Gene Expression Profiling of Bronchoalveolar Lavage Cells Preceding a Clinical Diagnosis of Chronic Lung Allograft Dysfunction.

BackgroundChronic Lung Allograft Dysfunction (CLAD) is the main limitation to long-term survival after lung transplantation. Although CLAD is usually not responsive to treatment, earlier identification may improve treatment prospects.MethodsIn a nested case control study, 1-year post transplant surveillance bronchoalveolar lavage (BAL) fluid samples were obtained from incipient CLAD (n = 9) and CLAD free (n = 8) lung transplant recipients. Incipient CLAD cases were diagnosed with CLAD within 2 years, while controls were free from CLAD for at least 4 years following bronchoscopy. Transcription profiles in the BAL cell pellets were assayed with the HG-U133 Plus 2.0 microarray (Affymetrix). Differential gene expression analysis, based on an absolute fold change (incipient CLAD vs no CLAD) >2.0 and an unadjusted p-value ≤0.05, generated a candidate list containing 55 differentially expressed probe sets (51 up-regulated, 4 down-regulated).ResultsThe cell pellets in incipient CLAD cases were skewed toward immune response pathways, dominated by genes related to recruitment, retention, activation and proliferation of cytotoxic lymphocytes (CD8+ T-cells and natural killer cells). Both hierarchical clustering and a supervised machine learning tool were able to correctly categorize most samples (82.3% and 94.1% respectively) into incipient CLAD and CLAD-free categories.ConclusionsThese findings suggest that a pathobiology, similar to AR, precedes a clinical diagnosis of CLAD. A larger prospective investigation of the BAL cell pellet transcriptome as a biomarker for CLAD risk stratification is warranted

Protection against Bronchiolitis Obliterans Syndrome Is Associated with Allograft CCR7+CD45RA− T Regulatory Cells

Bronchiolitis obliterans syndrome (BOS) is the major obstacle to long-term survival after lung transplantation, yet markers for early detection and intervention are currently lacking. Given the role of regulatory T cells (Treg) in modulation of immunity, we hypothesized that frequencies of Treg in bronchoalveolar lavage fluid (BALF) after lung transplantation would predict subsequent development of BOS. Seventy BALF specimens obtained from 47 lung transplant recipients were analyzed for Treg lymphocyte subsets by flow cytometry, in parallel with ELISA measurements of chemokines. Allograft biopsy tissue was stained for chemokines of interest. Treg were essentially all CD45RA−, and total Treg frequency did not correlate to BOS outcome. The majority of Treg were CCR4+ and CD103− and neither of these subsets correlated to risk for BOS. In contrast, higher percentages of CCR7+ Treg correlated to reduced risk of BOS. Additionally, the CCR7 ligand CCL21 correlated with CCR7+ Treg frequency and inversely with BOS. Higher frequencies of CCR7+ CD3+CD4+CD25hiFoxp3+CD45RA− lymphocytes in lung allografts is associated with protection against subsequent development of BOS, suggesting that this subset of putative Treg may down-modulate alloimmunity. CCL21 may be pivotal for the recruitment of this distinct subset to the lung allograft and thereby decrease the risk for chronic rejection

An Unorthodox Introduction to QCD

These are lecture notes presented at the 2017 CTEQ Summer School at the University of Pittsburgh and the 2018 CTEQ Summer School at the University of Puerto Rico, Mayaguez. The title is a reference to hep-th/0309149 and introduces perturbative QCD and its application to jet substructure from a bottom-up perspective based on the approximation of QCD as a weakly-coupled, conformal field theory. Using this approach, a simple derivation of the Sudakov form factor with soft gluon emission modeled as a Poisson process is presented. Topics of the identification and discrimination of quark- versus gluon-initiated jets and jet grooming are also discussed.Comment: 16 pages, 18 figures. Comments welcome!, v2: updated to include both lectures from the 2018 CTEQ schoo

Immune response CC chemokines CCL2 and CCL5 are associated with pulmonary sarcoidosis

Abstract Background Pulmonary sarcoidosis involves an intense leukocyte infiltration of the lung with the formation of non-necrotizing granulomas. CC chemokines (chemokine (C-C motif) ligand 2 (CCL2)-CCL5) are chemoattractants of mononuclear cells and act through seven transmembrane G-coupled receptors. Previous studies have demonstrated conflicting results with regard to the associations of these chemokines with sarcoidosis. In an effort to clarify previous discrepancies, we performed the largest observational study to date of CC chemokines in bronchoalveolar lavage fluid (BALF) from patients with pulmonary sarcoidosis. Results BALF chemokine levels from 72 patients affected by pulmonary sarcoidosis were analyzed by enzyme-linked immunosorbent assay (ELISA) and compared to 8 healthy volunteers. BALF CCL3 and CCL4 levels from pulmonary sarcoidosis patients were not increased compared to controls. However, CCL2 and CCL5 levels were elevated, and subgroup analysis showed higher levels of both chemokines in all stages of pulmonary sarcoidosis. CCL2, CCL5, CC chemokine receptor type 1 (CCR1), CCR2 and CCR3 were expressed from mononuclear cells forming the lung granulomas, while CCR5 was only found on mast cells. Conclusions These data suggest that CCL2 and CCL5 are important mediators in recruiting CCR1, CCR2, and CCR3 expressing mononuclear cells as well as CCR5-expressing mast cells during all stages of pulmonary sarcoidosis

Capillary Proliferation in Systemic-Sclerosis-Related Pulmonary Fibrosis: Association with Pulmonary Hypertension

We sought to determine if any histopathologic component of the pulmonary microcirculation can distinguish systemic sclerosis (SSc)-related pulmonary fibrosis (PF) with and without pulmonary hypertension (PH)

New Developments in Creatine Supplementation Research: Mechanisms of Athletic Performance Enhancement

In the last decade creatine supplementation has become the most popular ergogenic aid among athletes, with particular performance enhancements found in high-power output, anaerobic exercises. Physiologically, creatine and phosphocreatine provide an energy reservoir in skeletal muscle. Recent studies have also shown that the ergogenic effects of creatine are caused by muscle protein metabolism (or reduced catabolism), satellite cell proliferation, protective oxidant scavenging, and membrane stabilization. In addition, creatine supplementation is considered to be a potential therapy for a wide variety of disease states including muscular dystrophy, heart failure, Parkinson's disease, Huntington's disease, and Alzheimer's disease. To date, a large number of studies have shown no serious side effects after short- (<10 days) and medium-term (<12 weeks) supplementation, and the first long-term (<5 years) study of supplementation found no effects on renal function. Still recent findings of cytotoxic creatine metabolites, along with two isolated reports of renal dysfunction, are some cause for concern, and more long-term research is required

Primary Graft Dysfunction and Long-Term Outcomes Following Lung Transplantation

Background: Primary graft dysfunction (PGD) is an early complication of lung transplantation associated with poor early outcomes, however less is known about its prolonged effects on morbidity and mortality. We hypothesized that PGD is associated with long-term mortality and chronic rejection in the form of bronchiolitis obliterans syndrome. Methods: A retrospective study of 279 adult lung transplant recipients between 2000 and 2007 was performed. PGD grade was determined both immediately after transplantation (T0) and at 72 hours post-transplant (T72). Chronic rejection defined as stage 1 bronchiolitis obliterans syndrome (BOS), long-term mortality in 90-day survivors were modeled using competing risk and extended Cox models with time-dependent covariates with internal validation performed via bootstrapping. Cumulative incidence plots for the outcome of BOS were created for each PGD grade and at both time points.Results: We found that there was a significant stepwise increase in the hazard ratio for both BOS and mortality with increasing PGD grade. This association was most severe among patients with grade 3 PGD at T72, and the association with BOS persisted in adjusted multivariable models with a hazard ratio of 3.75 (95% CI 1.11-21.4, p < 0.001). Stratified analyses in recipients with either single or bilateral transplants were also consistent with this finding. The association between PGD and long-term mortality also persisted after adjustment for baseline covariates, but in multivariable models of mortality that also incorporated BOS as a time-dependent variable, PGD was no longer significantly associated with mortality. Conclusions: These results suggest that severe PGD in the early perioperative period may play a causal role in the subsequent development of BOS after lung transplantation in some patients, and that the development of BOS in patients with PGD may account for increased rates of death even among recipients with severe PGD who survive the early perioperative period