Exclusive semileptonic BB-meson decays using lattice QCD and unitarity

We present the results of the application of the Dispersion Matrix approach to exclusive semileptonic $B$-meson decays. This method allows to determine the hadronic form factors in a non-perturbative and completely model-independent way. Starting from lattice results available at large values of the momentum transfer, the behaviour of the form factors in their whole kinematical range is obtained without introducing any parameterization of their momentum dependence. We will focus on the determination of the Cabibbo-Kobayashi-Maskawa matrix elements $\vert V_{cb} \vert$ and $\vert V_{ub} \vert$ through the analysis of $B_{(s)} \to D_{(s)}^{(*)} \ell \nu$ and $B_{(s)} \to \pi(K) \ell \nu$ decays. New theoretical determinations of the Lepton Flavour Universality ratios relevant for these transitions will be also presented.Comment: 8 pages, 5 figures, 2 tables; contribution to QCD@Work - International Workshop on QCD - Theory and Experiment, 27 - 30 June 2022, Lecce (Italy). arXiv admin note: substantial text overlap with arXiv:2205.1395

The DM approach to semileptonic heavy-to-heavy and heavy-to-light BB decays

We present the results of the application of the Dispersion Matrix approach to semileptonic heavy-to-heavy and heavy-to-light $B$-meson decays. This method allows to determine the hadronic form factors in a non-perturbative and model-independent way. Starting from the available lattice results at large values of the momentum transfer, we obtain the behaviour of the form factors in their whole kinematical range without introducing any parameterization of their momentum dependence. We will focus on the determination of the Cabibbo-Kobayashi-Maskawa matrix elements $\vert V_{cb} \vert$ and $\vert V_{ub} \vert$ through the analysis of $B \to D^{(*)} \ell \nu$, $B_s \to D_s^{(*)} \ell \nu$, $B \to \pi \ell \nu$ and $B_s \to K \ell \nu$ decays. New theoretical determinations of the Lepton Flavour Universality ratios relevant for these transitions will be also presented, by focusing in particular on the $R(D_{(s)}^{(*)})$ ratios.Comment: 9 pages, 3 figures. Proceedings for the 39th International Symposium on Lattice Field Theory (Lattice 2022). arXiv admin note: substantial text overlap with arXiv:2209.15413, arXiv:2205.13952; text overlap with arXiv:2211.0723

Metals loads into the Mediterranean Sea: estimate of Sarno River inputs and ecological risk

The metals pollution in the Sarno River and its environmental impact on the Gulf of Naples (Tyrrhenian Sea, Central Mediterranean Sea) were estimated. Eight selected metals (As, Hg, Cd, Cr, Cu, Ni, Pb and Zn) were determined in the water dissolved phase (DP), suspended particulate matter (SPM) and sediment samples. Selected metals concentrations ranged from 0.32 to 1,680.39 μg l(-1) in water DP, from 103.6 to 7,734.6 μg l(-1) in SPM and from 90.7 to 2,470.3 mg kg(-1) in sediment samples. Contaminant discharges of selected metals into the sea were calculated in about 13,977.6 kg year(-1) showing that this river should account as one of the main contribution sources of metals to the Tyrrhenian Sea

Vanillin prevents doxorubicin-induced apoptosis and oxidative stress in rat H9c2 cardiomyocytes

Doxorubicin (doxo) is an effective anticancer compound in several tumor types. However, as a consequence of oxidative stress induction and ROS overproduction, its high cardiotoxicity demands urgent attention. Vanillin possesses antioxidant, antiproliferative, antidepressant and anti-glycating properties. Therefore, we investigated the potential vanillin protective effects against doxo-induced cardiotoxicity in H9c2 cells. Using multiparametric approach, we demonstrated that vanillin restored both cell viability and damage in response to doxo exposure. Contextually, vanillin decreased sub-G1 appearance and caspase-3 and PARP1 activation, reducing the doxo-related apoptosis induction. From a mechanistic point of view, vanillin hindered doxo-induced ROS accumulation and impaired the ERK phosphorylation. Notably, besides the cardioprotective effects, vanillin did not counteract the doxo effectiveness in osteosarcoma cells. Taken together, our results suggest that vanillin ameliorates doxo-induced toxicity in H9c2 cells, opening new avenues for developing alternative therapeutic approaches to prevent the anthracycline-related cardiotoxicity and to improve the long-term outcome of antineoplastic treatment

Azathioprine Biotransformation in Young Patients with Inflammatory Bowel Disease: Contribution of Glutathione-S Transferase M1 and A1 Variants

The contribution of candidate genetic variants involved in azathioprine biotransformation on azathioprine efficacy and pharmacokinetics in 111 young patients with inflammatory bowel disease was evaluated. Azathioprine doses, metabolites thioguanine-nucleotides (TGN) and methylmercaptopurine-nucleotides (MMPN) and clinical effects were assessed after at least 3 months of therapy. Clinical efficacy was defined as disease activity score below 10. Candidate genetic variants (TPMT rs1142345, rs1800460, rs1800462, GSTA1 rs3957357, GSTM1, and GSTT1 deletion) were determined by polymerase chain reaction (PCR) assays and pyrosequencing. Statistical analysis was performed using linear mixed effects models for the association between the candidate variants and the pharmacological variables (azathioprine doses and metabolites). Azathioprine metabolites were measured in 257 samples (median 2 per patient, inter-quartile range IQR 1-3). Clinical efficacy at the first evaluation available resulted better in ulcerative colitis than in Crohn's disease patients (88.0% versus 52.5% responders, p = 0.0003, linear mixed effect model, LME). TGN concentration and the ratio TGN/dose at the first evaluation were significantly higher in responder. TPMT rs1142345 variant (4.8% of patients) was associated with increased TGN (LME p = 0.0042), TGN/dose ratio (LME p < 0.0001), decreased azathioprine dose (LME p = 0.0087), and MMPN (LME p = 0.0011). GSTM1 deletion (58.1% of patients) was associated with a 18.5% decrease in TGN/dose ratio and 30% decrease in clinical efficacy. GSTA1 variant (12.8% of patients) showed a trend (p = 0.049, LME) for an association with decreased clinical efficacy; however, no significant effect on azathioprine pharmacokinetics could be detected. In conclusion, GSTs variants are associated with azathioprine efficacy and pharmacokinetics

Neutralization of extracellular NAMPT (nicotinamide phosphoribosyltransferase) ameliorates experimental murine colitis

Extracellular nicotinamide phosphoribosyltransferase (eNAMPT) is increased in inflammatory bowel disease (IBD) patients, and its serum levels correlate with a worse prognosis. In the present manuscript, we show that eNAMPT serum levels are increased in IBD patients that fail to respond to anti-TNF\u3b1 therapy (infliximab or adalimumab) and that its levels drop in patients that are responsive to these therapies, with values comparable with healthy subjects. Furthermore, eNAMPT administration in dinitrobenzene sulfonic acid (DNBS)-treated mice exacerbates the symptoms of colitis, suggesting a causative role of this protein in IBD. To determine the druggability of this cytokine, we developed a novel monoclonal antibody (C269) that neutralizes in vitro the cytokine-like action of eNAMPT and that reduces its serum levels in rodents. Of note, this newly generated antibody is able to significantly reduce acute and chronic colitis in both DNBS- and dextran sulfate sodium (DSS)-induced colitis. Importantly, C269 ameliorates the symptoms by reducing pro-inflammatory cytokines. Specifically, in the lamina propria, a reduced number of inflammatory monocytes, neutrophils, Th1, and cytotoxic T lymphocytes are found upon C269 treatment. Our data demonstrate that eNAMPT participates in IBD and, more importantly, that eNAMPT-neutralizing antibodies are endowed with a therapeutic potential in IBD. Key messages: What are the new findings?Higher serum eNAMPT levels in IBD patients might decrease response to anti-TNF therapy.The cytokine-like activity of eNAMPT may be neutralized with a monoclonal antibody.Neutralization of eNAMPT ameliorates acute and chronic experimental colitis.Neutralization of eNAMPT limits the expression of IBD inflammatory signature.Neutralization of eNAMPT impairs immune cell infiltration in lamina propria

Antioxidant activity of stryphnodendron rotundifolium mart. Stem bark fraction in an iron overload model

Stryphnodendron rotundifolium Mart., popularly known as “barbatimão”, is a plant species traditionally used by topical and oral routes for the treatment of infectious and inflammatory diseases. Considering the well-described antioxidant properties of this species, this study investigated the protective effects of its keto-aqueous extract using an in vitro model of iron overload. Phenolic compounds were quantified and identified by Ultra-Performance Liquid Chromatography coupled with quadrupole Time-Of-Flight Electrospray Ionization Mass Spectrometry (UPLC–ESI-qTOF-MS/MS) in positive and negative ions mode analysis. Antioxidant activity was analyzed following the iron-chelating–reducing capacity and deoxyribose degradation (2-DR) protection methods. The analysis identified condensed tannins (54.8 mg catechin/g dry fraction (DF), polyphenols (25 mg gallic acid/g DF), and hydrolyzable tannins (28.8 mg tannic acid/g DF). Among the constituents, prodelphinidin, procyanidin, and prorobinetinidine were isolated and identified. The extract sig-nificantly protected 2-DR degradation induced by Fe2+ (72% protection) or• OH (43% protection). The ortho-phenanthroline test revealed Fe2+-chelating and Fe3+-reducing activities of 93% and 84%, respectively. A preliminary toxicological analysis using Artemia salina revealed mortality below 10%, at a concentration of 0.25 mg/mL, indicating low toxicity under the present experimental conditions. In conclusion, the findings of the present study indicate that Stryphnodendron rotundifolium is a source of antioxidant compounds with the potential to be used in drug development in the context of iron overload disorders, which remains to be further investigated in vivo

Rituximab Unveils Hypogammaglobulinemia and Immunodeficiency in Children with Autoimmune Cytopenia

BACKGROUND: Rituximab (RTX; anti-CD20 mAb) is a treatment option in children with refractory immune thrombocytopenia, autoimmune hemolytic anemia (AHA), and Evans syndrome (ES). Prevalence and clinical course of RTX-induced hypogammaglobulinemia in these patients are poorly known. OBJECTIVE: To evaluate the prevalence and risk factors for persistent hypogammaglobulinemia (PH) after RTX use. METHODS: Clinical and immunologic data from children treated with RTX for immune thrombocytopenia, AHA, and ES were collected from 16 Italian centers and 1 UK center at pre-RTX time point (0), +6 months, and yearly, up to 4 years post-RTX. Patients with previously diagnosed malignancy or primary immune deficiency (PID) were excluded. RESULTS: We analyzed 53 children treated with RTX for immune thrombocytopenia (n = 36), AHA (n = 13), and ES (n = 4). Median follow-up was 30 months (range, 12-48). Thirty-two percent of patients (17 of 53) experienced PH, defined as IgG levels less than 2 SD for age at last follow-up (>12 months after RTX). Significantly delayed B-cell recovery was observed in children experiencing PH (hazard ratio, 0.55; P < .05), and 6 of 17 (35%) patients had unresolved B-cell lymphopenia at last follow-up. PH was associated with IgA and IgM deficiency, younger age at RTX use (51 vs 116 months; P < .01), a diagnosis of AHA/ES, and better response to RTX. Nine patients with PH (9 of 17 [53%]) were eventually diagnosed with a PID. CONCLUSIONS: Post-RTX PH is a frequent condition in children with autoimmune cytopenia; a sizable proportion of patients with post-RTX PH were eventually diagnosed with a PID. In-depth investigation for PID is therefore recommended in these patients