Archivio istituzionale della Ricerca - Università degli Studi di Parma
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The association of psychological resources and personality traits with preference for psychotherapy models: evidence from two explorative studies
No full textNew Challenging Systemic Therapies for Juvenile Scleroderma: A Comprehensive Review
No full textBackground: Juvenile scleroderma (JS) comprises a group of rare chronic autoimmune and fibrosing disorders in children, primarily presenting as juvenile localized scleroderma (jLS) or juvenile systemic sclerosis (jSS). While jLS predominantly affects the skin and subcutaneous tissues, jSS may involve multiple internal organs and is associated with increased morbidity and mortality. Due to the scarcity of pediatric-specific clinical trials, the current treatment strategies are largely empirical and often adapted from adult protocols. Objective: This narrative review aims to provide a comprehensive update on emerging systemic therapies for juvenile scleroderma, focusing on biologics, small molecule inhibitors, and advanced cellular interventions, to support the development of more personalized and effective pediatric treatment approaches. Methods: A literature search was conducted through PubMed and a manual bibliographic review, covering publications from 2001 to 2024. Only English-language studies involving pediatric populations were included, comprising randomized controlled trials, reviews, and case reports. Additional searches were performed for drugs that are specifically used in juvenile scleroderma. Results: Biologic agents such as tocilizumab, rituximab, and abatacept, along with small molecules including Janus kinase (JAK) inhibitors and imatinib, have demonstrated potential in managing refractory cases by reducing skin fibrosis and pulmonary involvement. Novel approaches—such as pamrevlumab, nintedanib, and chimeric antigen receptor (CAR-T) cell therapy—target fibrotic and autoimmune pathways but remain investigational in children. Autologous stem cell transplantation (ASCT) has also been explored in severe, treatment-resistant cases, although data are extremely limited. The overall evidence base is constrained by small sample sizes, a lack of controlled pediatric trials, and reliance on adult extrapolation. Conclusions: While innovative systemic therapies show promise for juvenile scleroderma, their widespread clinical application remains limited by insufficient pediatric-specific evidence. Large, multicenter, long-term trials are urgently needed to establish safety, efficacy, and optimal treatment algorithms that are tailored to the pediatric population
Lomitapide modifies high-density lipoprotein function in homozygous familial hypercholesterolaemia
No full textBackground Lomitapide reduces plasma low-density lipoprotein cholesterol (LDL-C) and is approved for the treatment of homozygous familial hypercholesterolemia (HoFH). This study aims to determine the effect of lomitapide on HDL and cholesterol efflux in a cohort of patients with HoFH. Patients and methods Analysis included plasma samples from 17 HoFH patients enrolled in the lomitapide phase 3 Aegerion clinical study (NCT00730236). Samples taken at baseline (pre-lomitapide) and weeks 56 and 66 (assumed steady-state on lomitapide) were analyzed for HDL-C levels and cholesterol efflux capacity (CEC) pathways via ABCA1, ABCG1, and SR-BI cholesterol uptake. Results Treatment with lomitapide is associated with a statistically significant decrease of both LDL-C and apo B when compared to baseline levels, p < 0.01. However, the reduction of Lp(a) appears only at a higher dose when compared to baseline (- 27% against values around - 55% for LDL-C and apo B). HDL-C shows a small 4.2% increase between the baseline and the treatment with a high dosage of lomitapide, while apo A-I displays an opposite small 3% decrease. Total efflux and ABCA1 mediated CEC decreased especially at higher dosage of lomitapide, with marked dose-dependent increase of SR-BI cholesterol uptake (+ 21.4% and + 64.3%, respectively, at a low and high dosages of lomitapide). However, ABCG1 did not change consistently. Conclusions Our report raises the hypothesis that lomitapide promotes lipidation of HDL particles independently of ABCA1 and ABCG1 through a process involving SR-BI pathway. This effect impairs the total efflux process suggesting that lomitapide drives the reverse cholesterol transport through SR-BI receptors in HoFH patients
Processing L2 action verbs shares the same mechanisms for processing L1 items: evidence from a combined behavioral and MEG study
No full textCardiovascular Events in Chronic Obstructive Pulmonary Disease: Squeezing ETHOS Dry for Clinical Evidence at Risk of Type I Error
No full textImpact of thermal treatment, pulsed electric fields, and high-pressure processing on the transcriptome of Escherichia coli ATCC 8739
No full textCurrent state-of-the-art of adrenal surgery in Italy: the cancer risk in surgical adrenal lesions (CRISAL) survey
No full textAdrenalectomies are growing worldwide because of the frequent diagnosis of incidentaloma and the use of minimally invasive surgery (MIS). The factors used to identify a malignant lesion and the best surgical technique are uncertain. In this context, the definition of high-volume center and expert surgeon is under debate. The Italian Society of Endoscopic Surgery and New Technologies (SICE) developed a nationwide survey to investigate the state-of-the-art of adrenal surgery in Italy. A web-based survey comprising 37 questions was developed and distributed to Italian surgeons involved in adrenal surgery. Two hundred forty-eight answers were analyzed. Consensus was reached among the survey participants regarding local infiltration (83%) and rapid growth of the lesion (81%) as markers of malignancy. Nearly 30% of the participants used MIS in case of malignant adrenal lesions. The lateral (50%) and anterior transperitoneal (44%) approaches were the most common among Italian surgeons. Approximately 40% of participants believe that 20–40 adrenalectomies/year are needed to define an expert surgeon and at least 20 procedures/year to define a high-volume center. Approximately half of participants performed < 10 adrenalectomies/year in centers with a median volume < 10 procedures/year. Based on participant feedback, this survey highlights local infiltration and rapid growth as the most significant markers of malignant adrenal lesions. While open adrenalectomy remains the gold standard for suspected malignant lesions, nearly 30% of the participants practice MIS even in these cases. The lateral and anterior transperitoneal approaches emerge as the most familiar for Italian surgeons. A substantial proportion of Italian patients with adrenal lesions undergo surgery performed by surgeons with an annual case volume < 10 procedures, at centers with a low annual volume of adrenalectomies. Moreover, there is a lack of standardized definitions for ‘expert surgeon’ and ‘high-volume center’ in this context
JAK3 Inhibitors: Covalent and Noncovalent Interactions of a Cyanamide Group Investigated by Multiscale Free-Energy Simulations
No full textJanus kinase type 3 (JAK3), an emerging target for treating autoimmune diseases, possesses a front pocket cysteine that is targeted by covalent modifiers, best represented by the marketed drug ritlecitinib (1). Recently, 2,3-dihydro-1H-inden-1-ylcyanamides have been developed as novel JAK3 inhibitors. Among them, the N-(6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,3-dihydro-1H-inden-1-yl)cyanamide inhibitor (2) and its methylated analogue (3), while being potent inhibitors, displayed different mechanisms of action (covalent vs noncovalent) and binding modes (Casimiro-Garcia et al., J Med Chem 2018). Prompted by this intriguing behavior, we applied a multiscale approach to characterize the reaction mechanism between the JAK3 front-pocket Cys909 and cyanamide-based inhibitors. Quantum mechanics/molecular mechanics simulations showed that 2 can readily form an isothiourea adduct with the Cys909 only when a conserved water molecule assists the reaction as a proton shuttle and that methylation of the 2,3-dihydro-1H-inden-1-ylcyanamide moiety of 2 hampers the isothiourea formation by displacing this water molecule. Metadynamics and thermodynamic integration simulations were applied to investigate the relative abundance of alternative poses accessible to 2,3-dihydro-1H-inden-1-ylcyanamides, explaining the effect of methylation on the relative binding mode preference. This multiscale approach provides new chemical insights into the mechanism of action of cyanamide inhibitors and emerges as an effective protocol to investigate the interaction between drugs and molecular targets
Monoclonal anti-CD38 therapy in human myeloma: retrospects and prospects
No full textMonoclonal antibody therapy using CD38 as a target remains central to managing human multiple myeloma (MM). CD38 was selected early on as a target for mAb-mediated therapy for MM, driven by findings from an early Cluster of Differentiation (CD) Workshop. The first CD38-targeting antibody to be approved yielded strong trial results, significantly improving survival rates and earning widespread patient acceptance. However, resistance to the therapy later emerged, complicating treatment management. Despite CD38’s still central role in MM therapy, too little attention has been paid to its broader roles–not only as a myeloma marker but also as an enzyme and adhesion molecule in physiology. This review, a collaborative effort between basic scientists and clinical experts, explores some of the lesser-known mechanisms of antibody action and interactions with CD38 at key stages of treatment. The review also highlights the relevance of the MM environment, focusing on the importance of the bone marrow (BM) niche. The goal is to identify new agents whose unique properties may enhance tumor eradication. By gaining a deeper understanding of interactions between therapeutic antibodies, myeloma cells, and the tumor microenvironment (TME), it is hoped that previously unrecognized vulnerabilities within the disease may be revealed, paving the way to more effective treatment strategies
Effect of age on the response to serotonergic and noradrenergic antidepressants: A systematic review, meta-regression and individual participant data pooled analysis
No full textIt is known that the serotonin and norepinephrine systems change with age. Consequently, response to antidepressants having different effects on these two systems may vary between patients of different ages. We systematically searched Embase/Medline/PsychINFO until December 2024 for randomised controlled trials (RCT) in patients with unipolar major depressive disorder comparing response rates to serotonergic versus noradrenergic antidepressants (PROSPERO pre-registration #CRD42020145386). Our primary outcome was to assess the effect of age on response rates to serotonergic versus noradrenergic antidepressants in unipolar depression. We then performed a pooled analysis of individual participant data (IPD). Seventy-four RCTs with a total of 8981 participants (4488 with serotonergic and 4493 with noradrenergic antidepressants) were included in the meta-analysis. We found no differences in the response rates to the two antidepressants, although the improvement in depressive symptoms was greater in the noradrenergic arm (subset of n = 31 studies, z = −2.61; p = 0.009); younger age was associated with a greater response to serotonergic than noradrenergic agents both in terms of response rates (estimate = −0.011; p-value = 0.041) and symptom improvement (estimate = −0.016; p-value<0.0001), even after controlling for year of publication, study design, baseline severity, type of noradrenergic medication, inpatients, and dropout rates. The effect of age on antidepressant response was also confirmed in the IPD pooled analysis (n = 339), in which responders to serotonergic antidepressants were significantly younger than non-responders (p-value = 0.028) and than responders to noradrenergic antidepressants (p-value = 0.034). Our study highlights the importance of age when considering the efficacy of serotonergic versus noradrenergic antidepressants as part of a precision psychiatry-oriented approach