Pharmacological modulation of mitochondrial calcium uniporter controls lung inflammation in cystic fibrosis

Mitochondria physically associate with the endoplasmic reticulum to coordinate interorganelle calcium transfer and regulate fundamental cellular processes, including inflammation. Deregulated endoplasmic reticulum–mitochondria cross-talk can occur in cystic fibrosis, contributing to hyperinflammation and disease progression. We demonstrate that Pseudomonasaeruginosainfection increases endoplasmic reticulum–mitochondria associations in cystic fibrosis bronchial cells by stabilizing VAPB-PTPIP51 (vesicle-associated membrane protein–associated protein B–protein tyrosine phosphatase interacting protein 51) tethers, affecting autophagy. Impaired autophagy induced mitochondrial unfolding protein response and NLRP3 inflammasome activation, contributing to hyperinflammation. The mechanism by which VAPB-PTPIP51 tethers regulate autophagy in cystic fibrosis involves calcium transfer via mitochondrial calcium uniporter. Mitochondrial calcium uniporter inhibition rectified autophagy and alleviated the inflammatory response in vitro and in vivo, resulting in a valid therapeutic strategy for cystic fibrosis pulmonary disease

SARS-CoV-2 infection in patients with inflammatory bowel disease: comparison between the first and second pandemic waves

In Italy, the incidence of SARS-CoV-2 infection peaked in April and November 2020, defining two pandemic waves of coronavirus disease 2019 (COVID-19). This study compared the characteristics and outcomes of patients with inflammatory bowel disease (IBD) and SARS-CoV-2 infections between pandemic waves.MethodsObservational longitudinal study of IBD patients with SARS-CoV-2 infection. Patients with established diagnoses of IBD and of SARS-CoV-2 infection were consecutively enrolled in two periods: (i) first wave, from 1 March 2020 to 31 May 2020; and (ii) second wave, from 15 September to 15 December 2020.ResultsWe enrolled 937 IBD patients (219 in the first wave, 718 in the second wave). Patients of the first wave were older (mean & PLUSMN; SD: 46.3 & PLUSMN; 16.2 vs. 44.1 & PLUSMN; 15.4 years, p = 0.06), more likely to have ulcerative colitis (58.0% vs. 44.4%, p < 0.001) and comorbidities (48.9% vs. 38.9%; p < 0.01), and more frequently residing in Northern Italy (73.1% vs. 46.0%, p < 0.001) than patients of the second wave. There were no significant differences between pandemic waves in sex (male: 54.3% vs. 53.3%, p = 0.82) or frequency of active IBD (44.3% vs. 39.0%, p = 0.18). The rates of negative outcomes were significantly higher in the first than second wave: pneumonia (27.8% vs. 11.7%, p < 0.001), hospital admission (27.4% vs. 9.7%, p < 0.001), ventilatory support (11.9% vs. 5.4%, p < 0.003) and death (5.5% vs. 1.8%, p < 0.007).ConclusionBetween the first and second SARS-CoV-2 pandemic waves, demographic, clinical and geographical features of IBD patients were different as were the symptoms and outcomes of infection. These differences are likely due to the different epidemiological situations and diagnostic possibilities between the two waves

traduzione dal tedesco di: J. FRIED, La politica economica di Federico Barbarossa in Germania

traduzione (collaborazione a) in volume (atti di convegno

One-year effectiveness and safety of ustekinumab in ulcerative colitis: a multicenter real-world study from Italy

Background: Efficacy and safety of ustekinumab for the treatment of ulcerative colitis (UC) has been demonstrated in clinical trials, but few real-world data are available so far. The aim of this study was to assess effectiveness and safety of ustekinumab in a cohort of refractory UC patients. Methods: Data of patients with moderate to severe UC treated with ustekinumab were retrospectively collected. Primary endpoint was steroid-free clinical remission at weeks 24 and 52 of therapy. Secondary endpoints were treatment response, endoscopic remission, treatment persistence at 12&nbsp;months and safety. Results: A total of 68 patients [males 63%; median (range) age 42 (16–72) years] were included. Almost all patients (97%) were biologics experienced. At weeks 24 and 52, 31% and 50% of patients achieved steroid-free clinical remission, 84% and 82% had clinical response, respectively. At the end of follow-up, there was a significant reduction of pMS from baseline (p&nbsp;&lt;&nbsp;0.001) and of steroid use (p&nbsp;&lt;&nbsp;0.001). At week 52, 22% of the available endoscopies (18/38) showed mucosal healing. The probability to persist in therapy at week 52 was 87%. Only one adverse event occurred. Conclusions: Data from our real-life cohort of refractory UC patients suggest satisfactory effectiveness and a good safety of ustekinumab

Beneficial effects of recombinant CER-001 high-density lipoprotein infusion in sepsis: results from a bench to bedside translational research project

Background: Sepsis is characterized by a dysregulated immune response and metabolic alterations, including decreased high-density lipoprotein cholesterol (HDL-C) levels. HDL exhibits beneficial properties, such as lipopolysaccharides (LPS) scavenging, exerting anti-inflammatory effects and providing endothelial protection. We investigated the effects of CER-001, an engineered HDL-mimetic, in a swine model of LPS-induced acute kidney injury (AKI) and a Phase 2a clinical trial, aiming to better understand its molecular basis in systemic inflammation and renal function. Methods: We carried out a translational approach to study the effects of HDL administration on sepsis. Sterile systemic inflammation was induced in pigs by LPS infusion. Animals were randomized into LPS (n = 6), CER20 (single dose of CER-001 20&nbsp;mg/kg; n = 6), and CER20 × 2 (two doses of CER-001 20&nbsp;mg/kg; n = 6) groups. Survival rate, endothelial dysfunction biomarkers, pro-inflammatory mediators, LPS, and apolipoprotein A-I (ApoA-I) levels were assessed. Renal and liver histology and biochemistry were analyzed. Subsequently, we performed an open-label, randomized, dose-ranging (Phase 2a) study included 20 patients with sepsis due to intra-abdominal infection or urosepsis, randomized into Group A (conventional treatment, n = 5), Group B (CER-001 5&nbsp;mg/kg BID, n = 5), Group C (CER-001 10&nbsp;mg/kg BID, n = 5), and Group D (CER-001 20&nbsp;mg/kg BID, n = 5). Primary outcomes were safety and efficacy in preventing AKI onset and severity; secondary outcomes include changes in inflammatory and endothelial dysfunction markers. Results: CER-001 increased median survival, reduced inflammatory mediators, complement activation, and endothelial dysfunction in endotoxemic pigs. It enhanced LPS elimination through the bile and preserved liver and renal parenchyma. In the clinical study, CER-001 was well-tolerated with no serious adverse events related to study treatment. Rapid ApoA-I normalization was associated with enhanced LPS removal and immunomodulation with improvement of clinical outcomes, independently of the type and gravity of the sepsis. CER-001-treated patients had reduced risk for the onset and progression to severe AKI (stage 2 or 3) and, in a subset of critically ill patients, a reduced need for organ support and shorter ICU length of stay. Conclusions: CER-001 shows promise as a therapeutic strategy for sepsis management, improving outcomes and mitigating inflammation and organ damage. Trial registration: The study was approved by the Agenzia Italiana del Farmaco (AIFA) and by the Local Ethic Committee (N° EUDRACT 2020–004202-60, Protocol CER-001- SEP_AKI_01) and was added to the EU Clinical Trials Register on January 13, 2021

Therapies for inflammatory bowel disease do not pose additional risks for adverse outcomes of SARS-CoV-2 infection: an IG-IBD study

none70noBackground: Older age and comorbidities are the main risk factors for adverse COVID-19 outcomes in patients with inflammatory bowel disease (IBD). The impact of IBD medications is still under investigation. Aims: To assess risk factors for adverse outcomes of COVID-19 in IBD patients and use the identified risk factors to build risk indices. Methods: Observational cohort study. Univariable and multivariable logistic regression was used to identify risk factors associated with pneumonia, hospitalisation, need for ventilatory support, and death. Results: Of the 937 patients (446 with ulcerative colitis [UC]) evaluated, 128 (13.7%) had asymptomatic SARS-CoV-2 infection, 664 (70.8%) had a favourable course, and 135 (15.5%) had moderate or severe COVID-19. In UC patients, obesity, active disease and comorbidities were significantly associated with adverse outcomes. In patients with Crohn's disease (CD), age, obesity, comorbidities and an additional immune-mediated inflammatory disease were identified as risk factors. These risk factors were incorporated into two indices to identify patients with UC or CD with a higher risk of adverse COVID-19 outcomes. In multivariable analyses, no single IBD medication was associated with poor COVID-19 outcomes, but anti-TNF agents were associated with a lower risk of pneumonia in UC, and lower risks of hospitalisation and severe COVID-19 in CD. Conclusion: The course of COVID-19 in patients with IBD is similar to that in the general population. IBD patients with active disease and comorbidities are at greater risk of adverse COVID-19 outcomes. IBD medications do not pose additional risks. The risk indices may help to identify patients who should be prioritised for COVID-19 re-vaccination or for therapies for SARS-CoV-2 infection.noneBezzio C.; Armuzzi A.; Furfaro F.; Ardizzone S.; Milla M.; Carparelli S.; Orlando A.; Caprioli F.A.; Castiglione F.; Vigano C.; Ribaldone D.G.; Zingone F.; Monterubbianesi R.; Imperatore N.; Festa S.; Daperno M.; Scucchi L.; Ferronato A.; Pastorelli L.; Balestrieri P.; Ricci C.; Cappello M.; Felice C.; Fiorino G.; Saibeni S.; Coppini F.; Alvisi P.; Gerardi V.; Variola A.; Mazzuoli S.; Lenti M.V.; Pugliese D.; Allocca M.; Ferretti F.; Roselli J.; Bossa F.; Giuliano A.; Piazza N.; Manes G.; Sartini A.; Buda A.; Micheli F.; Ciardo V.; Casella G.; Viscido A.; Bodini G.; Casini V.; Soriano A.; Amato A.; Grossi L.; Onali S.; Rottoli M.; Spagnuolo R.; Baroni S.; Cortelezzi C.C.; Baldoni M.; Vernero M.; Scaldaferri F.; Maconi G.; Guarino A.D.; Palermo A.; D'Inca R.; Scribano M.L.; Biancone L.; Carrozza L.; Ascolani M.; Costa F.; Di Sabatino A.; Zammarchi I.; Gottin M.; Conforti F.S.Bezzio, C.; Armuzzi, A.; Furfaro, F.; Ardizzone, S.; Milla, M.; Carparelli, S.; Orlando, A.; Caprioli, F. A.; Castiglione, F.; Vigano, C.; Ribaldone, D. G.; Zingone, F.; Monterubbianesi, R.; Imperatore, N.; Festa, S.; Daperno, M.; Scucchi, L.; Ferronato, A.; Pastorelli, L.; Balestrieri, P.; Ricci, C.; Cappello, M.; Felice, C.; Fiorino, G.; Saibeni, S.; Coppini, F.; Alvisi, P.; Gerardi, V.; Variola, A.; Mazzuoli, S.; Lenti, M. V.; Pugliese, D.; Allocca, M.; Ferretti, F.; Roselli, J.; Bossa, F.; Giuliano, A.; Piazza, N.; Manes, G.; Sartini, A.; Buda, A.; Micheli, F.; Ciardo, V.; Casella, G.; Viscido, A.; Bodini, G.; Casini, V.; Soriano, A.; Amato, A.; Grossi, L.; Onali, S.; Rottoli, M.; Spagnuolo, R.; Baroni, S.; Cortelezzi, C. C.; Baldoni, M.; Vernero, M.; Scaldaferri, F.; Maconi, G.; Guarino, A. D.; Palermo, A.; D'Inca, R.; Scribano, M. L.; Biancone, L.; Carrozza, L.; Ascolani, M.; Costa, F.; Di Sabatino, A.; Zammarchi, I.; Gottin, M.; Conforti, F. S

A spinal cord neuroprosthesis for locomotor deficits due to Parkinson's disease.

People with late-stage Parkinson's disease (PD) often suffer from debilitating locomotor deficits that are resistant to currently available therapies. To alleviate these deficits, we developed a neuroprosthesis operating in closed loop that targets the dorsal root entry zones innervating lumbosacral segments to reproduce the natural spatiotemporal activation of the lumbosacral spinal cord during walking. We first developed this neuroprosthesis in a non-human primate model that replicates locomotor deficits due to PD. This neuroprosthesis not only alleviated locomotor deficits but also restored skilled walking in this model. We then implanted the neuroprosthesis in a 62-year-old male with a 30-year history of PD who presented with severe gait impairments and frequent falls that were medically refractory to currently available therapies. We found that the neuroprosthesis interacted synergistically with deep brain stimulation of the subthalamic nucleus and dopaminergic replacement therapies to alleviate asymmetry and promote longer steps, improve balance and reduce freezing of gait. This neuroprosthesis opens new perspectives to reduce the severity of locomotor deficits in people with PD