Ezh2 (Enhancer of zeste homolog 2) protein is the enzymatic component of the Polycomb repressive complex 2 (PRC2), which represses gene expression by methylating lysine 27 of histone H3 (H3K27) and regulates cell proliferation and differentiation during embryonic development. Recently, hot-spot mutations of Ezh2 were identified in diffused large B-cell lymphomas and follicular lymphomas. To investigate if tumor growth is dependent on the enzymatic activity of Ezh2, we developed a potent and selective small molecule inhibitor, EI1, which inhibits the enzymatic activity of Ezh2 through direct binding to the enzyme and competing with the methyl group donor S-Adenosyl methionine. EI1-treated cells exhibit genome-wide loss of H3K27 methylation and activation of PRC2 target genes. Furthermore, inhibition of Ezh2 by EI1 in diffused large B-cell lymphomas cells carrying the Y641 mutations results in decreased proliferation, cell cycle arrest, and apoptosis. These results provide strong validation of Ezh2 as a potential therapeutic target for the treatment of cancer.
To identify risk factors for periprosthetic joint infection following primary total joint arthroplasty, a systematic search was performed in Pubmed, Embase and Cochrane library databases. Pooled odds ratios (ORs) or standardised mean differences (SMDs) with 95% confidence intervals (CIs) were calculated. Patient characteristics, surgical-related factors and comorbidities, as potential risk factors, were investigated. The main factors associated with infection after total joint arthroplasty (TJA) were male gender (OR, 1·48; 95% CI, 1.19-1.85), age (SMD, -0·10; 95% CI, -0.17--0.03), obesity (OR, 1·54; 95% CI, 1·25-1·90), alcohol abuse (OR, 1·88; 95% CI, 1·32-2·68), American Society of Anesthesiologists (ASA) scale > 2 (OR, 2·06; 95% CI, 1·77-2·39), operative time (SMD, 0·49; 95% CI, 0·19-0·78), drain usage (OR, 0·36; 95% CI, 0·18-0·74), diabetes mellitus (OR, 1·58; 95% CI, 1·37-1·81), urinary tract infection (OR, 1·53; 95% CI, 1.09-2.16) and rheumatoid arthritis (OR, 1·57; 95% CI, 1·30-1·88). Among these risk factors, ASA score > 2 was a high risk factor, and drain usage was a protective factor. There was positive evidence for some factors that could be used to prevent the onset of infection after TJA.
Compared with high tibial osteotomy and total knee arthroplasty, the authors found a simpler surgical procedure, partial fibular osteotomy, could effectively relieve knee pain and also correct the varus deformity for patients with medial compartment knee osteoarthritis (OA). From January 1996 to April 2012, a total of 156 patients with medial compartment OA were treated by proximal fibular osteotomy in the authors' hospital. A 2-cm-long section of fibula was resected 6 to 10 cm below the fibular head. A total of 110 patients with follow-up of more than 2 years were included in the study, including 34 males and 76 females with an average age of 59.2 years. Anteroposterior and lateral weight-bearing radiographs, the femorotibial angle (FTA) and lateral joint space, and the American Knee Society Score (KSS) and the visual analog scale (VAS) score of the knee joint were evaluated preoperatively and at final follow-up, respectively. At final follow-up, mean FTA and lateral joint space were 179.4°±1.8° and 6.9±0.7 mm, respectively, which were significantly smaller than those measured preoperatively (182.7°±2.0° and 12.2±1.1 mm, respectively; both P<.001). Mean KSS at final follow-up was 92.3±31.7, significantly higher than the mean preoperative score of 45.0±21.3 (P<.001). Mean VAS score and interquartile range were 2.0 and 2.0, significantly lower than the preoperative data (7 and 1.0, respectively; P<.001). The authors found that proximal fibular osteotomy can significantly improve both the radiographic appearance and function of the affected knee joint and also achieve long-term pain relief. This procedure may be an alternative treatment option for medial compartment OA.
Rationale: Idiopathic pulmonary fibrosis (IPF) is an untreatable and often fatal lung disease that is increasing in prevalence and is caused by complex interactions between genetic and environmental factors. Epigenetic mechanisms control gene expression and are likely to regulate the IPF transcriptome.Objectives: To identify methylation marks that modify gene expression in IPF lung. Methods:We assessed DNA methylation (comprehensive highthroughput arrays for relative methylation arrays [CHARM]) and gene expression (Agilent gene expression arrays) in 94 patients with IPF and 67 control subjects, and performed integrative genomic analyses to define methylation-gene expression relationships in IPF lung. We validated methylation changes by a targeted analysis (Epityper), and performed functional validation of one of the genes identified by our analysis.Measurements and Main Results: We identified 2,130 differentially methylated regions (DMRs; ,5% false discovery rate), of which 738 are associated with significant changes in gene expression and enriched for expected inverse relationship between methylation and expression (P , 2.2 3 10 216 ). We validated 13/15 DMRs by targeted analysis of methylation. Methylation-expression quantitative trait loci (methyl-eQTL) identified methylation marks that control cis and trans gene expression, with an enrichment for cis relationships (P , 2.2 3 10 216 ). We found five trans methyl-eQTLs where a methylation change at a single DMR is associated with transcriptional changes in a substantial number of genes; four of these DMRs are near transcription factors (castor zinc finger 1 [CASZ1], FOXC1, MXD4, and ZDHHC4). We studied the in vitro effects of change in CASZ1 expression and validated its role in regulation of target genes in the methyl-eQTL.Conclusions: These results suggest that DNA methylation may be involved in the pathogenesis of IPF.Keywords: DNA methylation; gene expression; pulmonary fibrosis; quantitative trait; mapping Idiopathic pulmonary fibrosis (IPF) appears to result from reprogramming of injured alveolar epithelial cells, which undergo early apoptosis, epithelial-mesenchymal transition, and produce mediators that lead to proliferation of resident fibroblasts and recruitment of fibrocytes. As the extracellular matrix (ECM) expands, myofibroblastic foci develop, resulting in further fibroproliferation in the ECM and the more extensive lung remodeling (1).
Background The clinical course of Idiopathic Pulmonary Fibrosis (IPF) is unpredictable. Clinical prediction tools are not accurate enough to predict disease outcomes. Methods All-comers with Idiopathic Pulmonary Fibrosis diagnosis were enrolled in a six-cohort study. Peripheral blood mononuclear cells or whole blood was collected at baseline from 425 participants and during follow up from 98 patients. The 52-gene signature was measured by the nCounter® analysis system in four cohorts and extracted from microarray data in two others. The Scoring Algorithm for Molecular Subphenotypes (SAMS) was used to classify patients into low or high risk groups based on a 52-gene signature. Mortality and transplant-free survival were studied using Competing risk and Cox proportional-hazard models, respectively. Time course data and response to anti-fibrotic drugs were analyzed using linear mixed-effect models. Findings The application of SAMS to the 52-gene signature identified two groups of IPF patients (low and high risk) with significant differences in mortality or transplant-free survival in each of the six cohorts (HR 2·03–4·37). Pooled data revealed similar results for mortality (HR:2·18, 95%CI:1·53–3·09, P<0·0001) or transplant-free survival (HR:2·04, 95%CI: 1·52–2·74, P<0·0001). Adding 52-gene risk profiles to the Gender, Age and Physiology (GAP) index significantly improved its mortality predictive accuracy. Temporal changes in SAMS scores were associated with changes in forced vital capacity (FVC) in two cohorts. Untreated patients did not shift their risk profile over time. A simultaneous increase in up score and decrease in down score was predictive of transplant-free survival (HR:3·18· 95%CI 1·16, 8·76, P=0·025) in the Pittsburgh cohort. A simultaneous decrease in up score and increase in down score after initiation of anti-fibrotic drugs was associated with a significant (P=0·005) improvement in FVC in the Yale cohort. Interpretation The peripheral blood 52-gene expression signature is predictive of outcome in patients with IPF. The potential value of the 52-gene signature in predicting response to therapy should be determined in prospective studies.
Objectives: Classification of patients with acute respiratory distress syndrome into hyper- and hypoinflammatory subphenotypes using plasma biomarkers may facilitate more effective targeted therapy. We examined whether established subphenotypes are present not only in patients with acute respiratory distress syndrome but also in patients at risk for acute respiratory distress syndrome (ARFA) and then assessed the prognostic information of baseline subphenotyping on the evolution of host-response biomarkers and clinical outcomes. Design: Prospective, observational cohort study. Setting: Medical ICU at a tertiary academic medical center. Patients: Mechanically ventilated patients with acute respiratory distress syndrome or ARFA. Interventions: None. Measurements and Main Results: We performed longitudinal measurements of 10 plasma biomarkers of host injury and inflammation. We applied unsupervised latent class analysis methods utilizing baseline clinical and biomarker variables and demonstrated that two-class models (hyper- vs hypoinflammatory subphenotypes) offered improved fit compared with one-class models in both patients with acute respiratory distress syndrome and ARFA. Baseline assignment to the hyperinflammatory subphenotype (39/104 [38%] acute respiratory distress syndrome and 30/108 [28%] ARFA patients) was associated with higher severity of illness by Sequential Organ Failure Assessment scores and incidence of acute kidney injury in patients with acute respiratory distress syndrome, as well as higher 30-day mortality and longer duration of mechanical ventilation in ARFA patients (p < 0.0001). Hyperinflammatory patients exhibited persistent elevation of biomarkers of innate immunity for up to 2 weeks postintubation. Conclusions: Our results suggest that two distinct subphenotypes are present not only in patients with established acute respiratory distress syndrome but also in patients at risk for its development. Hyperinflammatory classification at baseline is associated with higher severity of illness, worse clinical outcomes, and trajectories of persistently elevated biomarkers of host injury and inflammation during acute critical illness compared with hypoinflammatory patients. Our findings provide strong rationale for examining treatment effect modifications by subphenotypes in randomized clinical trials to inform precision therapeutic approaches in critical care.
Pulmonary inflammation, which is characterized by the presence of perivascular macrophages, has been proposed as a key pathogenic driver of pulmonary hypertension (PH), a vascular disease with increasing global significance. However, the mechanisms of expansion of lung macrophages and the role of blood-borne monocytes in PH are poorly understood. Using multicolor flow cytometric analysis of blood in mouse and rat models of PH and patients with PH, an increase in blood monocytes was observed. In parallel, lung tissue displayed increased chemokine transcript expression, including those responsible for monocyte recruitment, such as and, accompanied by an expansion of interstitial lung macrophages. These data indicate that blood monocytes are recruited to lung perivascular spaces and differentiate into inflammatory macrophages. Correspondingly, parabiosis between congenically different hypoxic mice demonstrated that most interstitial macrophages originated from blood monocytes. To define the actions of these cells in PH in vivo, we reduced blood monocyte numbers via genetic deficiency of or in chronically hypoxic male mice and by pharmacologic inhibition of Cxcl1 in monocrotaline-exposed rats. Both models exhibited decreased inflammatory blood monocytes, as well as interstitial macrophages, leading to a substantial decrease in arteriolar remodeling but with a less robust hemodynamic effect. This study defines a direct mechanism by which interstitial macrophages expand in PH. It also demonstrates a pathway for pulmonary vascular remodeling in PH that depends upon interstitial macrophage-dependent inflammation yet is dissociated, at least in part, from hemodynamic consequences, thus offering guidance on future anti-inflammatory therapeutic strategies in this disease.
Tissue fibrosis is characterized by uncontrolled deposition and diminished clearance of fibrous connective tissue proteins, ultimately leading to organ scarring. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) have recently emerged as pivotal drivers of mesenchymal cell activation in human fibrosis. Therapeutic strategies inhibiting YAP and TAZ have been hindered by the critical role that these proteins play in regeneration and homeostasis in different cell types. Here, we find that the Gαs-coupled dopamine receptor D1 (DRD1) is preferentially expressed in lung and liver mesenchymal cells relative to other resident cells of these organs. Agonism of DRD1 selectively inhibits YAP/TAZ function in mesenchymal cells and shifts their phenotype from profibrotic to fibrosis resolving, reversing in vitro extracellular matrix stiffening and in vivo tissue fibrosis in mouse models. Aromatic l-amino acid decarboxylase [DOPA decarboxylase (DDC)], the enzyme responsible for the final step in biosynthesis of dopamine, is decreased in the lungs of subjects with idiopathic pulmonary fibrosis, and its expression inversely correlates with disease severity, consistent with an endogenous protective role for dopamine signaling that is lost in pulmonary fibrosis. Together, these findings establish a pharmacologically tractable and cell-selective approach to targeting YAP/TAZ via DRD1 that reverses fibrosis in mice.
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