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1.
Clin Exp Rheumatol ; 37 Suppl 119(4): 115-124, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31573469

RESUMO

OBJECTIVES: Nintedanib is approved for the treatment of idiopathic pulmonary fibrosis (IPF) and was demonstrated to slow disease progression in patients with IPF by reducing decline in forced vital capacity by 50%. Recently, nintedanib has been reported to exert anti-fibrotic activity on systemic sclerosis (scleroderma, SSc) skin fibroblasts and to diminish skin and lung fibrosis in mouse models. The goal of the present study was to determine the effects of nintedanib on a cellular model of SSc-associated interstitial lung disease (ILD). METHODS: Study was performed using lung fibroblasts (LF) isolated from five patients with SSc-ILD and from three control subjects. RESULTS: Nintedanib inhibited LF proliferation and migration in a concentration- and time-dependent manner. The proliferation rate of LF stimulated with PDGF in the presence of nintedanib was reduced 1.9-fold within 24 h as compared to cells stimulated with PDGF alone. Migration of SSc-ILD LF incubated with 100 nM nintedanib was reduced from 62.8±12.5% to 39.1±9.0% in the presence of PDGF and from 38.2±7.9% to 26.6±7.2% in serum-free medium. Nintedanib attenuated PDGF-induced Ca2+ efflux, reduced α-SMA promoter activity and α-SMA protein expression. Furthermore, nintedanib blocked PDGF-induced differentiation of normal LF to myofibroblasts, reduced production of collagen and fibronectin, and decreased contractility of SSc-ILD LF in both floating and fixed collagen gels. CONCLUSIONS: Our data demonstrate significant antifibrotic efficacy of nintedanib in SSc-ILD LF suggesting that nintedanib has the potential not only to prevent but also to reverse the increased activity of LF consequently attenuating excessive lung fibrosis observed in SSc-ILD.


Assuntos
Fibrose Pulmonar Idiopática , Indóis/uso terapêutico , Doenças Pulmonares Intersticiais , Inibidores de Proteínas Quinases/uso terapêutico , Escleroderma Sistêmico , Células Cultivadas , Fibroblastos/efeitos dos fármacos , Humanos , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/etiologia , Pulmão/citologia , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/etiologia , Escleroderma Sistêmico/complicações
2.
Arthritis Rheumatol ; 2019 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-31233287

RESUMO

OBJECTIVE: To investigate the relationship between Krebs von den Lungen 6 (KL-6) and CCL18 levels and the severity and progression of systemic sclerosis (SSc)-related interstitial lung disease (ILD). METHODS: Patients enrolled in the Scleroderma Lung Study II (cyclophosphamide [CYC] versus mycophenolate mofetil [MMF]) were included. Baseline and 12-month plasma samples were analyzed by enzyme-linked immunosorbent assay to assess CCL18 and KL-6 levels. The forced vital capacity (FVC) and the diffusing capacity for carbon monoxide (DLco) were measured every 3 months. Joint models were created to investigate the relationship between baseline CCL18 and KL-6 levels and the course of the FVC and DLco over 1 year according to treatment arm. RESULTS: Baseline KL-6 and CCL18 levels each correlated with the extent of radiographic fibrosis. Levels of both CCL18 and KL-6 declined significantly at 1 year. In both treatment arms (n = 71 for CYC, n = 62 for MMF), a higher baseline KL-6 level predicted progression of ILD based on the course of FVC (P = 0.024 for CYC; P = 0.005 for MMF) and DLco (P < 0.001 for CYC; P = 0.004 for MMF) over 1 year. A higher baseline CCL18 level predicted progression of ILD based on the course of the FVC (P < 0.001 for CYC; P = 0.007 for MMF) and DLco (P = 0.001 for CYC; P < 0.001 for MMF) over 1 year, as well as mortality (P = 0.0008 for CYC arm only). CONCLUSION: In a rigorously conducted clinical trial for SSc-related ILD, KL-6 and CCL18 levels correlated with ILD severity and declined with immunosuppression. Patients with higher baseline KL-6 and CCL18 levels were more likely to experience disease progression despite treatment. KL-6 and CCL18 levels could be used to identify patients with a progressive ILD phenotype who may benefit from a more aggressive initial treatment approach.

3.
Semin Arthritis Rheum ; 49(2): 319-323, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31103239

RESUMO

BACKGROUND: Hypertrophic osteoarthropathy (HOA) is a syndrome characterized by abnormal proliferation of skin and osseous tissue frequently associated with underlying pulmonary disorders. Cardinal features include digital clubbing, periostitis and significant joint and bone pain. A number of recent reports have emerged of HOA and periostitis occurring in association with the antifungal agent voriconazole. METHODS: We present two additional cases of voriconazole-induced HOA and periostitis in lung transplant recipients with a review the medical literature. RESULTS: In both cases, symptoms were painful and severe enough to require opioid medication. Rapid improvement occurred within days of voriconazole cessation. A review of existing literature revealed an additional 17 cases of voriconazole-induced HOA and periostitis in lung transplant patients. CONCLUSION: We highlight the importance of recognizing the association of voriconazole with painful HOA and periostitis in lung transplant patients receiving antifungal therapy. Management of this painful condition involves cessation of voriconazole therapy, which may necessitate alternative anti-fungal drug therapies as well as adjustment of immunosuppressive drug dosage since voriconazole is a strong drug-inducer.

6.
Nano Lett ; 2018 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-30428677

RESUMO

Hydrogen atoms on a silicon surface, H-Si (100), behave as a resist that can be patterned with perfect atomic precision using a scanning tunneling microscope. When a hydrogen atom is removed in this manner, the underlying silicon presents a chemically active site, commonly referred to as a dangling bond. It has been predicted that individual dangling bonds function as artificial atoms, which, if grouped together, can form designer molecules on the H-Si (100) surface. Here, we present an artificial ring structure molecule spanning three dimer rows, constructed from dangling bonds, and verified by spectroscopic measurement of its molecular orbitals. We found that removing 8 hydrogen atoms resulted in a molecular analog to 1,4-disilylene-hexasilabenzene (Si8H8). Scanning tunneling spectroscopic measurements reveal molecular π and π* orbitals that agree with those expected for the same molecule in a vacuum; this is validated by density functional theory calculations of the dangling bond system on a silicon slab that show direct links both to the experimental results and to calculations for the isolated molecule. We believe the unique electronic structure of artificial molecules constructed in this manner can be engineered to enable future molecule-based electronics, surface catalytic functionality, and templating for subsequent site-selective deposition.

7.
J Rheumatol ; 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-30275260

RESUMO

OBJECTIVE: We sought to identify predictors of mortality and cardiopulmonary hospitalizations in patients at risk for pulmonary hypertension (PH) and enrolled in PHAROS, a prospective cohort study to investigate the natural history of PH in systemic sclerosis (SSc). METHODS: The at-risk population for PH was defined by the following entry criteria: echocardiogram systolic pulmonary arterial pressure > 40 mmHg, or DLCO < 55% predicted or ratio of % forced vital capacity/%DLCO > 1.6, measured by pulmonary function testing. Baseline clinical measures were evaluated as predictors of hospitalization and death between 2005 and 2014. Cox proportional hazards models were censored at date of PH onset or latest study visit and adjusted for age, sex, race, and disease duration. RESULTS: Of the 236 at-risk subjects who were followed for a median of 4 years (range 0.4-8.5 yrs), 35 developed PH after entering PHAROS (reclassified as PH group). In the at-risk group, higher mortality was strongly associated with male sex, low %DLCO, exercise oxygen desaturation, anemia, abnormal dyspnea scores, and baseline pericardial effusion. Risks for cardiopulmonary hospitalization were associated with increased dyspnea and pericardial effusions, although PH patients with DLCO < 50% had the highest risk of cardiopulmonary hospitalizations. CONCLUSION: Risk factors for poor outcome in patients with SSc who are at risk for PH were similar to others with SSc-PH and SSc-pulmonary arterial hypertension, including male sex, DLCO < 50%, exercise oxygen desaturation, and pericardial effusions. This group should undergo right heart catheterization and receive appropriate intervention if PH is confirmed.

8.
Artigo em Inglês | MEDLINE | ID: mdl-29741230

RESUMO

OBJECTIVES: A pilot study showed that an internet-based self-management program improves self-efficacy in systemic sclerosis (SSc). The objective of the present study was to compare the internet-based self-management program to an educational book developed for people with SSc in measures of self-efficacy and other patient-reported outcomes. METHODS: A 16-week randomized, controlled trial. RESULTS: Of the 267 participants who completed baseline questionnaires and were randomized to the intervention (internet) or control (book) condition, 123 (93%) in the internet and 124 (94%) in the control completed the 16-week RCT. The mean (SD) age of all participants was 53.7 (11.7) years, 91% were female, and 79.4% had some college or a higher degree. The mean (SD) disease duration after diagnosis of SSc was 8.97 (8.50) years. There were no statistical differences between the 2 groups for the primary outcome measure (PROMIS Self Efficacy Managing Symptoms: mean change of 0.35 in the internet group vs. 0.94 in control group, p=0.47) and secondary outcome measures, except the EQ5D visual analog scale (p=0.05). Internet group participants agreed that the self-management modules were of importance to them, the information was presented clearly, and the website was easy to use and at an appropriate reading level. CONCLUSION: Our RCT showed that the internet-based self-management website was not statistically superior to an educational patient-focused book in improving self-efficacy and other measures. The participants were enthusiastic for the content and presentation of the self-management website. This article is protected by copyright. All rights reserved.

9.
Arthritis Rheumatol ; 70(10): 1654-1660, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29732714

RESUMO

OBJECTIVE: Whole-exome sequencing (WES) studies in systemic sclerosis (SSc) patients of European American (EA) ancestry have identified variants in the ATP8B4 gene and enrichment of variants in genes in the extracellular matrix (ECM)-related pathway that increase SSc susceptibility. This study was undertaken to evaluate the association of the ATP8B4 gene and the ECM-related pathway with SSc in a cohort of African American (AA) patients. METHODS: SSc patients of AA ancestry were enrolled from 23 academic centers across the US under the Genome Research in African American Scleroderma Patients consortium. Unrelated AA individuals without serologic evidence of autoimmunity who were enrolled in the Howard University Family Study were used as unaffected controls. Functional variants in genes reported in the 2 WES studies in EA patients with SSc were selected for gene association testing using the optimized sequence kernel association test (SKAT-O) and pathway analysis by Ingenuity Pathway Analysis in 379 patients and 411 controls. RESULTS: Principal components analysis demonstrated that the patients and controls had similar ancestral backgrounds, with roughly equal proportions of mean European admixture. Using SKAT-O, we examined the association of individual genes that were previously reported in EA patients and none remained significant, including ATP8B4 (P = 0.98). However, we confirmed the previously reported association of the ECM-related pathway with enrichment of variants within the COL13A1, COL18A1, COL22A1, COL4A3, COL4A4, COL5A2, PROK1, and SERPINE1 genes (corrected P = 1.95 × 10-4 ). CONCLUSION: In the largest genetic study in AA patients with SSc to date, our findings corroborate the role of functional variants that aggregate in a fibrotic pathway and increase SSc susceptibility.

10.
Optik (Stuttg) ; 156: 635-645, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29503467

RESUMO

Accurate optics-based dimensional measurements of features sized well-below the diffraction limit require a thorough understanding of the illumination within the optical column and of the three-dimensional scattered fields that contain the information required for quantitative metrology. Scatterfield microscopy can pair simulations with angle-resolved tool characterization to improve agreement between the experiment and calculated libraries, yielding sub-nanometer parametric uncertainties. Optimized angle-resolved illumination requires bi-telecentric optics in which a telecentric sample plane defined by a Köhler illumination configuration and a telecentric conjugate back focal plane (CBFP) of the objective lens; scanning an aperture or an aperture source at the CBFP allows control of the illumination beam angle at the sample plane with minimal distortion. A bi-telecentric illumination optics have been designed enabling angle-resolved illumination for both aperture and source scanning modes while yielding low distortion and chief ray parallelism. The optimized design features a maximum chief ray angle at the CBFP of 0.002° and maximum wavefront deviations of less than 0.06 λ for angle-resolved illumination beams at the sample plane, holding promise for high quality angle-resolved illumination for improved measurements of deep-subwavelength structures using deep-ultraviolet light.

11.
Nanoscale ; 10(9): 4488-4499, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29459919

RESUMO

Advanced hydrogen lithography techniques and low-temperature epitaxial overgrowth enable the patterning of highly phosphorus-doped silicon (Si:P) monolayers (ML) with atomic precision. This approach to device fabrication has made Si:P monolayer systems a testbed for multiqubit quantum computing architectures and atomically precise 2-D superlattice designs whose behaviors are directly tied to the deterministic placement of single dopants. However, dopant segregation, diffusion, surface roughening, and defect formation during the encapsulation overgrowth introduce large uncertainties to the exact dopant placement and activation ratio. In this study, we develop a unique method by combining dopant segregation/diffusion models with sputter profiling simulation to monitor and control, at the atomic scale, dopant movement using room-temperature grown locking layers (LLs). We explore the impact of LL growth rate, thickness, rapid thermal annealing, surface accumulation, and growth front roughness on dopant confinement, local crystalline quality, and electrical activation within Si:P 2-D systems. We demonstrate that dopant movement can be more efficiently suppressed by increasing the LL growth rate than by increasing the LL thickness. We find that the dopant segregation length can be suppressed below a single Si lattice constant by increasing the LL growth rates at room temperature while maintaining epitaxy. Although dopant diffusivity within the LL is found to remain high (on the order of 10-17 cm2 s-1) even below the hydrogen desorption temperature, we demonstrate that exceptionally sharp dopant confinement with high electrical quality within Si:P monolayers can be achieved by combining a high LL growth rate with low-temperature LL rapid thermal annealing. The method developed in this study provides a key tool for 2-D fabrication techniques that require precise dopant placement to suppress, quantify, and predict a single dopant's movement at the atomic scale.

12.
N Engl J Med ; 378(1): 35-47, 2018 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-29298160

RESUMO

BACKGROUND: Despite current therapies, diffuse cutaneous systemic sclerosis (scleroderma) often has a devastating outcome. We compared myeloablative CD34+ selected autologous hematopoietic stem-cell transplantation with immunosuppression by means of 12 monthly infusions of cyclophosphamide in patients with scleroderma. METHODS: We randomly assigned adults (18 to 69 years of age) with severe scleroderma to undergo myeloablative autologous stem-cell transplantation (36 participants) or to receive cyclophosphamide (39 participants). The primary end point was a global rank composite score comparing participants with each other on the basis of a hierarchy of disease features assessed at 54 months: death, event-free survival (survival without respiratory, renal, or cardiac failure), forced vital capacity, the score on the Disability Index of the Health Assessment Questionnaire, and the modified Rodnan skin score. RESULTS: In the intention-to-treat population, global rank composite scores at 54 months showed the superiority of transplantation (67% of 1404 pairwise comparisons favored transplantation and 33% favored cyclophosphamide, P=0.01). In the per-protocol population (participants who received a transplant or completed ≥9 doses of cyclophosphamide), the rate of event-free survival at 54 months was 79% in the transplantation group and 50% in the cyclophosphamide group (P=0.02). At 72 months, Kaplan-Meier estimates of event-free survival (74% vs. 47%) and overall survival (86% vs. 51%) also favored transplantation (P=0.03 and 0.02, respectively). A total of 9% of the participants in the transplantation group had initiated disease-modifying antirheumatic drugs (DMARDs) by 54 months, as compared with 44% of those in the cyclophosphamide group (P=0.001). Treatment-related mortality in the transplantation group was 3% at 54 months and 6% at 72 months, as compared with 0% in the cyclophosphamide group. CONCLUSIONS: Myeloablative autologous hematopoietic stem-cell transplantation achieved long-term benefits in patients with scleroderma, including improved event-free and overall survival, at a cost of increased expected toxicity. Rates of treatment-related death and post-transplantation use of DMARDs were lower than those in previous reports of nonmyeloablative transplantation. (Funded by the National Institute of Allergy and Infectious Diseases and the National Institutes of Health; ClinicalTrials.gov number, NCT00114530 .).


Assuntos
Ciclofosfamida/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Imunossupressores/uso terapêutico , Escleroderma Sistêmico/terapia , Adolescente , Adulto , Idoso , Ciclofosfamida/efeitos adversos , Intervalo Livre de Doença , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Imunossupressores/efeitos adversos , Infecção/etiologia , Análise de Intenção de Tratamento , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Escleroderma Sistêmico/tratamento farmacológico , Escleroderma Sistêmico/mortalidade , Condicionamento Pré-Transplante , Transplante Autólogo , Adulto Jovem
13.
PLoS One ; 13(1): e0189498, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29293537

RESUMO

Gene-level analysis of ImmunoChip or genome-wide association studies (GWAS) data has not been previously reported for systemic sclerosis (SSc, scleroderma). The objective of this study was to analyze genetic susceptibility loci in SSc at the gene level and to determine if the detected associations were shared in African-American and White populations, using data from ImmunoChip and GWAS genotyping studies. The White sample included 1833 cases and 3466 controls (956 cases and 2741 controls from the US and 877 cases and 725 controls from Spain) and the African American sample, 291 cases and 260 controls. In both Whites and African Americans, we performed a gene-level analysis that integrates association statistics in a gene possibly harboring multiple SNPs with weak effect on disease risk, using Versatile Gene-based Association Study (VEGAS) software. The SNP-level analysis was performed using PLINK v.1.07. We identified 4 novel candidate genes (STAT1, FCGR2C, NIPSNAP3B, and SCT) significantly associated and 4 genes (SERBP1, PINX1, TMEM175 and EXOC2) suggestively associated with SSc in the gene level analysis in White patients. As an exploratory analysis we compared the results on Whites with those from African Americans. Of previously established susceptibility genes identified in Whites, only TNFAIP3 was significant at the nominal level (p = 6.13x10-3) in African Americans in the gene-level analysis of the ImmunoChip data. Among the top suggestive novel genes identified in Whites based on the ImmunoChip data, FCGR2C and PINX1 were only nominally significant in African Americans (p = 0.016 and p = 0.028, respectively), while among the top novel genes identified in the gene-level analysis in African Americans, UNC5C (p = 5.57x10-4) and CLEC16A (p = 0.0463) were also nominally significant in Whites. We also present the gene-level analysis of SSc clinical and autoantibody phenotypes among Whites. Our findings need to be validated by independent studies, particularly due to the limited sample size of African Americans.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Grupo com Ancestrais do Continente Europeu/genética , Estudo de Associação Genômica Ampla , Escleroderma Sistêmico/genética , Humanos , Polimorfismo de Nucleotídeo Único
14.
PLoS One ; 12(11): e0188588, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29176766

RESUMO

OBJECTIVE: M10 is a ten amino acid peptide generated from the intracellular cytoplasmic tail of the hepatocyte growth factor (HGF) receptor c-Met following cleavage by caspase-3. Recently we reported that M10 interacts with Smad2 and demonstrates antifibrotic properties in vitro and in vivo and can be advanced into a novel antifibrotic remedy. The current study was undertaken to develop an immunoassay to measure M10 concentration in biological specimens. EXPERIMENTAL DESIGN: An Indirect Enzyme-Linked Immunosorbent Assay (ELISA) for detection of M10 in biological fluids was developed using pharmaceutical grade synthetic M10 as a calibrator and commercially available anti-c-Met C12 antibody. RESULTS: M10 ELISA specifically detected in plasma M10, but not a scrambled peptide, following a single intraperitoneal administration of M10 (1mg/kg) to mice. The detection limit was 9.6 ng/ml, and the measuring limit was between 15 ng/ml and 200 ng/ml. The recovery limits of M10 were between 80% and 120%; intra-assay coefficient of variation was between 5.3% and 6.3%; inter-assay coefficient of variation was between 5.0% and 8.0% over the buffer concentration tested in the range from 15 ng /ml to 250 ng /ml. The peak of M10 concentration following a single intraperitoneal injection (1mg/kg) was achieved within 6 hours and declined to minimal levels by 48 hours. The experimentally obtained half-life for M10 was comparable to the theoretically predicted half-life for M10. CONCLUSIONS: We have established a highly sensitive ELISA to detect the antifibrotic peptide M10 in plasma samples, which should prove to be a novel tool to study the pharmacokinetics and efficacy of M10 in the treatment of fibroproliferative disorders.


Assuntos
Ensaio de Imunoadsorção Enzimática/métodos , Peptídeos/análise , Peptídeos/uso terapêutico , Animais , Anticorpos/metabolismo , Calibragem , Feminino , Fibrose , Meia-Vida , Limite de Detecção , Masculino , Camundongos Endogâmicos C57BL , Peptídeos/sangue , Peptídeos/farmacocinética , Sensibilidade e Especificidade
16.
Front Pharmacol ; 8: 174, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28420992

RESUMO

Monocytes from systemic sclerosis (SSc, scleroderma) patients and healthy African Americans (AA) are deficient in the regulatory protein caveolin-1 leading to enhanced migration toward chemokines and fibrogenic differentiation. While dermal fibrosis is the hallmark of SSc, loss of subcutaneous adipose tissue is a lesser-known feature. To better understand the etiology of SSc and the predisposition of AA to SSc, we studied the adipogenic potential of SSc and healthy AA monocytes. The ability of SSc and healthy AA monocytes to differentiate into adipocyte-like cells (ALC) is inhibited compared to healthy Caucasian (C) monocytes. We validated that monocyte-derived ALCs are distinct from macrophages by flow cytometry and immunocytochemistry. Like their enhanced fibrogenic differentiation, their inhibited adipogenic differentiation is reversed by the caveolin-1 scaffolding domain peptide (CSD, a surrogate for caveolin-1). The altered differentiation of SSc and healthy AA monocytes is additionally regulated by peroxisome proliferator-activated receptor γ (PPARγ) which is also present at reduced levels in these cells. In vivo studies further support the importance of caveolin-1 and PPARγ in fibrogenesis and adipogenesis. In SSc patients, healthy AA, and mice treated systemically with bleomycin, adipocytes lose caveolin-1 and PPARγ and the subcutaneous adipose layer is diminished. CSD treatment of these mice leads to a reappearance of the caveolin-1+/PPARγ+/FABP4+ subcutaneous adipose layer. Moreover, many of these adipocytes are CD45+, suggesting they are monocyte derived. Tracing experiments with injected EGFP+ monocytes confirm that monocytes contribute to the repair of the adipose layer when it is damaged by bleomycin treatment. Our observations strongly suggest that caveolin-1 and PPARγ work together to maintain a balance between the fibrogenic and adipogenic differentiation of monocytes, that this balance is altered in SSc and in healthy AA, and that monocytes make a major contribution to the repair of the adipose layer.

17.
J Biol Chem ; 292(25): 10490-10519, 2017 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-28389561

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a progressive clinical syndrome of fatal outcome. The lack of information about the signaling pathways that sustain fibrosis and the myofibroblast phenotype has prevented the development of targeted therapies for IPF. Our previous study showed that isolated fibrogenic lung fibroblasts have high endogenous levels of the hyaluronan receptor, CD44V6 (CD44 variant containing exon 6), which enhances the TGFß1 autocrine signaling and induces fibroblasts to transdifferentiate into myofibroblasts. NADPH oxidase 4 (NOX4) enzyme, which catalyzes the reduction of O2 to hydrogen peroxide (H2O2), has been implicated in the cardiac and lung myofibroblast phenotype. However, whether CD44V6 regulates NOX4 to mediate tissue repair and fibrogenesis is not well-defined. The present study assessed the mechanism of how TGF-ß-1-induced CD44V6 regulates the NOX4/reactive oxygen species (ROS) signaling that mediates the myofibroblast differentiation. Specifically, we found that NOX4/ROS regulates hyaluronan synthesis and the transcription of CD44V6 via an effect upon AP-1 activity. Further, CD44V6 is part of a positive-feedback loop with TGFß1/TGFßRI signaling that acts to increase NOX4/ROS production, which is required for myofibroblast differentiation, myofibroblast differentiation, myofibroblast extracellular matrix production, myofibroblast invasion, and myofibroblast contractility. Both NOX4 and CD44v6 are up-regulated in the lungs of mice subjected to experimental lung injury and in cases of human IPF. Genetic (CD44v6 shRNA) or a small molecule inhibitor (CD44v6 peptide) targeting of CD44v6 abrogates fibrogenesis in murine models of lung injury. These studies support a function for CD44V6 in lung fibrosis and offer proof of concept for therapeutic targeting of CD44V6 in lung fibrosis disorders.


Assuntos
Comunicação Autócrina , Receptores de Hialuronatos/biossíntese , Fibrose Pulmonar Idiopática/metabolismo , Miofibroblastos/metabolismo , NADPH Oxidases/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta1/metabolismo , Animais , Diferenciação Celular/genética , Modelos Animais de Doenças , Feminino , Humanos , Receptores de Hialuronatos/genética , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/patologia , Masculino , Camundongos , Miofibroblastos/patologia , NADPH Oxidase 4 , NADPH Oxidases/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptores de Fatores de Crescimento Transformadores beta/genética , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Fator de Transcrição AP-1/genética , Fator de Transcrição AP-1/metabolismo , Fator de Crescimento Transformador beta1/genética
18.
Ann Am Thorac Soc ; 14(5): 682-689, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28282243

RESUMO

RATIONALE: Patients with systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH) continue to have an unacceptably high mortality rate despite the progress achieved with pulmonary arterial vasodilator therapies. OBJECTIVES: We sought to determine whether SSc-PAH is a clinically distinct pulmonary vascular disease phenotype when compared with idiopathic pulmonary arterial hypertension (IPAH) on the basis of progression of echocardiographic right ventricular (RV) dysfunction. METHODS: Retrospective analysis of echocardiographic data in 13 patients with SSc-PAH and 11 patients with IPAH was used to delineate the progression of RV dysfunction during single or combination pulmonary arterial vasodilator therapy. All patients had right heart catheterization-confirmed pulmonary arterial hypertension as well as complete baseline (at the time of diagnosis) and follow-up (most recent) echocardiograms. We excluded patients with significant scleroderma-associated interstitial lung disease. Adjusting for time of follow-up and disease duration, we performed mixed model regression analyses comparing the changes between the two groups for different echocardiographic variables: tricuspid annular plane systolic excursion, tricuspid regurgitation jet velocity, right atrial area, and RV diameter. RESULTS: The mean ages for the SSc-PAH and IPAH groups were 60.8 and 48.2 years, respectively. The mean follow-up periods for the two groups were 3.8 and 1.95 years, respectively. Tricuspid annular plane systolic excursion did not improve in patients with SSc-PAH, whereas it increased in the patients with IPAH (-0.38 mm, P = 0.87; vs. +5.6 mm, P = 0.02). The other echocardiographic variables showed a trend toward worsening in the SSc-PAH group and improvement in the IPAH group. CONCLUSIONS: Our results indicate that, in patients with SSc-PAH, echocardiographic RV function does not improve over time compared with that of patients with IPAH, despite institution of pulmonary artery vasodilator therapies.


Assuntos
Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/fisiopatologia , Escleroderma Sistêmico/complicações , Disfunção Ventricular Direita/fisiopatologia , Adulto , Idoso , Cateterismo Cardíaco , Bases de Dados Factuais , Progressão da Doença , Ecocardiografia , Hipertensão Pulmonar Primária Familiar/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Estudos Retrospectivos , South Carolina , Disfunção Ventricular Direita/diagnóstico por imagem , Função Ventricular Direita
19.
Medicine (Baltimore) ; 96(51): e8980, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29390428

RESUMO

Racial differences exist in the severity of systemic sclerosis (SSc). To enhance our knowledge about SSc in African Americans, we established a comprehensive clinical database from the largest multicenter cohort of African American SSc patients assembled to date (the Genome Research in African American Scleroderma Patients (GRASP) cohort).African American SSc patients were enrolled retrospectively and prospectively over a 30-year period (1987-2016), from 18 academic centers throughout the United States. The cross-sectional prevalence of sociodemographic, clinical, and serological features was evaluated. Factors associated with clinically significant manifestations of SSc were assessed using multivariate logistic regression analyses.The study population included a total of 1009 African American SSc patients, comprised of 84% women. In total, 945 (94%) patients met the 2013 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for SSc, with the remaining 64 (6%) meeting the 1980 ACR or CREST (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia) criteria. While 43% were actively employed, 33% required disability support. The majority (57%) had the more severe diffuse subtype and a young age at symptom onset (39.1 ±â€Š13.7 years), in marked contrast to that reported in cohorts of predominantly European ancestry. Also, 1 in 10 patients had a severe Medsger cardiac score of 4. Pulmonary fibrosis evident on computed tomography (CT) chest was present in 43% of patients and was significantly associated with anti-topoisomerase I positivity. 38% of patients with CT evidence of pulmonary fibrosis had a severe restrictive ventilator defect, forced vital capacity (FVC) ≤50% predicted. A significant association was noted between longer disease duration and higher odds of pulmonary hypertension, telangiectasia, and calcinosis. The prevalence of potentially fatal scleroderma renal crisis was 7%, 3.5 times higher than the 2% prevalence reported in the European League Against Rheumatism Scleroderma Trials and Research (EUSTAR) cohort.Our study emphasizes the unique and severe disease burden of SSc in African Americans compared to those of European ancestry.


Assuntos
Escleroderma Sistêmico/epidemiologia , Adulto , Afro-Americanos , Mapeamento Cromossômico , Estudos de Coortes , Estudos Transversais , Bases de Dados Factuais , Feminino , Humanos , Masculino , Prevalência , Estudos Prospectivos , Estudos Retrospectivos , Escleroderma Sistêmico/sangue , Escleroderma Sistêmico/etnologia , Escleroderma Sistêmico/fisiopatologia , Índice de Gravidade de Doença , Fatores Socioeconômicos , Estados Unidos/epidemiologia
20.
Opt Lett ; 41(21): 4959-4962, 2016 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-27805660

RESUMO

The full 3-D scattered field above finite sets of features has been shown to contain a continuum of spatial frequency information and, with novel optical microscopy techniques and electromagnetic modeling, deep-subwavelength geometrical parameters can be determined. Similarly, by using simulations, scattering geometries and experimental conditions can be established to tailor scattered fields that yield lower parametric uncertainties while decreasing the number of measurements and the area of such finite sets of features. Such optimized conditions are reported through quantitative optical imaging in 193 nm scatterfield microscopy using feature sets up to four times smaller in area than state-of-the-art critical dimension targets.

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