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BackgroundAutoreactive proteinase 3 (PR3+) B cells have recently been phenotypically and functionally characterized, and the presence of defective central antigen-independent and peripheral antigen-dependent checkpoints in patients with ANCA-associated vasculitis (AAV) has been shown. This work aimed to investigate the central tolerance-checkpoint controlling immature PR3+ B cells in the bone marrow (BM), before their migration into the periphery as transitional B cells.ObjectivesWe investigated the presence and the specific phenotypic features of PR3+ B cells in BM mononuclear cells (BMMC) of non-vasculitis controls (No-AAV), comparing them to paired peripheral blood mononuclear cells (PBMC) of No-AAV and PBMC of PR3-AAV patients, and the central tolerance-checkpoint for PR3+ B cells.MethodsWe used a customized flow-cytometry assay, using PR3 as ligand to target autoreactive PR3+ B cells (PR3+B cells). Adult PR3-ANCA positive AAV (PR3-AAV) patients with a clinical diagnosis of granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) were selected among consecutive subjects with AAV seen in our Rheumatology Unit. Subjects without vasculitis (No AAV) were selected among consecutive subjects undergoing bone marrow aspirate to exclude hematologic conditions of myeloid origin and eventually resulted healthy or in long-term complete remission during follow-up of myeloid neoplasms. PMBC from AAV patients and paired samples of BMMC and PBMC from No AAV were collected and analyzed.ResultsThe proportion of PR3+ B cells within BMMC (median [IQR25-75%]; 1.98%[1.77-2.75]) was higher than within PBMC of No-AAV (0.9%[0.63-1.44], p<0.01 by paired comparison) and similar to their proportion within PBMC of PR3-AAV patients (1.82%[1.66-3.21]; p>0.05). When focusing on immature/transitional CD24++CD38++B cells only in No-AAV, we observed distinct phenotypes within BMMC versus PBMC (i.e. higher proportion of CD27-CD10+ and lower expression of CD21, IgD, IgM within BMMC versus PBMC), representing two separate developmental steps of B cell maturation. Within CD24++CD38++ B cells, BMMC contained the greatest proportion of PR3+ B cells as compared to PBMC (3.35%[1.99-4.92] versus 1.23%[0.62-1.55], p<0.01). We observed a significant decline of the PR3+ fraction from T1-like/immature subset (IgD-IgM+; 2.80%[1.23-4.02]) to T2-like/early transitional subset (IgD+IgM+; 1.76%[0.96-2.68], p<0.01) in BMMC, while no significant reduction was observed between the latter subset and the transitional compartment of PBMC (1.26%[0.62-1.56], p>0.05).ConclusionTo prevent PR3-related autoimmunity, autoreactive PR3+ B cells pass a stringent selection in the BM, and their removal by central tolerance-checkpoint activity occurs mainly between T1-like/immature to T2-like/early transitional B cells of BMMC.References[1]Cornec D. Identification and phenotyping of circulating autoreactive proteinase 3-specific B cells in patients with PR3-ANCA associated vasculitis and healthy controls. J of Autoimmunity, 2017.[2]Berti A. Circulating autoreactive proteinase 3+ B cells and tolerance checkpoints in ANCA-associated vasculitis. JCI Insight, 2021.Acknowledgements:NIL.Disclosure of InterestsAlvise Berti Speakers bureau: GSK, Michele Tomasi: None declared, Isabella Pesce: None declared, Enrico Lista: None declared, Anna Guella: None declared, Giuseppe Paolazzi: None declared, Roberto Bortolotti: None declared, Guido Grandi: None declared, Sophie Hillion: None declared, Ulrich Specks: None declared, Divi Cornec: None declared.

Chronic kidney disease (CKD) and hemodialysis (HD) patients have a high incidence of bone disease and increased fracture risk, making effective management of their bone health a clinical challenge. Denosumab, a human monoclonal antibody, has been investigated as a therapeutic option in this patient population. In this review, we summarize the current evidence on the efficacy and safety of denosumab in CKD and HD patients. A comprehensive search of the relevant literature was conducted, including randomized controlled trials, observational studies, and meta-analyses. The findings suggest that denosumab reduces the risk of fractures and improves bone mineral density in all stages of CKD. The results of this review support the use of denosumab as a promising option for managing bone disease in CKD and HD patients.

Extended-spectrum ß-lactamase (ESBL)-producing and are the most common uropathogens causing UTI (urinary tract infection) in type 2 diabetes mellitus (T2DM). Circulatory inflammatory markers such as C-reactive protein (CRP) and neutrophil-to-lymphocyte ratio (NLR) are usually dysregulated during UTI. However, the differential regulation of these inflammatory signatures during and UTI in T2DM has not been determined. A case-control study on 466 patients was performed to investigate the inflammatory signatures indicative of ESBL- and UTIs in T2DM. Serum CRP levels and blood NLR for these patients were determined and associated with and ESBL uropathogen using multivariate logistic regression analysis. Urinary interleukin 8 (IL-8) levels were also assessed and associated with these two UTI uropathogens in T2DM. The association of the two ESBL-uropathogens with the survival outcomes of T2DM patients was also analyzed using Cox-proportional hazard model. T2DM patients with ESBL- UTI had lower serum CRP levels (median, CRP mg/dL 33.7 vs 39.8, respectively; P=0.023) and higher blood NLR (median, NLR 3.2 vs 2.6, respectively; P=0.010) compared to those with UTIs ( <0.001). Moreover, in T2DM, the urinary IL-8 levels was higher in ESBL- compared to those with UTIs ( <0.0001). After adjusting for confounders, including age, gender, serum albumin, hemoglobulin, leukocytes, and platelet counts, T2DM patients with blood NLR ≥ 3.5 were at higher risk for ESBL- UTIs than ESBL- UTIs (odds ratio [OR], 3.61, 95% confidence interval, Cl, 1.49-8.73; P=0.004). Moreover, T2DM patients with ESBL- UTIs had higher all-cause mortality (hazard ratio [HR], 4.09; 95%, 1.14-14.59) than those with UTIs. Serum CRP levels, blood NLR, and IL-8 urinary levels differentiate ESBL- from UTIs in T2DM.

Wine has one of the broadest chemical profiles, and the common oenological practice of adding the antioxidant and antimicrobial sulfur dioxide has a major impact on its metabolomic fingerprint. In this study, we investigated novel discovered oenological reactions primarily occurring between wine metabolites and sulfur dioxide. The sulfonated derivatives of epicatechin, procyanidin B2, indole acetic acid, indole lactic acid and tryptophol were synthesized and for the first time quantified in wine. Analysis of 32 metabolites in 195 commercial wines (1986–2016 vintages) suggested that sulfonation of tryptophan metabolites characterised white wines, in contrast to red wines, where sulfonation of flavanols was preferred. The chemical profile of the oldest wines was strongly characterised by sulfonated flavanols and indoles, indicating that could be fundamental metabolites in explaining quality in both red and white aged wines. These findings offer new prospects for more precise use of sulfur dioxide in winemaking.

Proanthocyanidins are key metabolites that explain wine sensorial character (bitterness and astringency) and red wine color changes during aging. Therefore, a fast and accurate method to evaluate the degree of polymerization and the structural composition of the polymeric proanthocyanidins is a crucial analytical tool. Phloroglucinolysis is the most used method for this analysis but, unfortunately, the phloroglucinol adducts of the monomeric flavan-3-ols are not commercially available, making the results less accurate. The aim of this work was the isolation by semi-preparative high performance liquid chromatography (HPLC) of these non-commercial compounds and their use for the development of an accurate UHPLC-MS/MS protocol. The purity of each adduct was established via quantitative 1H-nuclear magnetic resonance (NMR) measurements with 3-trimethylsilyl-propionic-d4 acid sodium salt as the calibration standard. The developed method was applied to evaluate the proanthocyanidins profile of Sagrantino di Montefalco wines in comparison to other well-known tannic wines. Commercial, 6–8 years old Sagrantino wines were demonstrated to be very rich in epicatechin type B procyanidins, to have low galloylation %, and to have a high mean degree of polymerization of the proanthocyanidins with respect to the other analyzed wines.

Comparable clinical efficacy and safety of the reference rituximab (MABTHERA) and its biosimilars has been established in randomized trials. However, safety concerns are often raised when switching from reference to biosimilar products and between different biosimilars. In this prospective observational study we aimed at evaluating the safety of switching between reference and biosimilar rituximab (TRUXIMA and RIXATHON) at Trento General Hospital (Italy). All patients (n = 83) with Non Hodgkin’s Lymphoma (NHL, n = 72) and Chronic Lymphocytic Leukemia (CLL, n = 11) who received rituximab between March 2018 and March 2019 were asked to take part in the study. In 2017 and 2018 two tenders were carried out and two different biosimilars became available in the hospital, these were used sequentially. Thus, patients with or without previous treatments with the originator rituximab either received a biosimilar or were switched between different biosimilars. The incidence of adverse events in these groups of patients is described. The study population received 465 rituximab infusions and all received biosimilars. Fifty patients (60%) experienced at least one switch between different biosimilars or between rituximab originator and biosimilar, whereas 33 (40%) received one of the two biosimilars and one patient received reference rituximab. Adverse events (n = 146) were reported in 71 patients (84.5%). Treatment-related grade 3–4 events were reported in 5 patients (5.9%), whereas grade 1 rituximab related infusion events were observed in 6 patients (7.1%). No safety signal emerged in association with the use of a specific biosimilar nor with the practice of switching. Adverse events were similar, in terms of seriousness and frequency, to those described in the literature, providing further support to the clinical safety of rituximab biosimilars.

Background:Immunocheckpoint inhibitors (ICIs) revolutionized cancer therapy due to their efficacy on long-term survival. The most employed drugs are directed against CTLA-4 and PD1/PDL-1, whose main role is to stimulate immune system and enhance antitumour response, regulating T-cellular response[1]. However, this uncontrolled and non-selective immune response may lead to different immune-related adverse events (irAEs) [2]. Rheumatic toxicity has an overall incidence of about 10%. The most frequent manifestation is the joint involvement (5-7%), including inflammatory arthralgia, arthritis, polymyalgia rheumatica (PMR)-like syndrome (ir-arthritis phenotype). Glucocorticoids (GCs) represent the first line therapy; conventional and biologic disease modifying anti-rheumatic drugs (cs- and bDMARDs) are employed in most severe cases to reduce GCs but the impact on oncological outcome is debated [3,4].Objectives:to describe a monocentric cohort of oncologic patients (pts) with ir-arthritis phenotype toxicity and to analyse the role of an early use of cs- and bDMARDs on oncological outcome.Methods:retrospective analysis of oncologic pts with ir-arthritis phenotype followed from January 2019 to November 2023. Pts with a pre-existing rheumatic disease (pRD) were included. The severity of irAEs was established according to the Common Terminology Criteria for Adverse Events (CTCAE). The chi-square/Fisher’s test and the t-test were applied to evaluate association between different variables (age, cancer type, first line ICI, pRD, therapies) and oncological outcome in terms of progression or not. The Charlson index (CCI) was used to assess the influence of comorbidities on the overall outcome.Results:31 pts (21 males) with a mean age of 69.5y were included. The most frequent neoplasms were non-small cell lung cancer (35%) and melanoma (19%). The most employed drugs were anti-PD1. Five pts had a pRD (3 PMR, 1 rheumatoid arthritis and 1 psoriatic arthritis) and were treated with methotrexate (MTX) or hydroxychloroquine (HCQ) at the beginning of ICI. The mean (±standard deviation, SD) time to irAEs onset was 17 weeks (±23) with severity grade G2/G3 in the large majority (90%) and with a median follow-up of 15 months (IQR: 5-23). Twelve pts developed PMR-like syndrome, 12 arthritis, 7 inflammatory arthralgia. All pts with pRD relapsed. All pts started GCs (mean initial dose PN-eq 30 mg and mean cumulative dose PN-eq 1.3 g), in 20 pts ICI was transiently interrupted. Due to recurrence of irAEs during two-month GC tapering, a csDMARD or an IL6 inhibitor was started in 15 and 5 pts, respectively (Table 1). During the follow-up, 14 pts had an oncological progression and/or died, while 17 had a stable disease or a partial/complete response. An association between csDMARD use and no cancer progression was noted (p= 0.045) (Table 2). At last follow-up, all pts were recovered from irAEs.Conclusion:In our cohort, an early introduction of DMARDs showed to be effective in counteracting irAEs, sparing GC, without negatively affecting the oncological outcome.REFERENCES:[1] Weinmann, S. C. & Pisetsky, D. S. Mechanisms of immune-related adverse events during the treatment of cancer with immune checkpoint inhibitors. Rheumatol. Oxf. Engl. 58, vii59–vii67 (2019).[2] Shen, P. et al. Rheumatic Manifestations and Diseases From Immune Checkpoint Inhibitors in Cancer Immunotherapy. Front. Med. 8, 762247 (2021).[3] Reid, P. & Cappelli, L. C. Treatment of rheumatic adverse events of cancer immunotherapy. Best Pract. Res. Clin. Rheumatol. 36, 101805 (2022).[4] Kostine, M. et al. EULAR points to consider for the diagnosis and management of rheumatic immune-related adverse events due to cancer immunotherapy with checkpoint inhibitors. Ann. Rheum. Dis. 80, 36–48 (2021).Acknowledgements:NIL.Disclosure of Interests:None declared.

Grapevine is a world-wide cultivated economically relevant crop. The process of berry ripening is non-climacteric and does not rely on the sole ethylene signal. Abscisic acid (ABA) is recognized as an important hormone of ripening inception and color development in ripening berries. In order to elucidate the effect of this signal at the molecular level, pre-véraison berries were treated for 20 h with 0.2 mM ABA and berry skin transcriptional modulation was studied by RNA-seq after the treatment and 24 h later, in the absence of exogenous ABA. This study highlighted that a small amount of ABA triggered its own biosynthesis and had a transcriptome-wide effect (1893 modulated genes) characterized by the amplification of the transcriptional response over time. By comparing this dataset with the many studies on ripening collected within the grapevine transcriptomic compendium Vespucci, an extended overlap between ABA- and ripening modulated gene sets was observed (71% of the genes), underpinning the role of this hormone in the regulation of berry ripening. The signaling network of ABA, encompassing ABA metabolism, transport and signaling cascade, has been analyzed in detail and expanded based on knowledge from other species in order to provide an integrated molecular description of this pathway at berry ripening onset. Expression data analysis was combined with promoter analysis to identify candidate target genes of ABA responsive element binding protein 2 (VvABF2), a key upstream transcription factor of the ABA signaling cascade which is up-regulated at véraison and also by ABA treatments. Two transcription factors, VvMYB143 and VvNAC17, and two genes involved in protein degradation, Armadillo-like and Xerico-like genes, were selected for validation by VvABF2-mediated promoter -activation in tobacco. VvNAC17 and Armadillo-like promoters were induced by ABA via VvABF2, while VvMYB143 responded to ABA in a VvABF2-independent manner. This knowledge of the ABA cascade in berry skin contributes not only to the understanding of berry ripening regulation but might be useful to other areas of viticultural interest, such as bud dormancy regulation and drought stress tolerance.

Flavanols are an important class of natural products occurring in almost all plants, fruits and vegetables; they have a great influence on wine ageing potential, astringency, colour stability and biological activities. In wine, flavanols react with sulfur dioxide ( SO 2 ), the most widely used preservative in oenology, leading to sulfonated products. Here we report a kinetic investigation, through LC-MS quantitative measurements carried out at different pH (3 and 4) and temperature values (23, 30, 40, 50 and 60 ∘ C ), of the reaction products obtained by SO 2 addition to both monomeric (epicatechin and catechin) and dimeric flavanols (procyanidin B2 and procyanidin B3). The results proved that: (a) the major sulfonation route that leads quickly and in good yields to monomeric 4 β -sulfonated derivatives passes through the acid-catalysed depolymerisation of proanthocyanidins; (b) monomeric flavanols lead to the same 4 β -sulfonated products, although in a considerably slower manner, and also to other sulfonated regioisomers; (c) the kinetic data in our hands, in particular the temperature dependence of the observed rates, suggest the involvement of two completely different reaction mechanisms for the SO 2 addition to dimeric and monomeric flavanol substrates; (d) direct sulfonation of epicatechin is slightly faster than that of catechin.

Alen Zabotti,1 Nicola Cabas,1 Ivan Giovannini,1 Silvia Guella,1 Lorenzo Cereser,2 Chiara Zuiani,2 Giuseppe Stinco,3 Luca Quartuccio,1 Enzo Errichetti31Department of Medical and Biological Sciences, Rheumatology Institute, Azienda sanitaria universitaria Friuli Centrale, Udine, Italy; 2Department of Medicine, Institute of Radiology, Azienda sanitaria universitaria Friuli Centrale, Udine, Italy; 3Department of Medical and Biological Sciences, Dermatology Institute, Azienda Sanitaria Universitaria Friuli Centrale, Udine, ItalyCorrespondence: Enzo Errichetti, Institute of Dermatology, Department of Medical Area, University of Udine, Piazzale Santa Maria della Misericordia, 15, Udine, 33100, Italy, Tel +39 0432559822, Email [email protected]