-γ/IL-10 ratio and CD8+/Treg ratios revealed that CT treatment shifted T cell responses to ENO1, G3P (glyceraldheyde-3-phosphate dehydrogenase), K2C8 (keratin, type II cytoskeletal 8) and FUBP1 (far upstream binding protein 1), four of the most recognized TAA, from regulatory to effector. In PDA mice models, treatment with GEM prior to ENO1 DNA vaccination unleashed CD4 antitumor activity and strongly impaired tumor progression compared with mice that were vaccinated or GEM-treated alone.Conclusions Overall, these data indicate that, in PDA, CT enhances immune responses to TAA and renders them suitable targets for IT.

Background Leucojum aestivum L. is an important medicinal plant which produces Amaryllidaceae alkaloids, especially galanthamine and lycorine. Research is currently exploring the possibility of producing these alkaloids using biotechnological methods, including in vitro cultures. The biosynthesis of alkaloids may be affected by the types and concentrations of carbohydrate sources used in the medium. In the present investigation we performed such studies on in vitro cultures of L. aestivum with a view to obtaining plant material of good quality, characterized, in particular, by a high content of valuable Amaryllidaceae alkaloids. Methods We examined the effects of various types of carbohydrate sources—sucrose, glucose, fructose and maltose—at different concentrations (30, 60 and 90 g/L)—on the quality of L. aestivum plants grown in the RITA® bioreactor. The plants’ quality was assessed by their biomass increments, as well by as analysing photosynthetic pigments, endogenous sugar, phenolics and Amaryllidaceae alkaloid content. We also investigated the effect of sugars on the activity of the antioxidant enzymes catalase (CAT), peroxidase (POD) and superoxide dismutase (SOD). Results The highest biomass increments were observed in plants cultivated in the medium containing 90 g/L sucrose. The highest CAT activity was noted in cultures growing in the medium supplemented with 90 g/L maltose, while the highest POD activity was observed in the presence of 90 g/L fructose and 60 g/L maltose. No differences in SOD activity were observed. Moreover, the sugars did not affect the contents of chlorophyll a and carotenoids, whereas the highest amount of chlorophyll b was recorded in plants growing in the medium with 60 g/L maltose. No statistically significant differences were observed in the contents of endogenous sugars and phenolics in any in vitro conditions. However, the addition of sugar had a decisive effect on the biosynthesis of the Amaryllidaceae alkaloids. The highest distribution of alkaloids occurred in plants cultured in the medium containing 60 g/L sucrose. Six Amaryllidaceae alkaloids were detected in the plant tissue. The addition of 30 g/L fructose in the medium resulted in the accumulation of five alkaloids, including ismine, which was not identified in other analysed tissues. The highest concentration of galanthamine was observed in plants cultured in the presence of 30 g/L fructose and 60 g/L sucrose (39.2 and 37.5 µg/g of dry weight (DW), respectively). The plants grown in the medium containing 60 g/L sucrose exhibited the highest lycorine content (1048 µg/g of DW). Conclusions The type and concentration of sugar used in the medium have an essential influence on the biosynthesis of Amaryllidaceae alkaloids in L. aestivum plants cultured in a RITA® bioreactor. The results point to an interesting approach for commercial production of galanthamine and lycorine.

Background: In the Italian Breast Cancer Intergroup Studies (IBIS) 3 phase III trial, we compared cyclophosphamide, methotrexate, 5-fluorouracil (CMF) alone to sequential epirubicin/CMF regimens in patients with rapidly proliferating early breast cancer (RPEBC). We performed a post hoc analysis in the subgroup of patients with hormone-receptor-positive RPEBC on the prognostic role of progesterone receptor (PgR) status. Methods: RPEBC was defined by thymidine labeling index (TLI) >3% or grade 3 or S-phase >10% or Ki67 >20%. We analyzed 466 patients with hormone-receptor-positive RPEBC receiving sequential epirubicin/CMF regimens followed by tamoxifen, and for whom the status of ER and PgR was available. Results: Considering both cut-off values of 10% and 20%, PgR expression was significantly associated with age, menopausal status, and ER expression; HER2 status was associated with PgR status only at a cutoff value of 20% PgR. Upon univariate analysis, tumor size, nodal status, and PgR were significantly associated with disease-free survival (DFS) and overall survival (OS), while age class and local treatment type were associated only with DFS. Patients with PgR

An endogenous molecular clockwork drives various cellular pathways including metabolism and the cell cycle. Its dysregulation is able to prompt pathological phenotypes including cancer. Besides dramatic metabolic alterations, cancer cells display severe changes in the clock phenotype with likely consequences in tumor progression and treatment response. In this study, we use a comprehensive systems-driven approach to investigate the effect of clock disruption on metabolic pathways and its impact on drug response in a cellular model of colon cancer progression. We identified distinctive time-related transcriptomic and metabolic features of a primary tumor and its metastatic counterpart. A mapping of the expression data to a comprehensive genome-scale reconstruction of human metabolism allowed for the in-depth functional characterization of 24 h-oscillating transcripts and pointed to a clock-driven metabolic reprogramming in tumorigenesis. In particular, we identified a set of five clock–regulated glycolysis genes, ALDH3A2, ALDOC, HKDC1, PCK2, and PDHB with differential temporal expression patterns. These findings were validated in organoids and in primary fibroblasts isolated from normal colon and colon adenocarcinoma from the same patient. We further identified a reciprocal connection of HKDC1 to the clock in the primary tumor, which is lost in the metastatic cells. Interestingly, a disruption of the core-clock gene BMAL1 impacts on HKDC1 and leads to a time-dependent rewiring of metabolism, namely an increase in glycolytic activity, as well as changes in treatment response. This work provides novel evidence regarding the complex interplay between the circadian clock and metabolic alterations in carcinogenesis and identifies new connections between both systems with pivotal roles in cancer progression and response to therapy. Keywords: Circadian clock, Colorectal cancer, Metabolic rewiring, Tumor progression, High-throughput circadian data, Metabolic network reconstruction, Circadian regulation of metabolism, Treatment response, Glycolysis

Objectives: To evaluate the effectiveness of the measles-mumps-rubella (MMR) vaccine in reducing hospitalizations for infectious disease, targeted and not targeted, as well as from respiratory diseases in children in Rome. Methods: The cohort was recomposed through record linkage of 2 archives (vaccination register and hospital discharge records. Results: The analysis included 11,004 children. 20.9% did not receive the MMR vaccination, 49% and 30.1% received one and 2 doses. There were no hospitalizations for rubella, 2 for mumps, and 12 for measles. The vaccine was highly protective against measles and mumps hospitalizations (HR = 0.10; 95% CI: 0.03.0.34). Regarding all infectious diseases there were 414 hospitalizations, and the vaccine was protective (HR = 0.29; 95% CI: 0.25 to 0.34). Concerning respiratory diseases, there were 809 admissions (7.4%), and the vaccine was highly protective (HR: 0.18; 95% CI: 0.07 to 0.48). Conclusions: MMR vaccination is effective for the primary prevention of target and not targeted infectious diseases and may also limit hospitalizations for respiratory diseases.

Background: Most of the patients with Pancreatic Ductal Adenocarcinoma (PDA) are not eligible for a curative surgical resection. For this reason there is an urgent need for personalized therapies. PDA is the result of complex interactions between tumor molecular profile and metabolites produced by its microenvironment. Despite recent studies identified PDA molecular subtypes, its metabolic classification is still lacking.Methods: We applied an integrative analysis on transcriptomic and genomic data of glycolytic genes in PDA. Data were collected from public datasets and molecular glycolytic subtypes were defined using hierarchical clustering. The grade of purity of the cancer samples was assessed estimating the different amount of stromal and immunological infiltrate among the identified PDA subtypes. Analyses of metabolomic data from a subset of PDA cell lines allowed us to identify the different metabolites produced by the metabolic subtypes. Sera of a cohort of 31 PDA patients were analyzed using Q-TOF mass spectrometer to measure the amount of metabolic circulating proteins present before and after chemotherapy.Results: Our integrative analysis of glycolytic genes identified two glycolytic and two non-glycolytic metabolic PDA subtypes. Glycolytic patients develop disease earlier, have poor prognosis, low immune-infiltrated tumors, and are characterized by a gain in chr12p13 genomic region. This gain results in the over-expression of GAPDH, TPI1, and FOXM1. PDA cell lines with the gain of chr12p13 are characterized by an higher lipid uptake and sensitivity to drug targeting the fatty acid metabolism. Our sera proteomic analysis confirms that TPI1 serum levels increase in poor prognosis gemcitabine-treated patients.Conclusions: We identify four metabolic PDA subtypes with different prognosis outcomes which may have pivotal role in setting personalized treatments. Moreover, our data suggest TPI1 as putative prognostic PDA biomarker.

For the first time, the study of the antioxidant activity, the characterization of the phytoconstituants, and the evaluation of in vitro and in vivo toxicity of A. djiboutiensis leave and latex are performed. The antioxidant activity of both latex (ADL) and the methanolic extract of leaves (ADM) is determined using 1-diphenyl-2-picrylhydrazyl (DPPH), 2,2′-azino-bis 3-ethylbenzothiazoline-6-sulphonic acid (ABTS) scavenging radical methods and ferric reducing/antioxidant power (FRAP) assay. The phytochemical study of latex is done using Liquid Chromatography-Mass Spectrometry (LC-MS/MS) and a molecular networking-based approach. The evaluation of in vivo toxicity is performed on mice by oral gavage with a suspension of ADL. Our results show that weak antioxidant activity of ADL and ADM in opposition to their high polyphenol, 83.01 mg and 46.4 mg expressed in gallic acid equivalent (GAE)/g of dry weight (DW), respectively, and flavonoid contents 13.12 mg and 4.25 mg expressed in quercetin equivalent (QE)/g dry weight (DW), respectively. Using the Global Natural Products Social Molecular Networking (GNPS) website, nine (9) anthraquinones derivatives, ten (10) chromones derivatives, two (2) flavonols/ chromones isomers are annotated in the molecular network. The treated mice do not display abnormalities in their general physical appearance and biochemistry parameters, compared to the controls. Only glucose and calcium levels are slightly higher in male treated mice compared to the vehicles.

Basically the Health Technology Assessment (HTA) is based on the scientific method and aims to produce information used in the field of health policy choices that need to be effective, efficient and safe. For this reason they Systematic Reviews (SR) and Meta-Analysis (MA) are generally used. Typically, a single evaluation, even if resulting from an appropriate experimental study, can hardly be considered sufficient to help in make decisions on a health intervention mainly for statistical considerations (sample size is rather limited). Furthermore, if there were more primary studies, the results would not completely be in agreement with each other or may be dissimilar as they would be drawn from different social and economic backgrounds and thus are only partially comparable. The SR and MA consolidate existing relevant search results in order to resolve any inconsistency or ambiguity between the existing studies and produce results that are obvious or significant results in individual studies. Often, when one decides to conduct an HTA, evidence of efficacy are lacking both quantitatively and qualitatively and / or the application contexts are often very dissimilar. Even in this case, the SR and MA do not generate new data but can produce new knowledge from existing evidence. Also the use of RS and MA to assess the availability or lack of sufficient evidence (for example on the efficacy of an intervention / treatment) or to indicate the need to conduct further studies and to generate new evidence pointing out which aspects should be taken into consideration.

HEalth Risk from Environmental Pollution Levels in Urban Systems (HEREPLUS) project has been thought and carried out to fill some of the identified gaps in the evidence base and develop and apply an integrated methodology for assessing and quantifying the health risk associated to outdoor pollution exposure and for investigating the potential mitigating role of urban green. Results of HEREPLUS have demonstrated that these are no watertight compartments and that some issues should be tackled in an integrated approach. For instance, benefits from a proper selection of vegetation species in a city could be assessed in terms of load of pollutants removed from the atmosphere, and furthermore this data translated into health benefits. Additionally, health outcomes could be better interpreted in terms of a spatial analysis that previously had defined the high risk areas associated to a specific pollutant and, in consequence, action plans can be defined taking into account this geo-referenced information.

Objective: To perform a systematic review of the scientific literature to identify risk factors associated with hepatitis B viruses (HBV) infection among blood donors. Methods: The literature search was carried out on PubMed and Scopus databases using the keywords “risk factors” “HBV infection” and “blood donors”. No date or language restrictions were applied to the search. This literature review was completed in March 2014. The selection process and the reporting of the review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement. The Newcastle Ottawa scale was using to evaluate the quality of each single primary study. Results: Out of 172 records resulted in the search, 5 papers were included in the final analysis because they are within acceptance criteria. Two of the selected studies were cross-sectional and three of them were case-control studies. Significant association resulted with some demographic and behavioral risk factors, such as marital status, dental treatment/procedure history, no stable relationship or multiple partners and family history of HBV infection. Conclusions: The systematic review performed encourages to conduct further research among blood donors in order to fully understand risk factors among donors in more extensive thus to provide valuable information about surveillance.

An endophytic fungus isolated from Vernonia amygdalina, a medicinal plant from Sudan, was taxonomically characterized as Curvularia papendorfii. Ethyl acetate crude extract of C. papendorfii revealed an important antiviral effect against two viral pathogens, the human coronavirus HCoV 229E and a norovirus surrogate, the feline coronavirus FCV F9. For the last one, 40% of the reduction of the virus-induced cytopathogenic effect at lower multiplicity of infection (MOI) 0.0001 was observed. Selective antibacterial activity was obtained against Staphylococcus sp. (312 µg/mL), and interesting antiproliferative activity with half maximal inhibitory concentration (IC50) value of 21.5 ± 5.9 µg/mL was observed against human breast carcinoma MCF7 cell line. Therefore, C. papendorfii crude extract was further investigated and fractionated. Twenty-two metabolites were identified by gas chromatography coupled to mass spectrometry (GC–MS), and two pure compounds, mannitol and a new polyhydroxyacid, called kheiric acid, were characterized. A combination of spectroscopic methods was used to elucidate the structure of the new aliphatic carboxylic acid: kheiric acid (3,7,11,15-tetrahydroxy-18-hydroxymethyl-14,16,20,22,24-pentamethyl-hexacosa-4E,8E,12E,16,18-pentaenoic acid). Kheiric acid showed an interesting result with a minimum inhibitory concentration (MIC) value of 62.5 µg/mL against meticillin-resistant Staphylococcus aureus (MRSA). Hence, endophytes associated with medicinal plants from Sudan merit more attention, as they could be a treasure of new bioactive compounds.

Water extract of Acacia seyal bark is used traditionally by the population in Djibouti for its anti-infectious activity. The evaluation of in vitro antibacterial, antioxidant activities and cytotoxicity as well as chemical characterization of Acacia seyal bark water and methanolic extracts were presented. The water extract has a toxicity against the MRC-5 cells at 256 μg/mL while the methanolic extract has a weak toxicity at the same concentration. The methanolic extract has a strong antioxidant activity with half maximal inhibitory concentration (IC50) of 150 ± 2.2 μg/mL using 1-diphenyl-2-picrylhydrazyl (DPPH) and IC50 of 27 ± 1.3 μg/mL using 2,2′-azino-bis 3-ethylbenzthiazoline-6-sulphonic acid (ABTS) radical methods. For ferric reducing/antioxidant power (FRAP) assay, the result is 45.74 ± 5.96 μg Vitamin C Equivalent (VCE)/g of dry weight (DW). The precipitation of tannins from methanol crude extract decreases the MIC from 64 µg/mL to 32 µg/mL against Staphylococcus aureus and Corynebacterium urealyticum. However, the antioxidant activity is higher before tannins precipitation than after (IC50 = 150 µg/mL for methanolic crude extract and 250 µg/mL after tannins precipitation determined by DPPH method). By matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) analysis, the results showed that the condensed tannins consist of two types of catechin and gallocatechin-based oligomers. The fractionation led to the identification of three pure compounds: two flavanols catechin and epicatechin; one triterpene as lupeol; and a mixture of three steroids and one fatty acid: campesterol, stigmasterol, clionasterol, and oleamide.

Chronic hepatitis C is characterized by metabolic disorders and by a microenvironment in the liver dominated by oxidative stress, inflammation and regeneration processes that can in the long term lead to liver cirrhosis and hepatocellular carcinoma. Several lines of evidence suggest that mitochondrial dysfunctions play a central role in these processes. However, how these dysfunctions are induced by the virus and whether they play a role in disease progression and neoplastic transformation remains to be determined. Most in vitro studies performed so far have shown that several of the hepatitis C virus (HCV) proteins also localize to mitochondria, but the consequences of these interactions on mitochondrial functions remain contradictory and need to be confirmed in the context of productively replicating virus and physiologically relevant in vitro and in vivo model systems. In the past decade we have been proposing a temporal sequence of events in the HCV-infected cell whereby the primary alteration is localized at the mitochondria-associated ER membranes and causes release of Ca2+ from the ER, followed by uptake into mitochondria. This ensues successive mitochondrial dysfunction leading to the generation of reactive oxygen and nitrogen species and a progressive metabolic adaptive response consisting in decreased oxidative phosphorylation and enhanced aerobic glycolysis and lipogenesis. Here we resume the major results provided by our group in the context of HCV-mediated alterations of the cellular inter-compartmental calcium flux homeostasis and present new evidence suggesting targeting of ER and/or mitochondrial calcium transporters as a novel therapeutic strategy.

INTRODUCTION: Cardiovascular diseases (CVD) remain the biggest cause of disability and premature death throughout the world. AIM: The aim of this study was to describe and determine the prevalence of major cardiovascular risk factors emerged at the first medical examination carried out by a group of an oil and gas contractor company workers in the observation period 2000-2010. METHODS: An observational cross-sectional study was conducted on 1073 workers (mean age 41 years, SD = 9.5) presenting overweight BMI (body mass index) values, hypertension and cholesterol problems. RESULTS: In particular, we found that workers > 45 years had significant higher risk to have obesity (OR = 3.8, CI 95% = 2.5-5.7), hypertension (OR = 2.7, CI 95% = 2.1-3.6), high blood fasting glucose (OR = 2.6, CI 95% = 1.2-5.5), high cholesterol (OR = 2.7, CI 95% = 2.0-3.6), high triglycerides (OR = 1.8, CI 95% = 1.4-2.4) compared to younger (< 45 years).

It’s necessary to increase the knowledge of children aged 5-9 years and their parents on the subject of eating and promoting physical activity. The present paper describes the research protocol of a randomized field trial that aims: a) to increase the knowledge of food pyramid and b) to modify the nutrition behavior in order to improve the Mediterranean diet, especially: to increase fruit and vegetables consumption. The subjects enrolled in the trial will be children of the primary schools that will be randomized to receive or not an intervention through the use of games (cards and table games), which include also physical activities.

The association of anti-EGFR to gemcitabine and oxaliplatin (GEMOX) chemotherapy did not improve survival in biliary tract carcinoma (BTC) patients. Multiple mechanisms might be involved in the resistance to anti-EGFR. Here, we explored the mutation profile of EGFR extracellular domain (ECD), of tyrosine kinase domain (TKD), and its amplification status. EGFR mutational status of exons 12, 18-21 was analyzed in 57 tumors by Sanger sequencing. EGFR amplification was evaluated in 37 tumors by Fluorescent In Situ Hybridization (FISH). Kaplan-Meier curves were calculated using the log-rank test. Six patients had mutations in exon 12 of EGFR ECD and 7 in EGFR TKD. Neither EGFR ECD nor TKD mutations affected progression free survival (PFS) or overall survival (OS) in the entire population. In the panitumumab plus GEMOX (P-GEMOX) arm, ECD mutated patients had a worse OS, while EGFR TKD mutated patients had a trend towards shorter PFS and OS. Overall, the presence of mutations in EGFR or in its transducers did not affect PFS or OS, while the extrahepatic cholangiocarcinoma (ECC) mutated patients had a worse prognosis compared to WT. Nineteen out of 37 tumors were EGFR amplified, but the amplification did not correlate with survival. ECC EGFR amplified patients had improved OS, whereas the amplification significantly correlated with poor PFS (p = 0.03) in gallbladder carcinoma patients. The high molecular heterogeneity is a predominant feature of BTC: the alterations found in this work seem to have a prognostic impact rather than a predictive role towards anti-EGFR therapy.

Cardiovascular diseases are the leading causes of mortality and morbidity in Western countries. The possible synergistic effect of poor adherence to a Mediterranean diet (MD) and other risk factors for acute myocardial infarction (AMI) such as hypertension, cholesterol, ever smoker, BMI> 25, diabetes, has not been deeply studied.Case-control study.Patients with first AMI and controls from four tertiary referral Italian centers were screened for enrolment. Dietary information was collected through a questionnaire and a MD adherence score was calculated. Physical activity and smoking habits were also registered. The Synergy Index was calculated according to Rothman.127 cases and 173 controls were enrolled. The analysis was conducted using a dichotomous variable for the MD score with values ≥7 representing good adherence. Multivariate analysis showed the following variables associated to AMI: ever smoker (OR = 2.08), diabetes (OR = 1.42), hypertension (OR = 2.08), hypercholesterolemia (OR = 2.47), BMI> 25 (OR = 1.99), while a protective effect emerged both in subjects scoring > 7 on the MD score (OR = 0.55) and in subjects resident of Southern Italy (OR = 0.38). A synergistic effect does exist between poor adherence to the MD and the following risk factors: hypertension, hypercholesterolemia, BMI >25, diabetes and being a resident in central and northern Italy.Synergy between heart disease risk factors and MD underlines the need to enlarge the list of known modifiable cardiovascular risk factors to include and promote adherence to Mediterranean dietary habits.

This project aims to develop a Center of Preventive Medicine and Health Care for the students of Medicine and Health profession at Sapienza University of Rome. At the beginning of the university career students, both residents and nonresident s, have to face several difficulties such as: starting smoking or the increase in cigarette consumption ; the independent management of their own health (especially for non residents consequently to the distance of the family doctor) ; unhealthy diet; tuberculosis (TB) biological risk during their university training. These aspects , especially if present at the same time, act as a source stress and adversely affect the quality of life and the academic performance. Specific aims of the project will be: implementing an ambulatory of Preventive Medicine; implementing a virtual ambulatory of general medicine; creating a website on the problems mentioned above. Data collected will be computerized to keep an electronic health record (HER) and to use the information for the purposes of scientific research. The Centre will act in close relationship with the Central Administration, with the Headmasters of the Medical Faculties, and in close collaboration with the Center of Occupational Medicine of Sapienza University.

Human alveolar echinococcosis (AE) is a severe zoonotic disease caused by the metacestode stage of Echinococcus multilocularis. AE is commonly associated with a long incubation period that may last for more than ten years. The objective of this systematic literature review was to identify and summarize the current knowledge on statistically relevant potential risk factors (PRFs) associated with AE in humans.Six bibliographic databases were searched, generating a total of 1,009 publications. Following the removal of duplicate records and the exclusion of papers that failed to meet the criteria of a previously agreed a priori protocol, 23 publications were retained; however, 6 of these did not contain data in a format that allowed their inclusion in the meta-analysis. The remaining 17 publications (6 case-control and 11 cross-sectional studies) were meta-analysed to investigate associations between AE and PRFs. Pooled odds ratios (OR) were used as a measure of effect and separately analysed for case-control and cross-sectional studies. In the case-control studies, the following PRFs for human AE showed higher odds of outcome: "dog ownership", "cat ownership", "have a kitchen garden", "occupation: farmer", "haymaking in meadows not adjacent to water", "went to forests for vocational reasons", "chewed grass" and "hunting / handling foxes". In the cross-sectional studies, the following PRFs showed higher odds of outcome: "dog ownership", "play with dogs", "gender: female", "age over 20 years", "ethnic group: Tibetan", "low income", "source of drinking water other than well or tap", "occupation: herding" and "low education". Our meta-analysis confirmed that the chance of AE transmission through ingestion of food and water contaminated with E. multilocularis eggs exists, but showed also that food- and water-borne PRFs do not significantly increase the risk of infection.This systematic review analysed international peer-reviewed articles that have over the years contributed to our current understanding of the epidemiology of human AE. The identification of potential risk factors may help researchers and decision makers improve surveillance and/or preventive measures that aim at decreasing human infection with E. multilocularis. More primary studies are needed to confirm potential risk factors and their role in the epidemiology of human AE.

OBJECTIVES: To examine smoking prevalence, attitudes, knowledge and behaviours/beliefs among Health Professional School students according to the Global Health Professional Student Survey (GHPSS) approach. METHODS: A cross-sectional study was carried out in Catania University Medical Schools. The GHPSS questionnaires were self-administered. Logistic regression model was performed. The level of significance was p < 0.05. RESULTS: 422 students answered to the questionnaire. Prevalence of current smokers was 38.2%. 94.3% of the total sample believe that health professionals should receive specific training to quit smoking, but only 21.3% of the sample received it during the study courses. CONCLUSIONS: Given the high prevalence of smokers among health professionals and their key role both as advisers and behavioral models, our results highlight the importance of focusing attention on smoking cessation training addressed to them.

Targeting metabolism is emerging as a promising therapeutic strategy for modulation of the immune response in human diseases. In the presented study we used the lipopolysaccharide (LPS)-mediated activation of RAW 264.7 macrophage-like cell line as a model to investigate changes in the metabolic phenotype and to test the effect of p-hydroxyphenylpyruvate (pHPP) on it. pHPP is an intermediate of the PHE/TYR catabolic pathway, selected as analogue of the ethyl pyruvate (EP), which proved to exhibit antioxidant and anti-inflammatory activities. The results obtained show that LPS-priming of RAW 264.7 cell line to the activated M1 state resulted in up-regulation of the inducible nitric oxide synthase (iNOS) expression and consequently of NO production and in release of the pro-inflammatory cytokine IL-6. All these effects were prevented dose dependently by mM concentrations of pHPP more efficiently than EP. Respirometric and metabolic flux analysis of LPS-treated RAW 264.7 cells unveiled a marked metabolic shift consisting in downregulation of the mitochondrial oxidative phosphorylation and upregulation of aerobic glycolysis respectively. The observed respiratory failure in LPS-treated cells was accompanied with inhibition of the respiratory chain complexes I and IV and enhanced production of reactive oxygen species. Inhibition of the respiratory activity was also observed following incubation of human neonatal fibroblasts (NHDF-neo) with sera from septic patients. pHPP prevented all the observed metabolic alteration caused by LPS on RAW 264.7 or by septic sera on NHDF-neo. Moreover, we provide evidence that pHPP is an efficient reductant of cytochrome c. On the basis of the presented results a working model, linking pathogen-associated molecular patterns (PAMPs)-mediated immune response to mitochondrial oxidative metabolism, is put forward along with suggestions for its therapeutic control.

Telomerase, a fundamental marker of neoplastic transformation, is widely expressed in both premalignant intraepithelial lesions and in most malignant lesions of the uterine cervix. We determined telomerase activity (TA) in uterine cervix by Repeat Amplification Protocol (TRAP) in a series of 62 cases, 44 with benign diseases (inflammation and/or metaplasia and/or acanthosis) and 18 with cervical intraepithelial neoplasia (CIN). No significant differences in TA were observed between benign lesions (median AEU value 36, range 0–119) and CIN (median AEU value 30, range 0–65). Conversely, TA was significantly higher in subjects who showed CIN evolution (65 range 45–119) than in disease-free individuals (34 range 0–95, p = 0.017) and in 1 patient with a CIN2 lesion who relapsed after 5 years. Our results suggest that TA of the uterine cervix is capable of predicting CIN evolution or relapse, thus indicating its potential usefulness as a prognostic marker in clinical surveillance programs.

Bladder cancer has an incidence of 15 cases per 100,000 persons in the global population and is the most common tumor of the urinary tract. Imaging techniques, cytoscopy, and cytology are either invasive or not sufficiently accurate to detect early stage tumors, and the need for new diagnostic markers still remains. Among the markers most recently proposed to improve diagnostic accuracy and especially sensitivity, increasing attention has been focused on the role of the ribonucleoprotein, telomerase. Relevant papers on the etiology, diagnosis, and evaluation of bladder cancer using telomerase in urine were searched for and considered. The PubMed search was performed using the text terms "bladder cancer", "diagnosis", and "telomerase". Previous studies have shown that the quantitative Telomerase Repeat Amplification Protocol (TRAP) assay performed in voided urine is an important non-invasive tool for the diagnosis of bladder tumors since it has very high sensitivity and specificity, even for early stage and low grade tumors. The main limitation of this test is the rate of false positive results due to the presence of inflammatory or non-tumor cells (i.e., epithelial cells from the lower genital tract), which express telomerase activity (TA). Consequently, an in situ analysis would seem to be important to identify the nature of telomerase-positive cells. Immunocytochemical detection of the hTERT subunit by a specific antibody seemed to open up the possibility to identify different cellular components of urine. However, the lack of a strict relationship between hTERT protein expression and telomerase activity has, to a certain extent, made this approach less relevant. In conclusion, telomerase activity in urine determined by TRAP seems to be marker of great potential, even more advantageous in cost/benefit terms when used in selected symptomatic patients or professionally high-risk subgroups.

Background: A variety of molecular markers have been evaluated for the development of a non-invasive approach to the diagnosis of colorectal cancer. We aimed to validate the diagnostic accuracy, using the same threshold as in the previous pilot study, of fluorescent long DNA test as a relatively simple and inexpensive tool for colorectal cancer detection.

The aim of this study was to test the effect of a small volume administration of p-hydroxyphenylpyruvate (pHPP) in a rat model of profound hemorrhagic shock and to assess a possible metabolic mechanism of action of the compound. The results obtained show that hemorrhaged rats treated with 2-4% of the estimated blood volume of pHPP survived significantly longer (p