PTP4A1 promotes TGFβ signaling and fibrosis in systemic sclerosis.

Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of skin and internal organs. Protein tyrosine phosphatases have received little attention in the study of SSc or fibrosis. Here, we show that the tyrosine phosphatase PTP4A1 is highly expressed in fibroblasts from patients with SSc. PTP4A1 and its close homolog PTP4A2 are critical promoters of TGFβ signaling in primary dermal fibroblasts and of bleomycin-induced fibrosis in vivo. PTP4A1 promotes TGFβ signaling in human fibroblasts through enhancement of ERK activity, which stimulates SMAD3 expression and nuclear translocation. Upstream from ERK, we show that PTP4A1 directly interacts with SRC and inhibits SRC basal activation independently of its phosphatase activity. Unexpectedly, PTP4A2 minimally interacts with SRC and does not promote the SRC-ERK-SMAD3 pathway. Thus, in addition to defining PTP4A1 as a molecule of interest for TGFβ-dependent fibrosis, our study provides information regarding the functional specificity of different members of the PTP4A subclass of phosphatases

Synoviocyte-targeted therapy synergizes with TNF inhibition in arthritis reversal

Fibroblast-like synoviocytes (FLS) are joint-lining cells that promote rheumatoid arthritis (RA) pathology. Current disease-modifying antirheumatic agents (DMARDs) operate through systemic immunosuppression. FLS-targeted approaches could potentially be combined with DMARDs to improve control of RA without increasing immunosuppression. Here, we assessed the potential of immunoglobulin-like domains 1 and 2 (Ig1&2), a decoy protein that activates the receptor tyrosine phosphatase sigma (PTPRS) on FLS, for RA therapy. We report that PTPRS expression is enriched in synovial lining RA FLS and that Ig1&2 reduces migration of RA but not osteoarthritis FLS. Administration of an Fc-fusion Ig1&2 attenuated arthritis in mice without affecting innate or adaptive immunity. Furthermore, PTPRS was down-regulated in FLS by tumor necrosis factor (TNF) via a phosphatidylinositol 3-kinase–mediated pathway, and TNF inhibition enhanced PTPRS expression in arthritic joints. Combination of ineffective doses of TNF inhibitor and Fc-Ig1&2 reversed arthritis in mice, providing an example of synergy between FLS-targeted and immunosuppressive DMARD therapies.publishedVersio

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

Studio delle componenti riconosciute dalle IgE nel polline di Lolium perenne e analisi comparativa dei profili di sensibilizzazione di pazienti allergici

Negli ultimi anni, le indagini proteomiche hanno fornito un potente aiuto nella caratterizzazione molecolare di fonti allergeniche complesse, con rilevanti implicazioni nella diagnosi e nel trattamento immunoterapico delle allergie. In questo lavoro è stato seguito un approccio proteomico per caratterizzare il polline di Lolium perenne, una fonte comune di allergia stagionale, che affligge un numero sempre più ampio di persone in tutto il mondo. Gli esperimenti di shotgun peptidico effettuati in nanoLiquid Ultra Pressure Chromatography accoppiati con protocolli di acquisizione rapida Q-TOF MS-MS/MS e immunoblot 2-DE, combinati con analisi MALDI-TOFTOF hanno permesso l'identificazione di tutti gli allergeni già noti in questa graminacea. Le analisi comparative degli immunoblot hanno evidenziato una classe di pazienti caratterizzata da un pattern 2-DE più complesso associato con elevati livelli di anticorpi IgE e da un'alta suscettibilità a sensibilizzazioni multiple nei confronti di diverse fonti allergeniche. Le analisi dei cluster hanno rivelato che tutti questi pazienti erano reattivi alla profilina, che è considerata il principale allergene cross-reattivo nel polline delle graminacee. Inoltre, le analisi di spettrometria di massa hanno rivelato la presenza di altre componenti reattive alle IgE nel polline di Lolium perenne che potrebbero essere coinvolte nella polisensibilizzazione, come la ciclofilina, la fructosiltransferasi e la legumina.In the last years, proteomic investigation provided a powerful tool in molecular characterization of complex allergen sources, with relevant implications in both diagnosis and immunotherapic treatment of allergies. We followed a proteomic approach to characterize ryegrass (Lolium perenne) pollen, a common cause of seasonal allergic diseases affecting an increasing part of world population. Peptide shotgun experiments performed on nanoLiquid Ultra Pressure Chromatography coupled with fast Q-TOF MS-MS/MS acquisition protocols (MSE) and 2-DE immunoblot combined with MALDI-TOFTOF analysis allowed the detection of all previously identified ryegrass allergens. Comparative analysis of immunoblot highlighted a class of patients characterized by a more complex 2-DE pattern associated with increased levels of IgE antibodies and by higher susceptibility to multiple sensitization toward different allergen sources. Cluster analysis revealed that all these patients recognized profilin, considered the main cross-reactive allergen in grass pollen. Furthermore, mass spectrometry analysis revealed the presence of other IgE reactive components in ryegrass pollen that might be involved in polysensitization, such as cyclophilin, fructosyltransferase and legumin-like protein

Choroidal neovascular membrane following hormonal stimulation for in vitro fertilization

PURPOSE: To report the onset of choroidal neovascularization (CNV) following hormonal stimulation for in vitro fertilization (IVF) in a healthy young woman. METHODS: A 31-year-old woman presented with visual impairment following hormonal stimulation for IVF. Clinical history was collected and best-corrected visual acuity (BCVA), complete eye examination, optical coherence tomography (OCT), fluorescein angiography (FA), and indocyanine green angiography were -performed. RESULTS: Clinical history was negative with the exception of the use of medications for IVF in the previous weeks. Ocular examination revealed the presence of a CNV in the right eye, confirmed by OCT and FA, with a BCVA of 0.7 decimal units. Possible ocular and systemic diseases associated with CNV development were investigated and excluded. Treatment with 3 monthly intravitreal injections of anti-vascular endothelial growth factor (VEGF) was effective in reducing CNV size and restoring visual acuity. CONCLUSIONS: This is the first report describing the development of CNV following hormonal stimulation for IVF. The development of CNV may be associated with changes of sex hormones, cytokines, and angiogenic factor levels, including VEGF, induced by hormonal stimulation

Polyethylene-Glycol-Modified Single-Walled Carbon Nanotubes for Intra-Articular Delivery to Chondrocytes

Osteoarthritis (OA) is a common and debilitating degenerative disease of articular joints for which no disease-modifying medical therapy is currently available. Inefficient delivery of pharmacologic agents into cartilage-resident chondrocytes after systemic administration has been a limitation to the development of anti-OA medications. Direct intra-articular injection enables delivery of high concentrations of agents in close proximity to chondrocytes; however, the efficacy of this approach is limited by the fast clearance of small molecules and biomacromolecules after injection into the synovial cavity. Coupling of pharmacologic agents with drug delivery systems able to enhance their residence time and cartilage penetration can enhance the effectiveness of intra-articularly injected anti-OA medications. Herein we describe an efficient intra-articular delivery nanosystem based on single-walled carbon nanotubes (SWCNTs) modified with polyethylene glycol (PEG) chains (PEG-SWCNTs). We show that PEG-SWCNTs are capable to persist in the joint cavity for a prolonged time, enter the cartilage matrix, and deliver gene inhibitors into chondrocytes of both healthy and OA mice. PEG-SWCNT nanoparticles did not elicit systemic or local side effects. Our data suggest that PEG-SWCNTs represent a biocompatible and effective nanocarrier for intra-articular delivery of agents to chondrocytes

PILOT STUDY ON MULTISLICE SPIRAL CT-ANGIOGRAPHY CAPABILITY IN DETECTING CAROTID UNSTABLE PLAQUE

ROMA, PALAZZO DEI CONGRESSI