Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 88
Filtrar
1.
Eur Respir J ; 2019 Oct 10.
Artículo en Inglés | MEDLINE | ID: mdl-31601718

RESUMEN

Ontologically distinct populations of macrophages differentially contribute to organ fibrosis through unknown mechanisms. We applied lineage tracing, single-cell RNA-seq and single molecule fluorescent in situ hybridisation to a spatially-restricted model of asbestos-induced pulmonary fibrosis. We demonstrate that tissue-resident alveolar macrophages, tissue-resident peribronchial and perivascular interstitial macrophages and monocyte-derived alveolar macrophages are present in the fibrotic niche. Deletion of monocyte-derived alveolar macrophages but not tissue-resident alveolar macrophages ameliorated asbestos-induced lung fibrosis. Monocyte-derived alveolar macrophages were specifically localised to fibrotic regions in the proximity of fibroblasts where they expressed molecules known to drive fibroblast proliferation, including PDGFA. Using single-cell RNA-seq and spatial transcriptomics in both humans and mice, we identified M-CSFR signaling as one of the novel druggable targets controlling self-maintenance and persistence of these pathogenic monocyte-derived alveolar macrophages. Pharmacological blockade of M-CSFR signaling led to the disappearance of monocyte-derived alveolar macrophages and ameliorated fibrosis. Our findings suggest that inhibition of M-CSFR signaling during fibrosis disrupts an essential fibrotic niche that includes monocyte-derived alveolar macrophages and fibroblasts during asbestos-induced fibrosis.

2.
J Am Acad Dermatol ; 2019 Jun 13.
Artículo en Inglés | MEDLINE | ID: mdl-31202873

RESUMEN

BACKGROUND: Reflectance confocal microscopy (RCM) allows accurate noninvasive in-vivo diagnosis for skin cancer. However, its impact in daily routine on the physician's diagnostic confidence and management is unknown. OBJECTIVES: We sought to assess the physician´s diagnostic confidence and management before and after RCM of equivocal skin lesions. METHODS: Prospective, two-center, observational study. During clinical practice, seven dermatologists recorded their diagnostic confidence level, diagnosis and management before and after RCM of clinically/dermoscopically-equivocal lesions concerning for skin cancer. We also evaluated the diagnostic accuracy before and after RCM. RESULTS: We included 272 consecutive lesions from 226 individuals (mean age 53.5 years). Diagnostic confidence increased from 6.2 to 8.1 after RCM (p<0.001), both when RCM reassured or changed the diagnosis. Lesion management changed in 33.5% cases after RCM, (to observation n=51; to biopsy/excision n=31). After RCM, the number needed to excise was 1.2. Sensitivity for malignancy before and after RCM was 78.2% and 85.1%, respectively. Specificity before and after RCM was 78.8 % and 80%, respectively. LIMITATIONS: Small sample size, real-life environment, different expertise among RCM users. CONCLUSION: Physician's diagnostic confidence and accuracy increases after RCM when evaluating equivocal tumors, frequently resulting in management changes, while keeping high diagnostic accuracy.

5.
Am J Respir Crit Care Med ; 199(12): 1517-1536, 2019 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-30554520

RESUMEN

Rationale: The contributions of diverse cell populations in the human lung to pulmonary fibrosis pathogenesis are poorly understood. Single-cell RNA sequencing can reveal changes within individual cell populations during pulmonary fibrosis that are important for disease pathogenesis. Objectives: To determine whether single-cell RNA sequencing can reveal disease-related heterogeneity within alveolar macrophages, epithelial cells, or other cell types in lung tissue from subjects with pulmonary fibrosis compared with control subjects. Methods: We performed single-cell RNA sequencing on lung tissue obtained from eight transplant donors and eight recipients with pulmonary fibrosis and on one bronchoscopic cryobiospy sample from a patient with idiopathic pulmonary fibrosis. We validated these data using in situ RNA hybridization, immunohistochemistry, and bulk RNA-sequencing on flow-sorted cells from 22 additional subjects. Measurements and Main Results: We identified a distinct, novel population of profibrotic alveolar macrophages exclusively in patients with fibrosis. Within epithelial cells, the expression of genes involved in Wnt secretion and response was restricted to nonoverlapping cells. We identified rare cell populations including airway stem cells and senescent cells emerging during pulmonary fibrosis. We developed a web-based tool to explore these data. Conclusions: We generated a single-cell atlas of pulmonary fibrosis. Using this atlas, we demonstrated heterogeneity within alveolar macrophages and epithelial cells from subjects with pulmonary fibrosis. These results support the feasibility of discovery-based approaches using next-generation sequencing technologies to identify signaling pathways for targeting in the development of personalized therapies for patients with pulmonary fibrosis.

6.
J Am Acad Dermatol ; 80(5): 1414-1427.e3, 2019 May.
Artículo en Inglés | MEDLINE | ID: mdl-30529706

RESUMEN

BACKGROUND: There is lack of uniformity in reflectance confocal microscopy (RCM) terminology for nonmelanocytic lesions (NMLs). OBJECTIVE: To review published RCM terms for NMLs and identify likely synonymous terms. METHODS: We conducted a systematic review of original research articles published up to August 19, 2017, adhering to Preferred Reporting Items for Systemic Reviews and Meta-Analyses guidelines. Two investigators gathered all published RCM terms used to describe basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and seborrheic keratosis/solar lentigo/lichen planus-like keratosis (SK/SL/LPLK). Synonymous terms were grouped on the basis of similarity in definition and histopathologic correlates. RESULTS: The inclusion criteria was met by 31 studies. Average frequency of use per term was 1.6 (range 1-8). By grouping synonymous terms, the number of terms could be reduced from 58 to 18 for BCC, 58 to 36 for SCC, 23 to 12 for SK/SL/LPLK, and from 139 to 66 terms (52.5% reduction) in total. The frequency of term usage stratified by anatomic layer (suprabasal epidermis vs epidermal basal layer, dermoepidermal junction, and superficial dermis) was 27 (25.7%) versus 78 (74.2%) for BCC; 60 (64.5%) versus 33 (34.5%) for SCC, and 15 (45.4%) versus 18 (54.5%) for SK/SL/LPLK, respectively. LIMITATIONS: Articles that were not peer reviewed were excluded. CONCLUSION: Systematic review of published RCM terms provides the basis for future NMLs terminology consensus.


Asunto(s)
Carcinoma Basocelular/diagnóstico por imagen , Carcinoma de Células Escamosas/diagnóstico por imagen , Neoplasias Cutáneas/diagnóstico por imagen , Terminología como Asunto , Humanos , Queratosis Seborreica/diagnóstico por imagen , Lentigo/diagnóstico por imagen , Microscopía Confocal
7.
Respir Res ; 19(1): 233, 2018 Nov 26.
Artículo en Inglés | MEDLINE | ID: mdl-30477498

RESUMEN

Idiopathic pulmonary fibrosis (IPF) is characterized by progressive scarring of the lung parenchyma, leading to respiratory failure and death. High resolution computed tomography of the chest is often diagnostic for IPF, but its cost and the risk of radiation exposure limit its use as a screening tool even in patients at high risk for the disease. In patients with lung cancer, investigators have detected transcriptional signatures of disease in airway and nasal epithelial cells distal to the site of disease that are clinically useful as screening tools. Here we assessed the feasibility of distinguishing patients with IPF from age-matched controls through transcriptomic profiling of nasal epithelial curettage samples, which can be safely and repeatedly sampled over the course of a patient's illness. We recruited 10 patients with IPF and 23 age-matched healthy control subjects. Using 3' messenger RNA sequencing (mRNA-seq), we identified 224 differentially expressed genes, most of which were upregulated in patients with IPF compared with controls. Pathway enrichment analysis revealed upregulation of pathways related to immune response and inflammatory signaling in IPF patients compared with controls. These findings support the concept that fibrosis is associated with upregulation of inflammatory pathways across the respiratory epithelium with possible implications for disease detection and pathobiology.

8.
Cell Metab ; 2018 Oct 11.
Artículo en Inglés | MEDLINE | ID: mdl-30318339

RESUMEN

Urban particulate matter air pollution induces the release of pro-inflammatory cytokines including interleukin-6 (IL-6) from alveolar macrophages, resulting in an increase in thrombosis. Here, we report that metformin provides protection in this murine model. Treatment of mice with metformin or exposure of murine or human alveolar macrophages to metformin prevented the particulate matter-induced generation of complex III mitochondrial reactive oxygen species, which were necessary for the opening of calcium release-activated channels (CRAC) and release of IL-6. Targeted genetic deletion of electron transport or CRAC channels in alveolar macrophages in mice prevented particulate matter-induced acceleration of arterial thrombosis. These findings suggest metformin as a potential therapy to prevent some of the premature deaths attributable to air pollution exposure worldwide.

9.
Expert Rev Respir Med ; 12(9): 725-732, 2018 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-30073878

RESUMEN

INTRODUCTION: Cystic fibrosis (CF) is the most common, life-limiting autosomal recessive disease in Caucasians, and is caused by defects in production of the CFTR ion channel. Until recently, there were no available treatments targeting the disease-causing defects in CFTR but newly developed CFTR modulators are changing the course of disease in CF. The newest modulator, tezacaftor, is a CFTR corrector that was recently approved by the FDA to be used in combination with the first approved CFTR potentiator, ivacaftor. Areas covered: A detailed review of the clinical trials and published literature, focusing on safety and efficacy, leading to the approval of tezacaftor in CF. Expert commentary: Recent trials have demonstrated that the combination of tezacaftor-ivacaftor is a slightly superior combination to its predecessor, lumacaftor-ivacaftor, with respect to an increase in FEV1, adverse event profile, and drug-drug interactions. It is also approved for a large number of non-F508del, residual function mutations that are predicted to respond based on in vitro testing. The horizon for continued improvements in CFTR-targeted treatments is promising, with three-drug combinations currently in Phase 3 clinical trials, and other drugs with novel mechanisms of action being studied. Within the next 5 years, the vast majority of patients with CF are expected to have a modulator approved for their genotype.

11.
Bone Marrow Transplant ; 53(9): 1124-1130, 2018 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-29523886

RESUMEN

Pulmonary chronic graft-versus-host disease (p-CGVHD) following allogeneic HSCT is devastating with limited proven treatments. Although sporadically associated with pulmonary toxicity, the proteasome inhibitor bortezomib may be efficacious in p-CGVHD. We sought to establish safety and tolerability of bortezomib in pilot, open-label trial of patients with p-CGVHD. The primary endpoint was adverse events. Efficacy was assessed by comparing FEV1 decline prior to p-CGVHD diagnosis to during the bortezomib treatment period. The impact on pulmonary function testing of prior long-term bortezomib treatment in multiple myeloma (MM) patients was also assessed as a safety analysis. Seventeen patients enrolled in the pilot study with a mean time to p-CGVHD diagnosis of 3.36 years (±1.88 years). Bortezomib was well tolerated without early dropouts. The median FEV1 decline prior to the diagnosis of p-CGVHD was -1.06%/month (-5.36, -0.33) and during treatment was -0.25%/month (-9.42, 3.52). In the safety study, there was no significant difference in any PFT parameter between 73 patients who received bortezomib and 68 patients who did not for MM. Thus, we conclude that bortezomib has acceptable safety and tolerability in patients with compromised pulmonary function. The efficacy of proteosomal inhibition should be assessed in a large trial of chronic p-CGVHD patients.

12.
J Cyst Fibros ; 17(1): 34-42, 2018 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-29221674

RESUMEN

RATIONALE: The association between CFTR genotype, sweat chloride and mortality has been inconsistent, but no previous analyses have examined the association stratified by individual genotypes. OBJECTIVES: To evaluate the genotype-specific association between sweat chloride and mortality. METHODS: The CFF Patient Registry was assessed and included all patients in the registry between 1996 and 2012 with at least one F508del allele. We excluded patients without a documented genotype or plausible sweat chloride level. The primary outcome was time to mortality during the observation period. We examined 15 genotypes using the three most prevalent alleles in each of 5 classes. We compared subgroups of sweat chloride using Kaplan-Meier curves, log-rank tests, and multivariable Cox PH models. The overall predictive value of sweat chloride on mortality was assessed using area under the receiver operating characteristic curves. MEASUREMENTS AND MAIN RESULTS: 18,893 subjects met inclusion criteria. Sweat chloride distribution was similar across genotypes in patients with class 1 mutations, but was significantly different across genotypes in mutation classes 2-5. The R117H/F508del genotype patients demonstrated an association between sweat chloride and mortality (HR: 1.32 for every 10mmol/L increase in sweat chloride [95% CI 1.12-1.54]. There were also significant associations in patients with F508del/F508del, I507del/F508del, G551D/F508del and 2789+5G→A/F508del genotypes, though the clinical relevance for these genotypes is unclear. CONCLUSIONS: There is significant variability in sweat chloride distribution across CFTR class 2-5 genotypes. The relationship between sweat chloride and mortality varies by genotype with a relatively strong relationship in R117H/F508del patients.

13.
Arch Pathol Lab Med ; 142(3): 383-390, 2018 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-29219617

RESUMEN

CONTEXT: - Distinguishing chromophobe renal cell carcinoma (chRCC), especially in the presence of eosinophilic cytoplasm, from oncocytoma on hematoxylin-eosin can be difficult and often requires time-consuming ancillary procedures that ultimately may not be informative. OBJECTIVE: - To explore the potential of multiphoton microscopy (MPM) as an alternative and rapid diagnostic tool in differentiating oncocytoma from chRCC at subcellular resolution without tissue processing. DESIGN: - Unstained, deparaffinized tissue sections from 27 tumors (oncocytoma [n = 12], chRCC [n = 12], eosinophilic variant of chRCC [n = 1], and atypical oncocytic renal neoplasm [n = 2]) were imaged with MPM. Morphologic evaluation and automated quantitative morphometric analysis were conducted to distinguish between chRCC and oncocytoma. RESULTS: - The typical cases of oncocytomas (12 of 12) and chRCC (12 of 12) could be readily differentiated on MPM based on the morphologic features similar to hematoxylin-eosin. The most striking MPM signature of both of the tumors was the presence of autofluorescent intracytoplasmic granules, which are not seen on hematoxylin-eosin-stained slides. Although we saw these granules in both types of tumors, they appeared distinct, based on their size, shape, cytoplasmic distribution, and autofluorescence wavelengths, and were valuable in arriving at a definitive diagnosis. For oncocytomas and chRCC, high diagnostic accuracies of 100% and 83.3% were achieved on blinded MPM and morphometric analysis, respectively. CONCLUSIONS: - To the best of our knowledge, this is the first demonstration of MPM to distinguish chRCC from oncocytoma in fixed tissues. Our study was limited by small sample size and only a few variants of oncocytic tumors. Prospective studies are warranted to assess the utility of MPM as a diagnostic aid in oncocytic renal tumors.

14.
J Cyst Fibros ; 17(2): 228-235, 2018 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-29126871

RESUMEN

OBJECTIVE: Evaluation of the safety, tolerability, and efficacy of lumacaftor/ivacaftor in patients with cystic fibrosis (CF) with severe lung disease. METHODS: Patients with CF 12 years of age and older, homozygous for F508del-CFTR, with percent predicted forced expiratory volume in 1 second (ppFEV1) <40 received lumacaftor 400 mg/ivacaftor 250mg every 12h (full dose) for 24weeks in an open-label, prospective study (NCT02390219). Dose modification to half dose for 1-2weeks (including at initiation) was permitted. Safety and tolerability were the primary outcome measures; clinical outcomes were also assessed. RESULTS: Of 46 patients (initiated on full dose: n=28; initiated on half dose: n=18), 35 (76%) completed 24weeks of treatment. The most common adverse events included infective pulmonary exacerbation, abnormal respiration, cough, and dyspnea. Compared with patients initiating on full dose, patients initiating at half dose had less frequent respiratory events (56% vs 71%) of shorter median duration (4 vs 9days). No dose modifications or discontinuations as a result of respiratory events occurred in patients initiating on half dose who were then increased to the full dose over 2weeks (versus three each for patients on full dose). Following an initial reduction, ppFEV1 was similar to baseline from week 4 throughout the remainder of the study (least squares mean [95% confidence interval] at week 24: -0.4 [-1.9, 1.1]; p=0.6249). Compared with the 24weeks prior to study, the annualized hospitalization rate was lower (rate ratio: 0.41; p=0.00026) and the duration of intravenous antibiotics was shorter (mean [standard deviation] difference: -8.52 [24.91] days; p=0.0369) through study week 24. CONCLUSIONS: Compared with patients with higher lung function, respiratory events were more common in patients with ppFEV1<40; aside from these events, the lumacaftor/ivacaftor safety profile was consistent with previous studies. Results suggest that patients with ppFEV1<40 may benefit from treatment initiation at a lower dose with augmented monitoring before increasing to the full dose.

15.
J Thorac Cardiovasc Surg ; 155(4): 1871-1879.e3, 2018 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-29249487

RESUMEN

BACKGROUND: The association of body mass index (BMI) with survival after lung transplantation remains controversial, owing to conflicting evidence in the literature. Previous reports have used traditional BMI categories, included patients who underwent transplantation before implementation of the lung allocation score (LAS), or were limited by single-center experiences. Here we evaluated the association of individual BMI units with short-term and long-term mortality in a large national database following implementation of the LAS. METHODS: The Scientific Registry of Transplant Recipients database was used to collect data for 17,233 adult lung transplantations performed between May 2005 and June 2016. The primary outcome was all-cause mortality at 90 days and 1 year posttransplantation. Logistic regression modeling was used to independently predict mortality per BMI unit, adjusting for donor and recipient factors. RESULTS: BMI was an independent predictor of mortality at both 90 days and 1 year. At 90 days, a BMI of 25 was associated with the lowest predicted probability of death (0.053; 95% confidence interval [CI], 0.047-0.049), with increased odds of mortality at BMI ≤20 and ≥28. At 1 year, a BMI of 26 was associated with the lowest predicted probability of death (0.12; 95% CI, 0.11-0.13), with increased odds of mortality at BMI ≤24 and ≥28. CONCLUSIONS: Each individual BMI unit has a quantifiable effect on posttransplantation survival, and the patterns of effect do not fit into the predefined BMI categories. The mortality risk associated with BMI should be considered by transplant centers when making listing decisions and by regulatory bodies for estimating expected outcomes.

18.
BMC Pulm Med ; 17(1): 160, 2017 Nov 29.
Artículo en Inglés | MEDLINE | ID: mdl-29187171

RESUMEN

BACKGROUND: Pulmonary exacerbations (PEx) are a major driver of morbidity and mortality in cystic fibrosis and reducing their frequency by extending the time between them is an important therapeutic goal. Although treatment decisions for exacerbations are often made based on dynamic changes in lung function, it is not clear if these changes truly impact future exacerbation risk. We analyzed adults with chronic Pseudomonas aeruginosa infection to determine whether changes in FEV1 or duration of intravenous antibiotic therapy were associated with time to the next pulmonary exacerbation. METHODS: Medical records and Cystic Fibrosis Foundation Patient Registry data were examined retrospectively to assess whether various patient-specific demographic factors and exacerbation-specific characteristics were associated with time until next exacerbation using the Andersen-Gill model in order to control for previous exacerbation frequency history. RESULTS: We examined 59 patients with 221 CF pulmonary exacerbations over a 3-year study period. Mean age was 28.2 years and mean baseline FEV1 was 62% predicted. In our univariable model, fall in FEV1 at onset of exacerbation (median absolute -3% predicted change), recovery of FEV1 with treatment (median absolute +3% predicted change) and duration of IV antibiotics (median 16 days) were not associated with time to next exacerbation (median 93.5 days). Paradoxically each one-year increase in age was associated with a reduction in hazard of PEx by 3% (HR 0.97, P = 0.03, 95% CI 0.95-1.00). CONCLUSIONS: FEV1 drop and recovery associated with onset and treatment of a CF pulmonary exacerbation or duration of intravenous antibiotics were not predictive of time until next exacerbation. Our finding that older age may be associated with decreased hazard of exacerbation is likely due to a healthy survivor effect and should be controlled for in clinical trials of pulmonary exacerbations.


Asunto(s)
Antibacterianos/uso terapéutico , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/fisiopatología , Infecciones por Pseudomonas/tratamiento farmacológico , Pseudomonas aeruginosa , Adulto , Factores de Edad , Enfermedad Crónica , Fibrosis Quística/complicaciones , Progresión de la Enfermedad , Femenino , Volumen Espiratorio Forzado , Humanos , Masculino , Infecciones por Pseudomonas/complicaciones , Sistema de Registros , Estudios Retrospectivos , Factores de Tiempo , Adulto Joven
20.
Transl Res ; 190: 61-68, 2017 12.
Artículo en Inglés | MEDLINE | ID: mdl-29080401

RESUMEN

Pulmonary fibrosis is a relatively rare but devastating disease characterized by the excessive deposition of extracellular matrix. The increased matrix results in reduced lung compliance and increased work of breathing, while the obliteration of alveolar-capillary structures can result in hypoxemia and pulmonary hypertension, which manifests clinically as worsening shortness of breath, respiratory failure, and death. Unbiased genome-wide association studies combined with animal models suggest that damage to the alveolar epithelium is the initiating factor in pulmonary fibrosis. This epithelial injury leads to the activation and proliferation of myofibroblasts that secrete extracellular matrix proteins characteristic of fibrosis. The best described molecular link between alveolar epithelial dysfunction and myofibroblast activation and proliferation is the profibrotic cytokine transforming growth factor-ß (TGF-ß). We and others have found that mitochondrial and NAD(P)H oxidase-generated reactive oxygen species (ROS) play a signaling role to enhance TGF-ß signaling and promote fibrosis. The purpose of this article is to review how ROS signaling leads to the activation of TGF-ß. We suggest that an improved understanding of these pathways might explain the failure of nonselective antioxidants to improve outcomes in patients with pulmonary fibrosis and might identify novel targets for therapy.


Asunto(s)
Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/patología , Especies Reactivas de Oxígeno/metabolismo , Envejecimiento , Humanos , Estrés Oxidativo , Transducción de Señal
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA