Explore the vast range of titles available.

Background:Inflammatory Idiopathic Myositis (IIM) represents a specific group of rare rheumatologic diseases mainly characterized by skin and musculoskeletal involvement. However, interstitial lung disease (ILD) constitutes a key disease target in IIM, strongly affecting outcome and treatments.Objectives:We aimed at evaluating distribution and pattern of ILD in a selected cohort of IIM patients. Potential association between ILD and both the disease phenotype and the autoimmunity profile have been explored.Methods:We performed a cross sectional observational study including patients who fulfilled 2017 ACR/EULAR 2017 criteria for Dermatomyositis (DM), Polymyositis (PM), and Antisynthetasis Syndrome (ASS) (time frame June 2023-December 2023) referring to the Reference Centre of “Tor Vergata” University Hospital in Rome (Italy). Demographical data, including clinical and laboratory records, were collected. Concomitant ILD was defined based on chest computed tomography (chest CT) images: included patients were divided in two groups according to the presence of ILD. Continuous variables were compared with T test, categorical variables by using Chi-square or Fisher’s exact test. P<0.05 values were considered statistically significant.Results:The study cohort included 51 patients (68.6% women). Patients’ characteristics were summarized in Table 1. Patients with ILD were 51% (n=26; Group 1) while patients without were 49% (n=25 Group 2). Patients from Group 1 were older than those from group 2 at IIM diagnosis (p=0.04). ASS diagnosis resulted prevalent in Group 1 than Group 2 (p=0.01), while DM was significantly more frequent in Group 2 p=0.001). Patients in Group 1 showed a higher prevalence of dyspnoea (p<0.0001), arthralgias p=0.006), and arthritis (p=0.04) than those in Group 2. A significantly higher prevalence of Gottron papules and periorbital oedema has been registered in Group 2 than Group 1 (p<0.05). A diagnosis of malignancy occurred mainly in patients from Group 1 (p=0.02). Autoantibody profile resulted similar between two groups, excepted for anti-Jo1 patients who were mainly present in Group 1 (p=0.01) (Graphic 1).Conclusion:Our real-life data support the relevant association between concomitant ILD and specific IIM clinical pattern resulting mainly associated with joint involvement and IIM complicated by malignancy. Autoantibody profile might help in IIM patients’ stratification by potentially predicting ILD. Focusing on lung involvement in IIM represents a key tool to improve disease management and treatment strategies.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:None declared.

Background:Mixed connective tissue disease (MCTD) is a rare complex syndrome with features of different autoimmune connective tissue diseases (CTDs) in patients with antibodies targeting the U1 small nuclear ribonucleoprotein particle. In MCTD, immune-system abnormalities and, thus, fibrosis may involve skin and other internal organs, including lungs, also leading to diffuse microangiopathy. Lung involvement in terms of interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) are key manifestations strongly affecting morbidity and mortality in MCTD.Objectives:MCTD patients’ phenotypic pattern were analyzed according to the presence of concomitant lung involvement to explore potential association with microvascular damage.Methods:We performed a cross sectional observational study including patients with a defined diagnosis of MCTD, referring to the Reference Centre of “Tor Vergata” University Hospital in Rome (Italy). Recorded data included clinical and laboratory findings. Nail fold videocapillaroscopy (NVC) patterns and trans-thoracic echocardiographic PAPs value (PAPs>25 mmHg defined PAH) were analyzed. Concomitant ILD was defined based on chest computed tomography (chest CT) features: patients were thus divided in accordance with the presence of ILD. Continuous variables were compared with T test, categorical variables by using Chi-square or Fisher’s exact test. P<0.05 values were considered statistically significant.Results:The study cohort included 24 patients (95.8% women). Patients’ characteristics were shown in [Table 1]. Patients with ILD were 37.5% (n=9; Group 1) while patients without were 63.5% (n=15 Group 2). Disease duration was greater in Group 1 than in Group 2 (p=0.02). PAH has been revealed in a significantly higher percentage in Group 1 than Group 2 (P<0.01). Patients from Group 1 also exhibited a higher prevalence of telangiectasias, digital ulcers, pitting scars, and serositis than patients from Group 2 (p<0.02 for all the comparisons) along with a NVC late pattern (p<0.01) [Graphic 1]. A higher prevalence of cardiovascular and other respiratory comorbidities was observed in Group 1 than Group 2 (p<0.001 and p<0.05, respectively). A joint involvement showed a trend to be more frequent in Group 2. Patients from Group 1 showed a higher prevalence of both RoSSA-60 and -52 autoantibodies than those from Group 1 (p<0.01). Azathioprine resulted administered more frequently in Group 1 than in Group 2 (p<0.01).Conclusion:Our study documented in MCTD patients complicated with ILD a disease phenotype characterized by a more severe microvascular damage while confirming the role of specific autoantibodies profile in lung disease.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:None declared.

Background:ANCA-associated vasculitides (AAVs) are characterized by small blood vessel inflammation resulting in organ damage. Evidence suggests that positivity to ANCA antibodies could affect clinical phenotype. Pulmonary involvement is frequent and variable among AAV manifestations. Radiological findings, mainly computed tomography (CT) images, represent key tools for the detection of lung involvement, including interstitial lung disease (ILD), nodules, tracheobronchial inflammation, and alveolar hemorrhage. Lung diseases are a relevant factor for the overall outcome and the treatment-related damage in AAV. As previously documented, subclinical microvascular retinal changes occur in AAV patients as a disease-related damage thus correlating with the burden of the disease. Microvascular retinal changes might correlate with ANCA positivity and lung involvement in AAV patients.Objectives:In this study, we aimed to explore potential associations between retinal changes and ANCA positivity in AAV patients. In addition, retinal abnormalities have been analyzed in accordance with lung diseases.Methods:An observational study was conducted on consecutive patients who met the following inclusion criteria: i. a defined diagnosis of eosinophilic granulomatosis with polyangiitis (EGPA), granulomatosis with polyangiitis (GPA), and microscopic polyangiitis (MPA); ii. age ≥ 18 ≤ 75 yrs; iii. no ophthalmological disorders. Retinal changes have been documented by Optical coherence tomography angiography (OCT-A) that registered a quantitative analysis of vessel density (VD) in both superficial and deep capillary plexi. Lung diseases was defined as the presence of ILD, nodules, tracheobronchial inflammation, and alveolar hemorrhage by using CT scans. Continuous variables were compared with T test, categorical variables by using Chi-square or Fisher’s exact test. P<0.05 values were considered statistically significant.Results:A total of 25 AAV patients were included. 14 patients (56%) were ANCA positive (79% p-ANCA and 21% c-ANCA). Of the whole cohort, 15 patients (60%) had lung involvement, with ANCA positivity in 80% of them (75% p-ANCA). Data from the study cohort were reported in Table 1. A longer diagnostic delay was observed in ANCA-negative patients than in ANCA-positive (96.9 ± 88 months vs 25 ±36 months, P=0.01). At the OCT-A study, ANCA-negative patients showed a significantly lower foveal vascular density, documented in both the superficial (SFD) and the deep (DFD) scans, compared to ANCA-positive patients (p= 0.007 and p= 0.009, respectively). Among patients with lung involvement, ILD was documented in 33.3% of patients, tracheobronchial inflammation in 33.3%, nodules in 26.7%, and alveolar hemorrhage in a single case. Patients with lung involvement had a lower diagnostic delay than patients without (23 ±37.72 months vs 80.54 ± 80.1 months, p=0.04). Moreover, AAV patients without lung involvement had lower values of both SFD and DFD than patients with lung involvement (p < 0.0001 for both).Conclusion:This is the first OCT-A study in AAV patients highlighting differences in retinal microvascular network between ANCA-negative and ANCA-positive patients as well as potential correlation with concomitant lung diseases. Our preliminary findings support the idea that the presence of ANCA and/or lung involvement in AAV could reduce the diagnostic delay by increasing the index of suspicion. Therefore, the early diagnosis of AAV vasculitis could improve the therapeutic management leading to a reduced retinal vessels damage.REFERENCES: NIL.Acknowledgements:NIL.Disclosure of Interests:None declared.

Despite the availability of guideline recommendations, diagnostic confusion between COPD and asthma appears common, and often it is very difficult to decide whether the obstruction is caused by asthma or COPD in a patient with airway obstruction. However, there are well-defined features that help in differentiating asthma from COPD in the presence of fixed airflow obstruction. Nonetheless, the presentations of asthma and COPD can converge and mimic each other, making it difficult to give these patients a diagnosis of either condition. The association of asthma and COPD in the same patient has been designated mixed asthma-COPD phenotype or overlap syndrome. However, since the absence of a clear definition and the inclusion of patients with different characteristics under this umbrella term, it may not facilitate treatment decisions, especially in the absence of clinical trials addressing this heterogeneous population. We are realizing that neither asthma nor COPD are single diseases, but rather syndromes consisting of several endotypes and phenotypes, consequently comprising a spectrum of diseases that must be recognized and adequately treated with targeted therapy. Therefore, we must treat patients by personalizing therapy on the basis of those treatable traits present in each subject.

Objective This study aimed to assess the long-term outcome of patients with acromegaly. Design This is a multicenter, retrospective, observational study which extends the mean observation period of a previously reported cohort of Italian patients with acromegaly to 15 years of follow-up. Methods Only patients from the centers that provided information on the life status of at least 95% of their original cohorts were included. Life status information was collected either from clinical records or from the municipal registry offices. Standardized mortality ratios (SMRs) were computed comparing data with those of the general Italian population. Results A total of 811 patients were included. There were 153 deaths, with 90 expected and an SMR of 1.7 (95% CI 1.4–2.0, p  < 0.001). Death occurred after a median of 15 (women) or 16 (men) years from the diagnosis, without gender differences. Mortality remained elevated in the patients with control of disease (SMR 1.3, 95% CI 1.1–1.6). In the multivariable analysis, only older age and high IGF1 concentrations at last available follow-up visit were predictors of mortality. The oncological causes of death outweighed the cardiovascular ones, bordering on statistical significance with respect to the general population. Conclusions Mortality remains significantly high in patients with acromegaly, irrespectively of disease status, as long as the follow-up is sufficiently long with a low rate of patients lost to follow-up. Therapy strategy including radiotherapy does not have an impact on mortality. Oncological causes of death currently outweigh the cardiovascular causes.

Under basal growth conditions, p53 function is tightly controlled by the members of MDM family, MDM2 and MDM4. The Mdm2 gene codes, in addition to the full-length p90(MDM2), for a short protein, p76(MDM2) that lacks the p53-binding domain. Despite this property and at variance with p90(MDM2), this protein acts positively toward p53, although the molecular mechanism remains elusive. Here, we report that p76(MDM2) antagonizes MDM4 inhibitory function. We show that p76(MDM2) possesses intrinsic ubiquitinating and degrading activity, and through these activities controls MDM4 levels. Furthermore, the presence of p76(MDM2) decreases the association of MDM4 with p53 and p90(MDM2), and antagonizes p53 degradation by the heterodimer MDM4/p90(MDM2). The p76(MDM2)-mediated regulation of MDM4 occurs in the cytoplasm, under basal growth conditions. Conversely, upon DNA damage, phosphorylation of MDM4Ser403 dissociates p76(MDM2) and prevents MDM4 degradation. The overall negative control of MDM4 by p76(MDM2) reflects on p53 function as p76(MDM2) impairs MDM4-mediated inhibition of p53 activity. In agreement with the positive role of p76(MDM2) toward p53, the p76(MDM2)/p90(MDM2) ratio significantly decreases in a group of thyroid tumor samples compared with normal counterparts. Overall, these findings reveal a new mechanism in the control of p53 basal activity that may account for the distinct sensitivity of tissues to stress signals depending on the balance among MDM proteins. Moreover, these data suggest an oncosuppressive function for a product of the Mdm2 gene.

Activating mutations of the BRAF gene are the most common genetic alterations in papillary thyroid carcinomas (PTCs) and the T1799A transversion, resulting in BRAFV600E, appeared virtually unique in this cancer type. Here, we report on the identification in a classic PTC of a novel BRAF mutation, namely a 1795GTT insertion, resulting in BRAFV599Ins, and describe its biochemical and molecular characterization. Kinase assays carried out on BRAFV599Ins and BRAFV600E revealed a three- to five-fold increase in the enzymatic activity of both mutants with respect to BRAFWT. Similarly, evaluation of BRAF-induced phosphorylation of MEK, MAPK and RSK revealed a significant MAPK cascade activation in cells expressing BRAFV599Ins or BRAFV600E, but not in cells expressing BRAFWT. Molecular dynamic simulations showed a destabilization of the inactive conformation of the enzyme in both BRAFV599Ins and BRAFV600E mutants, but not in BRAFWT. The analysis of the interaction energies inside the catalytic site allowed to demonstrate the presence of repulsive electrostatic forces acting on the activation loop and moving from inward to outward of the mutant enzymes. Finally, focus assays in NIH-3T3 cells confirmed a high transformation rate in the cells transfected either with BRAFV599Ins or BRAFV600E. In conclusion, this study demonstrated that BRAFV599Ins, as BRAFV600E, is a 'gain of function' mutation, characterized by a constitutive catalytic activation, which accounts for its causative role in the studied PTC.

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease of unknown cause characterized by alveolar epithelial damage, patchy interstitial fibrosis and diffuse microvascular abnormalities. In IPF, alveolar clustering of iron-laden alveolar macrophages-a common sign of microhemorrhage, has been associated with vascular abnormalities and worsening of pulmonary hypertension. As iron-dependent ROS generation has been shown to induce unrestrained macrophage activation in disease models of vascular damage, we explored alveolar macrophage activation phenotype in IPF patients (n = 16) and healthy controls (CTR, n = 7) by RNA sequencing of bronchoalveolar lavage (BAL) cells. The frequencies of macrophages in BAL cells were 86+4% and 83.4+8% in IPF and CTR groups, respectively (p-value = 0.41). In IPF patients, BAL cells showed increased iron-dependent ROS generation (p-value<0.05 vs CTR). Gene expression analysis showed overrepresentation of Gene Ontology processes/functions and KEGG pathways enriched in upregulated M1-type inflammatory (p-value<0.01), M2-type anti-inflammatory/tissue remodeling (p-value<0.0001), and MTPP-type chronic inflammatory/angiogenic (p-value<0.0001) chemokine and cytokine genes. The ex vivo finding was confirmed by the induction of iron-dependent ROS generation and chemokine/cytokine overexpression of Ccl4, Cxcl10 (M1), Il1rn (M2), Cxcl2, and Cxcl7 (MTPP) in MH-S murine immortalized alveolar macrophages exposed to ferric ammonium citrate in culture (p-value<0.05 vs CTR). The data show alveolar macrophage expression of a pro-inflammatory, tissue remodeling and angiogenic complex activation pattern, suggesting that iron accumulation may play a role in macrophage activation.

Under basal growth conditions, p53 function is tightly controlled by the members of MDM family, MDM2 and MDM4. The Mdm2 gene codes, in addition to the full-length [p90.sup.MDM2], for a short protein, [p76.sup.MDM2] that lacks the p53-binding domain. Despite this property and at variance with [p90.sup.MDM2], this protein acts positively toward p53, although the molecular mechanism remains elusive. Here, we report that [p76.sup.MDM2] antagonizes MDM4 inhibitory function. We show that [p76.sup.MDM2] possesses intrinsic ubiquitinating and degrading activity, and through these activities controls MDM4 levels. Furthermore, the presence of [p76.sup.MDM2] decreases the association of MDM4 with p53 and [p90.sup.MDM2], and antagonizes p53 degradation by the hetero dimer MDM4/[p90.sup.MDM2].The[p76.sup.MDM2]-mediated regulation of MDM4 occurs in the cytoplasm, under basal growth conditions. Conversely, upon DNA damage, phosphorylation of MDM4Ser403 dissociates [p76.sup.MDM2] and prevents MDM4 degradation. The overall negative control of MDM4 by [p76.sup.MDM2] reflects on p53 function as [p76.sup.MDM2] impairs MDM4-mediated inhibition of p53 activity. In agreement with the positive role of [p76.sup.MDM2] toward p53, the [p76.sup.MDM2]/ [p90.sup.MDM2] ratio significantly decreases in a group of thyroid tumor samples compared with normal counterparts. Overall, these findings reveal a new mechanism in the control of p53 basal activity that may account for the distinct sensitivity of tissues to stress signals depending on the balance among MDM proteins. Moreover, these data suggest an oncosuppressive function for a product of the Mdm2 gene.

Inhaled corticosteroids (ICSs) are considered the cornerstone of asthma treatment. Despite the solid evidence documenting the efficacy and safety of ICSs at the level of the airways, their use can be affected by pulmonary and systemic adverse events (AEs) when administered chronically and/or at high doses. Thus, there is a pharmacological and medical need for new glucocorticoid (GC) receptor (GR) ligands with a more favorable therapeutic index, in order to overcome the shortcomings of currently available ICSs. The therapeutic profile of GCs can be improved by enhancing genomic mechanisms mediated by transrepression, which is assumed to be responsible for several anti-inflammatory and immunomodulatory actions, rather than transactivation, which causes most of the GC-associated AEs. It was assumed that an independent modulation of the molecular mechanisms underlying transactivation and transrepression could translate into the dissociation of beneficial effects from AEs. Therefore, current research is looking for GCs that are able to elicit prevalently transrepression with negligible transactivating activity. These compounds are known as selective glucocorticoid receptor agonists (SEGRAs). In this review, experimental GR agonists currently in pre-clinical and clinical development for the treatment of asthma have been systematically assessed. Several compounds are currently under pre-clinical development, but only three novel experimental GR agonists (GW870086X, AZD5423, AZD7594) seem to have some potential therapeutic relevance and have entered clinical trials for the treatment of asthma. Since data from pre-clinical studies have not always been confirmed in clinical investigations, well-designed randomized controlled trials are needed in asthmatic patients to confirm the potentially positive benefit/risk ratio of each specific SEGRA and to optimize the development strategy of these agents in respiratory medicine. Keywords: asthma, glucocorticoid agonists, SEGRA, efficacy, safety