Recommendations for coronavirus infection in rheumatic diseases treated with biologic therapy.

The Coronavirus-associated disease, that was first identified in 2019 in China (CoViD-19), is a pandemic caused by a bat-derived beta-coronavirus, named SARS-CoV2. It shares homology with SARS and MERS-CoV, responsible for past outbreaks in China and in Middle East. SARS-CoV2 spread from China where the first infections were described in December 2019 and is responsible for the respiratory symptoms that can lead to acute respiratory distress syndrome. A cytokine storm has been shown in patients who develop fatal complications, as observed in past coronavirus infections. The management includes ventilatory support and broad-spectrum antiviral drugs, empirically utilized, as a targeted therapy and vaccines have not been developed. Based upon our limited knowledge on the pathogenesis of CoViD-19, a potential role of some anti-rheumatic drugs may be hypothesized, acting as direct antivirals or targeting host immune response. Antimalarial drugs, commonly used in rheumatology, may alter the lysosomal proteases that mediates the viral entry into the cell and have demonstrated efficacy in improving the infection. Anti-IL-1 and anti-IL-6 may interfere with the cytokine storm in severe cases and use of tocilizumab has shown good outcomes in a small cohort. Baricitinib has both antiviral and anti-inflammatory properties. Checkpoints inhibitors such as anti-CD200 and anti-PD1 could have a role in the treatment of CoViD-19. Rheumatic disease patients taking immunosuppressive drugs should be recommended to maintain the chronic therapy, prevent infection by avoiding social contacts and pausing immunosuppressants in case of infection. National and international registries are being created to collect data on rheumatic patients with CoViD-19

Two-dimensional site seismic response analysis for a strategic building in Catania

This study is part of a more extensive research aimed to the seismic risk mitigation in Eastern Sicily. The earthquakes that occurred in Sicily in 1169, 1542, 1693, 1818, 1908 and more recently in 1990, testify the high level of seismic hazard in this region. It is well recognized that local seismic effects can exert a significant influence on the distribution of damage during earthquake. Traditionally, these effects are studied by means of simple one–dimensional (1-D) models of seismic wave propagation, which take only the influence of the stratigraphic profile and soil proprieties into to account for the site seismic response. It is known that the seismic response is strongly influenced by stratigraphic and topographic features that can reduce or amplify the earthquake induced ground motion depending on the soil stiffness and on the ground topography. This paper concerns the results of a two-dimensional (2-D) finite element analysis carried out to evaluate the response of the site where the National Institute of Geophysics and Volcanology (INGV) building is located in the town of Catania. The analysis, performed using as seismic input the accelerogram recorded in 1990 during the Santa Lucia earthquake, allowed to make some considerations about the expected accelerations at that the site and some comparison with the peak accelerations prescribed by Italian seismic code

A polymorphism in the human serotonin 5-HT2A receptor gene may protect against systemic sclerosis by reducing platelet aggregation

Introduction: Platelet aggregation may contribute to the pathogenesis of systemic sclerosis: following activation, platelets release significant amounts of serotonin - which promotes vasoconstriction and fibrosis, and further enhances aggregation. The C+1354T polymorphism in the exonic region of the serotonin 2A receptor gene determining the His452Tyr substitution was associated with blunted intracellular responses after serotonin stimulation, and may have a role in susceptibility to scleroderma. Methods: One hundred and fifteen consecutive systemic sclerosis patients and 140 well-matched healthy control individuals were genotyped by sequence-specific primer-PCR for the His452Tyr substitution of the serotonin 2A receptor gene, and associations were sought with scleroderma and its main clinical features. The functional relevance of the His452Tyr substitution was also assessed by evaluating the aggregation of platelet-rich plasma from His452/ His452 and His452/Tyr452 healthy individuals after stimulation with adenosine diphosphate ± serotonin. Results: The T allele of the C+1354T polymorphism was underrepresented in scleroderma patients compared with control individuals (5.2% versus 12.4%, P < 0.001, chi-square test and 1,000-fold permutation test) and its carriage reduced the risk for systemic sclerosis (odds ratio = 0.39, 95% confidence interval = 0.19 to 0.85, P < 0.01). Platelets from His452/Tyr452 healthy subjects more weakly responded to serotonin stimulation compared with platelets from His452/His452 individuals (3.2 ± 2.6-fold versus 9.6 ± 8.6-fold increase in aggregation, P = 0.017 by Kolmogorov-Smirnov test and P = 0.003 after correction for baseline adenosine diphosphate-induced aggregation values). Conclusion: The His452Tyr substitution may influence susceptibility to systemic sclerosis by altering platelet aggregation in response to serotonin

NMR Profiling of Exhaled Breath Condensate Defines Different Metabolic Phenotypes of Non-Cystic Fibrosis Bronchiectasis

Nuclear-magnetic-resonance (NMR) profiling of exhaled breath condensate (EBC) provides insights into the pathophysiology of bronchiectasis by identifying specific biomarkers. We evaluated whether NMR-based metabolomics discriminates the EBC-derived metabolic phenotypes ("metabotypes") of 41 patients with non-cystic fibrosis (nCF) bronchiectasis of various etiology [24 subjects with Primary Ciliary Dyskinesia (PCD); 17 patients with bronchiectasis not associated with PCD (nCF/nPCD)], who were compared to 17 healthy subjects (HS). NMR was used for EBC profiling, and Orthogonal Projections to Latent Structures with partial least-squares discriminant analysis (OPLS-DA) was used as a classifier. The results were validated by using the EBC from 17 PCD patients not included in the primary analysis. Different statistical models were built, which compared nCF/nPCD and HS, PCD and HS, all classes (nCF/nPCD-PCD-HS), and, finally, PCD and nCF/nPCD. In the PCD-nCF/nPCD model, four statistically significant metabolites were able to discriminate between the two groups, with only a minor reduction of the quality parameters. In particular, for nCF/nPCD, acetone/acetoin and methanol increased by 21% and 18%, respectively. In PCD patients, ethanol and lactate increased by 25% and 28%, respectively. They are all related to lung inflammation as methanol is found in the exhaled breath of lung cancer patients, acetone/acetoin produce toxic ROS that damage lung tissue in CF, and lactate is observed in acute inflammation. Interestingly, a high concentration of ethanol hampers cilia beating and can be associated with the genetic defect of PCD. Model validation with 17 PCD samples not included in the primary analysis correctly predicted all samples. Our results indicate that NMR of EBC discriminates nCF/nPCD and PCD bronchiectasis patients from HS, and patients with nCF/nPCD from those with PCD. The metabolites responsible for between-group separation identified specific metabotypes, which characterize bronchiectasis of a different etiology

Biofunctional Silk Kirigami With Engineered Properties.

The fabrication of multifunctional materials that interface with living environments is a problem of great interest. A variety of structural design concepts have been integrated with functional materials to form biodevices and surfaces for health monitoring. In particular, approaches based on kirigami-inspired cuts can engineer flexibility in materials through the creation of patterned defects. Here, the fabrication of a biodegradable and biofunctional "silk kirigami" material is demonstrated. Mechanically flexible, free-standing, optically transparent, large-area biomaterial sheets with precisely defined and computationally designed microscale cuts can be formed using a single-step photolithographic process. Using modeling techniques, it is shown how cuts can generate remarkable "self-shielding" leading to engineered elastic behavior and deformation. As composites with conducting polymers, flexible, intrinsically electroactive sheets can be formed. Importantly, the silk kirigami sheets are biocompatible, can serve as substrates for cell culture, and be proteolytically resorbed. The unique properties of silk kirigami suggest a host of applications as transient, "green", functional biointerfaces, and flexible bioelectronics

Lenvatinib exhibits antineoplastic activity in anaplastic thyroid cancer in vitro and in vivo

Lenvatinib is an oral, multitargeted tyrosine kinase inhibitor (TKI) of VEGFR1-VEGFR3, FGFR1-FGFR4, PDGFRα, RET and v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) signaling networks involved in tumor angiogenesis. We have evaluated the antitumor activity of lenvatinib in primary anaplastic thyroid cancer (ATC) cells, in the human cell line 8305C (undifferentiated thyroid cancer) and in an ATC-cell line (AF). The AF cell line was obtained from the primary ATC cultures and was the one that grew over 50 passages. The effect of lenvatinib (1 and 100 nM; and 1, 10, 25 and 50 μM) was investigated in primary ATC, 8305C and AF cells as well as in AF cells in CD nu/nu mice. Lenvatinib significantly reduced ATC cell proliferation (P<0.01, ANOVA) and increased the percentage of apoptotic ATC cells (P<0.001, ANOVA). Furthermore, lenvatinib inhibited migration (P<0.01) and invasion (P<0.001) in ATC. In addition, lenvatinib inhibited EGFR, AKT and ERK1/2 phosphorylation and downregulated cyclin D1 in the ATC cells. Lenvatinib also significantly inhibited 8305C and AF cell proliferation, increasing apoptosis. AF cells were subcutaneously injected into CD nu/nu mice and tumor masses were observed 20 days later. Tumor growth was significantly inhibited by lenvatinib (25 mg/kg/day), as well as the expression of VEGF-A and microvessel density in the AF tumor tissues. In conclusion, the antitumor and antiangiogenic activities of lenvatinib may be promising for the treatment of anaplastic thyroid cancer, and may consist a basis for future clinical therapeutic applications

Vandetanib has antineoplastic activity in anaplastic thyroid cancer, in vitro and in vivo

The antitumor activity of vandetanib [a multiple signal transduction inhibitor including the RET tyrosine kinase, epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF) receptor (VEGFR), ERK and with antiangiogenic activity], in primary anaplastic thyroid cancer (ATC) cells, in the human cell line 8305C [undifferentiated thyroid cancer (TC)] and in an ATC-cell line (AF), was investigated in the present study. Vandetanib (1 and 100 nM; 1, 10, 25 and 50 μM) was tested by WST-1, apoptosis, migration and invasion assays: in primary ATC cells, in the 8305C continuous cell line, and in AF cells; and in 8305C cells in CD nu/nu mice. Vandetanib significantly reduced ATC cell proliferation (P<0.01, ANOVA), induced apoptosis dose-dependently (P<0.001, ANOVA), and inhibited migration (P<0.01) and invasion (P<0.001). Furthermore, vandetanib inhibited EGFR, AKT and ERK1/2 phosphorylation and downregulated cyclin D1 in ATC cells. In 8305C and AF cells, vandetanib significantly inhibited the proliferation, inducing also apoptosis. 8305C cells were injected subcutaneously in CD nu/nu mice and tumor masses became detectable after 30 days. Vandetanib (25 mg/kg/day) significantly inhibited tumor growth and VEGF-A expression and microvessel density in 8305C tumor tissues. In conclusion, the antitumor and antiangiogenic activity of vandetanib is very auspicious in ATC, opening the way to a future clinical evaluation

2,6-Diphenyl-imidazopyridine derivatives as novel prototypes of anticancer agents targeting aldehyde dehydrogenase

Aldehyde dehydrogenase (ALDH) superfamily comprises 19 different enzyme types located in specific subcellular districts, including cytosol and mitocondria. Their main function is to oxidize endogenous and exogenous aldehydes produced in human cells. In particular, isoforms 1A1, 1A2 and 1A3 catalyze the transformation of retinal into retinoic acid, which is a potent differentiation tissue factor for cellular development. Overexpression of these three isoforms in cancer stem cells (CSC), underlined in recent studies, is to date extremely important in cancer field, as it offers the chance to use these proteins both as prognostic marker and as novel targets in the fight against cancer. Here we present a novel series of 2,6-diphenyl-imidazol[1,2-a]pyridines, designed as aldehyde dehydrogenase inhibitors by means of a structured-based optimizations of a previously developed lead, GA11. The novel compounds were evaluated in vitro for their activity and selectivity against the three isoforms of the ALDH1A family, and investigated through crystallization and modeling studies for their ability to interact with the catalytic site of the 1A3 isoform. Tested in vitro on different populations of CSCs, obtained from glioma, colorectal and prostate tissue specimens, they exhibited a relevant anti-proliferative efficacy, thus paving the way for treating cancer by means of the still untapped aldehyde dehydrogenases

Human amniotic fluid-derived and dental pulp-derived stem cells seeded into collagen scaffold repair critical-size bone defects promoting vascularization

INTRODUCTION: The main aim of this study is to evaluate potential human stem cells, such as dental pulp stem cells and amniotic fluid stem cells, combined with collagen scaffold to reconstruct critical-size cranial bone defects in an animal model. METHODS: We performed two symmetric full-thickness cranial defects on each parietal region of rats and we replenished them with collagen scaffolds with or without stem cells already seeded into and addressed towards osteogenic lineage in vitro. After 4 and 8 weeks, cranial tissue samples were taken for histological and immunofluorescence analysis. RESULTS: We observed a new bone formation in all of the samples but the most relevant differences in defect correction were shown by stem cell–collagen samples 4 weeks after implant, suggesting a faster regeneration ability of the combined constructs. The presence of human cells in the newly formed bone was confirmed by confocal analysis with an antibody directed to a human mitochondrial protein. Furthermore, human cells were found to be an essential part of new vessel formation in the scaffold. CONCLUSION: These data confirmed the strong potential of bioengineered constructs of stem cell–collagen scaffold for correcting large cranial defects in an animal model and highlighting the role of stem cells in neovascularization during skeletal defect reconstruction