Search Results (18)

Objectives: Despite continuous advances in diagnosis, such as the “Two week wait” policy for hospital specialist referral and fast-track diagnostic pathways, lung cancers are detected mostly at advanced stages. Our aim was to evaluate the fast-track diagnostic pathway in a tertiary hospital. Methods: Between March and September 2022, 114 consecutive patients with respiratory symptoms or radiology suspicions of lung cancer were referred to our “Pulmonary Point” outpatient clinic. The time intervals to take in the charges and conduct biopsy and ^18FDGPET-CT were prospectively collected. Furthermore, the patients’ experiences were evaluated by means of a six-item questionnaire investigating the outpatient clinic environment and accessibility, the kindness and professional approach of the healthcare professionals, the psychological support provided and an overall evaluation. The data were compared with those of 79 patients observed in the Thoracic Surgery Ambulatory in the pre-COVID-19 pandemic period of March–September 2019 before the fast-track diagnostic pathway for lung cancer was established. Results: The patients were referred to the “Pulmonary Point” outpatient clinic by a General Practitioner in 44 cases (38.5%), by other Specialists in 56 (49.1%) and by an Emergency Department in 14 (12.2%). Among the 114 patients, 104 (91.2%) were visited within 3 working days. Biopsies (FNAB, EBUS, bronchoscopy or surgical) were performed at a median period of 18 days (IQR: 9–26), and ^18FDGPET-CT was carried out at a median period of 16 days (IQR: 7–25). The patients referred to the Thoracic Surgery Ambulatory in the period of March–September 2019 were characterized by longer times to biopsy [26 days (IQR: 12–54), p < 0.001] and to ^18FDGPET-CT [25 days (IQR: 15–38), p = 0.003]. The patients referred in 2022 reported higher scores in the clinic environment (p < 0.001), psychological support provided (p < 0.001) and overall evaluation (p = 0.02) domains of the questionnaire. Conclusions: The establishment of a dedicated diagnostic pathway improves time to diagnosis and patients’ satisfaction. Full article

Background: Systemic sclerosis (SSc) is an autoimmune disease characterized by vascular and immunity alterations and skin/internal organ fibrosis. Aberrant levels of plasma CXCL4, CXCL4–RNA/DNA complexes, type I IFN (IFN-I) and anti-CXCL4 antibodies characterize SSc. These parameters influence each other: CXCL4–self-DNA/RNA complexes are triggers of IFN-I in plasmacytoid dendritic cells (pDCs), and anti-CXCL4 autoantibodies amplify this effect. Here, we assess the modulation over time of plasma CXCL4 and the related parameters of CXCL4–DNA/RNA complexes, anti-CXCL4 antibodies, IFN-α and TNF-α in an SSc cohort under the synthetic analogue of prostacyclin PGI2 (iloprost) treatment to address contribution of these parameters to pathogenesis and their role as biomarkers. Methods: We analyzed immunological parameters at baseline (T0) and after 3 (T3) and 6 (T6) months in 30 SSc patients. Responders were the patients that lowered their disease activity parameters after six months of treatment. Results: Anti-CXCL4 autoantibodies correlated with both IFN-α and TNF-α levels in SSc plasma. Responders significantly down-regulated serum IFN-α. In seven patients with a shorter disease duration, improvement coincides with a decrease in plasma IFN-α, CXCL4 and TNF-α. Iloprost efficiently blocks pDCs IFN-α production induced by CXCL4–DNA/RNA complexes in vitro. Conclusions: The data suggest a possible role of iloprost as a disease-modifying drug, mainly accompanied by down-regulation of plasma IFN-I levels. Since CXCL4, IFN-I and TNF-α down-modulation was evident and significant in improving SSc patients with a shorter disease duration, these results warrant future investigations on the early use of iloprost to slow SSc progression. Full article

The increasing frequency and intensity of extreme weather events are accelerating the mechanisms of surface degradation of heritage buildings, and it is therefore appropriate to find automatic techniques to reduce the time and cost of monitoring and to support their planned conservation. A fully automated approach is presented here for the segmentation and classification of the architectural elements that make up one of the façades of Palazzo Pitti. The aim of this analysis is to provide tools for a more detailed assessment of the risk of detachment of parts of the pietraforte sandstone elements. Machine learning techniques were applied for the segmentation and classification of information from a DEM obtained via a photogrammetric drone survey. An unsupervised geometry-based classification of the segmented objects was performed using K-means for identifying the most vulnerable elements according to their shapes. The results were validated through comparing them with those obtained via manual segmentation and classification, as well as with studies carried out by experts in the field. The initial results, which can be integrated with non-geometric information, show the usefulness of drone surveys in the context of automatic monitoring of heritage buildings. Full article

Psoriasis is a chronic inflammatory skin disease, which affects 2–4% of the population worldwide. T-cell derived factors such as Th17 and Th1 cytokines or cytokines such as IL-23, which favors Th17-expansion/differentiation, dominate in the disease. Therapies targeting these factors have been developed over the years. An autoimmune component is present, as autoreactive T-cells specific for keratins, the antimicrobial peptide LL37 and ADAMTSL5 have been described. Both autoreactive CD4 and CD8 T-cells exist, produce pathogenic cytokines, and correlate with disease activity. Along with the assumption that psoriasis is a T-cell-driven disease, Tregs have been studied extensively over the years, both in the skin and in circulation. This narrative review resumes the main findings about Tregs in psoriasis. We discuss how Tregs increase in psoriasis but are impaired in their regulatory/suppressive function. We debate the possibility that Tregs convert into T-effector cells under inflammatory conditions; for instance, they may turn into Th17-cells. We put particular emphasis on therapies that seem to counteract this conversion. We have enriched this review with an experimental section analyzing T-cells specific for the autoantigen LL37 in a healthy subject, suggesting that a shared specificity may exist between Tregs and autoreactive responder T-cells. This suggests that successful psoriasis treatments may, among other effects, restore Tregs numbers and functions. Full article

CXCL4 is an important biomarker of systemic sclerosis (SSc), an incurable autoimmune disease characterized by vasculopathy and skin/internal organs fibrosis. CXCL4 contributes to the type I interferon (IFN-I) signature, typical of at least half of SSc patients, and its presence is linked to an unfavorable prognosis. The mechanism implicated is CXCL4 binding to self-DNA, with the formation of complexes amplifying TLR9 stimulation in plasmacytoid dendritic cells (pDCs). Here, we demonstrate that, upon binding to self-RNA, CXCL4 protects the RNA from enzymatic degradation. As a consequence, CXCL4-RNA complexes persist in vivo. Indeed, we show for the first time that CXCL4-RNA complexes circulate in SSc plasma and correlate with both IFN-I and TNF-α. By using monocyte-derived DCs (MDDCs) pretreated with IFN-α as a model system (to mimic the SSc milieu of the IFN-I signature), we demonstrate that CXCL4-RNA complexes induce MDDC maturation and increase, in particular, pro-inflammatory TNF-α as well as IL-12, IL-23, IL-8, and pro-collagen, mainly in a TLR7/8-dependent but CXCR3-independent manner. In contrast, MDDCs produced IL-6 and fibronectin independently in their CXCL4 RNA-binding ability. These findings support a role for CXCL4-RNA complexes, besides CXCL4-DNA complexes, in immune amplification via the modulation of myeloid DC effector functions in SSc and also during normal immune responses. Full article

In this work, the consolidation efficiency of SiO₂ nanoparticles (synthesized in the Chemistry laboratories at the Tor Vergata University of Roma) was tested on Pietraforte sandstone surfaces belonging to the bell tower of San Lorenzo (Florence, Italy) and was fully investigated. Nanoparticles (synthesized in large-scale mass production) have been characterized by XRD—X-Ray Diffraction; Raman and FTIR—Fourier Transform Infrared spectroscopy; SEM—Scanning Electron Microscopy; while the Pietraforte sandstone morphology was examined by Porosimetry, capillary absorption test, surface hardness test, drilling resistance and tensile strength. The colorimetric measurements were also performed to characterize the optical modification exhibited by Pietraforte sandstones, especially after the SiO₂ treatments. Our results show that applying to the Pietraforte, the new consolidating agent based on SiO₂ nanoparticles, has several advantages, as they are more resistant to perforation, wear, and abrasion even long range (for long times of exposure and consolidating exercise against Florentine sandstone), compared to the CaCO₃ nanoparticles (tested in our previous paper), which instead show excellent performance but only close to their first application. This means that over time, their resistance to drilling decreases, they wear much more easily (compared to SiO₂-treated sandstone), and tend to exhibit quite a significant surface abrasion phenomena. The experimental results highlight that the SiO₂ consolidation efficiency on this kind of Florentine Pietraforte sandstone (having low porosity and a specific calcitic texture) seems to be higher in terms of water penetration protection, superficial cohesion forces, and an increase in surface resistance. Comparing the performance of SiO₂ nanoparticles with commercial consolidants in solvents such as Estel 1000 (tested here), we demonstrate that: (A) the restorative effects are obtained with a consolidation time over one week, significantly shorter when compared to the times of Estel 1000, exceeding 21 days; (B) SiO₂ nanoparticles perform better than Estel 1000 in terms of cohesion forces, also ensuring excellent preservation of the optical and color properties of the parent rock (without altering it after application). Full article

The Historic Center of Florence, a UNESCO World Heritage Site, includes many examples of architecture characterized by rough-hewn rusticated block facades—a very common masonry technique in the Florentine Renaissance—made in Pietraforte sandstone. The latter features numerous criticalities related to its intrinsic characteristics and to decay phenomena that are due to weathering and pollution. A multidisciplinary methodology has been developed starting from historic analysis and architectural survey to a complete optometric, mechanical, physical, mineralogical, and petrographic characterization of rough-hewn rusticated blocks, applied to the case study of the Palazzo Medici Riccardi facades. The studies performed in this work cover several research fields, from architecture to geology, going through material diagnostics, and aim at improving knowledge and designing new restoration solutions for Pietraforte building-material criticalities. The research proposes an operative protocol aimed at supporting restoration projects and monitoring plans, with the aim to protect historical, architectural, and artistic cultural heritage and to safeguard the people who visit the city of Florence every year. Full article

Cockayne syndrome group A (CS-A) is a rare recessive progeroid disorder characterized by sun sensitivity and neurodevelopmental abnormalities. Cells derived from CS-A patients present as pathological hallmarks excessive oxidative stress, mitochondrial fragmentation and apoptosis associated with hyperactivation of the mitochondrial fission dynamin related protein 1 (DRP1). In this study, by using human cell models we further investigated the interplay between DRP1 and CSA and we determined whether pharmacological or genetic inhibition of DRP1 affects disease progression. Both reactive oxygen and nitrogen species are in excess in CS-A cells and when the mitochondrial translocation of DRP1 is inhibited a reduction of these species is observed together with a recovery of mitochondrial integrity and a significant decrease of apoptosis. This study indicates that the CSA-driven modulation of DRP1 pathway is key to control mitochondrial homeostasis and apoptosis and suggests DRP1 as a potential target in the treatment of CS patients. Full article

Chemokine (C-X-C motif) ligand 4 (CXCL4) is a biomarker of unfavorable prognosis in Systemic Sclerosis (SSc), a potentially severe autoimmune condition, characterized by vasculitis, fibrosis and interferon (IFN)-I-signature. We recently reported that autoantibodies to CXCL4 circulate in SSc patients and correlate with IFN-α. Here, we used shorter versions of CXCL4 and CXCL4-L1, the CXCL4 non-allelic variant, to search for autoantibodies exclusively reacting to one or the other CXCL4 form. Moreover, to address whether anti-CXCL4/CXCL4-L1 antibodies were present before SSc onset and predicted SSc-progression, we longitudinally studied two VEDOSS (Very Early Diagnosis of Systemic Sclerosis) patient cohorts, separating SSc-progressors from SSc-non-progressors. We found that anti-CXCL4-specific autoantibodies were present in both SSc and VEDOSS patients (both SSc-progressors and SSc-non-progressors). Anti-CXCL4-L1-specific autoantibodies were especially detected in long-standing SSc (lsSSc). Anti-CXCL4/CXCL4-L1 antibodies correlated with IFN-α and with specific SSc-skin features but only in lsSSc and not in early SSc (eaSSc) or VEDOSS. Thus, a broader antibody response, with reactivity spreading to CXCL4-L1, is characteristic of lsSSc. The early anti-CXCL4 autoantibody response seems qualitatively different from, and likely less pathogenic than, that observed in advanced SSc. Lastly, we confirm that anti-CXCL4 autoantibodies are SSc-biomarkers and uncover that also CXCL4-L1 becomes an autoantigen in lsSSc. Full article

Sickle cell disease (SCD) is the most common hereditary disorder of hemoglobin (Hb), which affects approximately a million people worldwide. It is characterized by a single nucleotide substitution in the β-globin gene, leading to the production of abnormal sickle hemoglobin (HbS) with multi-system consequences. HbS polymerization is the primary event in SCD. Repeated polymerization and depolymerization of Hb causes oxidative stress that plays a key role in the pathophysiology of hemolysis, vessel occlusion and the following organ damage in sickle cell patients. For this reason, reactive oxidizing species and the (end)-products of their oxidative reactions have been proposed as markers of both tissue pro-oxidant status and disease severity. Although more studies are needed to clarify their role, antioxidant agents have been shown to be effective in reducing pathological consequences of the disease by preventing oxidative damage in SCD, i.e., by decreasing the oxidant formation or repairing the induced damage. An improved understanding of oxidative stress will lead to targeted antioxidant therapies that should prevent or delay the development of organ complications in this patient population. Full article

Structural and functional properties of ferrous Mycobacterium tuberculosis (Mt-Nb) and human (Hs-Nb) nitrobindins (Nbs) were investigated. At pH 7.0 and 25.0 °C, the unliganded Fe(II) species is penta-coordinated and unlike most other hemoproteins no pH-dependence of its coordination was detected over the pH range between 2.2 and 7.0. Further, despite a very open distal side of the heme pocket (as also indicated by the vanishingly small geminate recombination of CO for both Nbs), which exposes the heme pocket to the bulk solvent, their reactivity toward ligands, such as CO and NO, is significantly slower than in most hemoproteins, envisaging either a proximal barrier for ligand binding and/or crowding of H₂O molecules in the distal side of the heme pocket which impairs ligand binding to the heme Fe-atom. On the other hand, liganded species display already at pH 7.0 and 25 °C a severe weakening (in the case of CO) and a cleavage (in the case of NO) of the proximal Fe-His bond, suggesting that the ligand-linked movement of the Fe(II) atom onto the heme plane brings about a marked lengthening of the proximal Fe-imidazole bond, eventually leading to its rupture. This structural evidence is accompanied by a marked enhancement of both ligands dissociation rate constants. As a whole, these data clearly indicate that structural–functional relationships in Nbs strongly differ from what observed in mammalian and truncated hemoproteins, suggesting that Nbs play a functional role clearly distinct from other eukaryotic and prokaryotic hemoproteins. Full article

LL37 acts as T-cell/B-cell autoantigen in Systemic lupus erythematosus (SLE) and psoriatic disease. Moreover, when bound to “self” nucleic acids, LL37 acts as “danger signal,” leading to type I interferon (IFN-I)/pro-inflammatory factors production. T-cell epitopes derived from citrullinated-LL37 act as better antigens than unmodified LL37 epitopes in SLE, at least in selected HLA-backgrounds, included the SLE-associated HLA-DRB1*1501/HLA-DRB5*0101 backgrounds. Remarkably, while “fully-citrullinated” LL37 acts as better T-cell-stimulator, it loses DNA-binding ability and the associated “adjuvant-like” properties. Since LL37 undergoes a further irreversible post-translational modification, carbamylation and antibodies to carbamylated self-proteins other than LL37 are present in SLE, here we addressed the involvement of carbamylated-LL37 in autoimmunity and inflammation in SLE. We detected carbamylated-LL37 in SLE-affected tissues. Most importantly, carbamylated-LL37-specific antibodies and CD4 T-cells circulate in SLE and both correlate with disease activity. In contrast to “fully citrullinated-LL37,” “fully carbamylated-LL37” maintains both innate and adaptive immune-cells’ stimulatory abilities: in complex with DNA, carbamylated-LL37 stimulates plasmacytoid dendritic cell IFN-α production and B-cell maturation into plasma cells. Thus, we report a further example of how different post-translational modifications of a self-antigen exert complementary effects that sustain autoimmunity and inflammation, respectively. These data also show that T/B-cell responses to carbamylated-LL37 represent novel SLE disease biomarkers. Full article

The PietraAlberese is a marly limestone belonging to the Ligurian series (Monte Morello Formation of Eocene age). It is a material rarely mentioned in the historical Florentine architecture because the Pietraforte, the stone of the Medieval Florence and the Pietra Serena, the stone of the Renaissance, were the main lithotypes commonly used in those periods. Nevertheless, the Pietra Alberese has been widely utilized to build the town, because it is the only limestone cropping out in this part of Tuscany allowing the production of lime. In Prato and Pistoia, the Pietra Alberese was also used as stone (e.g., ashlars) in the structures and façades of many public and religious buildings. In this work, the geological setting and a mineralogical, petrographic and physical characterization of Pietra Alberese used as building stone are proposed together with a discussion about its durability. Moreover, the different compositional and macroscopic characteristics of two lithotypes (namely the sasso alberese and sasso porcino) utilized to produce the two types of lime used in the local traditional architecture (calcina dolce and calcina forte) are highlighted. Full article

Systemic sclerosis (SSc) is characterized by skin/internal organ fibrosis, vasculopathy and autoimmunity. Chemokine (C-X-C motif) ligand 4 (CXCL4) is an SSc biomarker, predicting unfavorable prognosis and lung fibrosis. CXCL4 binds DNA/RNA and favors interferon (IFN)-α production by plasmacytoid dendritic cells (pDCs), contributing to the type I IFN (IFN-I) signature in SSc patients. However, whether CXCL4 is an autoantigen in SSc is unknown. Here, we show that at least half of SSc patients show consistent antibody reactivity to CXCL4. T-cell proliferation to CXCL4, tested in a limited number of patients, correlates with anti-CXCL4 antibody reactivity. Antibodies to CXCL4 mostly correlate with circulating IFN-α levels and are significantly higher in patients with lung fibrosis in two independent SSc cohorts. Antibodies to CXCL4 implement the CXCL4–DNA complex’s effect on IFN-α production by pDCs; CXCL4–DNA/RNA complexes stimulate purified human B-cells to become antibody-secreting plasma cells in vitro. These data indicate that CXCL4 is indeed an autoantigen in SSc and suggest that CXCL4, and CXCL4-specific autoantibodies, can fuel a harmful loop: CXCL4–DNA/RNA complexes induce IFN-α in pDCs and direct B-cell stimulation, including the secretion of anti-CXCL4 antibodies. Anti-CXCL4 antibodies may further increase pDC stimulation and IFN-α release in vivo, creating a vicious cycle which sustains the SSc IFN-I signature and general inflammation. Full article

High concentrations of free radicals are present in the blood of obese patients. Free radicals are associated with endothelial dysfunction, diabetes, and neoplastic transformation, all conditions that are closely related to obesity. The purpose of our study was to determine whether bariatric surgery modifies the production of free radicals in obese patients. In total, 20 patients with morbid obesity, who were candidates for laparoscopic sleeve gastrectomy (SG), and 18 controls were enrolled in the study. Oxidative stress was studied in obese subjects before and after sleeve gastrectomy. The evaluation of oxidative stress was carried out on blood samples using electron paramagnetic resonance, a refined spectroscopic technique used to identify and quantify the major free radicals, such as ^•OH, O₂^•, ONOO^-, and NO. Oxidative stress was higher in subjects with morbid obesity prior to surgery, compared to the controls (CP• 9.9 ± 0.3 µM vs. 5.8 ± 0.2 µM). After SG, values decreased to levels comparable to those of controls (CP• 5.4 ± 0.2 µM). Further analysis identified O₂^• as the main free radical responsible for the oxidative stress. Obesity is associated with an increased blood concentration of free radicals. The normalization of free radicals after sleeve gastrectomy highlights another important benefit of this bariatric surgery technique. Full article