Showing papers by "National Jewish Health published in 2020"

Phase 2 Trial of the DPP-1 Inhibitor Brensocatib in Bronchiectasis.

Abstract: Background Patients with bronchiectasis have frequent exacerbations that are thought to be related to neutrophilic inflammation. The activity and quantity of neutrophil serine proteases, i...

Home Oxygen Therapy for Adults with Chronic Lung Disease. An Official American Thoracic Society Clinical Practice Guideline.

Abstract: Background: Evidence-based guidelines are needed for effective delivery of home oxygen therapy to appropriate patients with chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD).Methods: The multidisciplinary panel created six research questions using a modified Delphi approach. A systematic review of the literature was completed, and the Grading of Recommendations Assessment, Development and Evaluation approach was used to formulate clinical recommendations.Recommendations: The panel found varying quality and availability of evidence and made the following judgments: 1) strong recommendations for long-term oxygen use in patients with COPD (moderate-quality evidence) or ILD (low-quality evidence) with severe chronic resting hypoxemia, 2) a conditional recommendation against long-term oxygen use in patients with COPD with moderate chronic resting hypoxemia, 3) conditional recommendations for ambulatory oxygen use in patients with COPD (moderate-quality evidence) or ILD (low-quality evidence) with severe exertional hypoxemia, 4) a conditional recommendation for ambulatory liquid-oxygen use in patients who are mobile outside the home and require >3 L/min of continuous-flow oxygen during exertion (very-low-quality evidence), and 5) a recommendation that patients and their caregivers receive education on oxygen equipment and safety (best-practice statement).Conclusions: These guidelines provide the basis for evidence-based use of home oxygen therapy in adults with COPD or ILD but also highlight the need for additional research to guide clinical practice.

Parkin, an E3 ubiquitin ligase, enhances airway mitochondrial DNA release and inflammation.

Abstract: Introduction Parkin (Park2), an E3 ubiquitin ligase, is critical to maintain mitochondrial function by regulating mitochondrial biogenesis and degradation (mitophagy), but recent evidence suggests the involvement of Parkin in promoting inflammation. In the present study, we determined if Parkin regulates airway mitochondrial DNA (mtDNA) release and inflammatory responses to type 2 cytokine interleukin (IL)-13 and allergens. Methods We measured Parkin mRNA expression in brushed bronchial epithelial cells and mtDNA release in the paired bronchoalveolar lavage fluid (BALF) from normal subjects and asthmatics. Parkin-deficient primary human tracheobronchial epithelial (HTBE) cells generated using the CRISPR-Cas9 system were stimulated with IL-13. To determine the in vivo function of Parkin, Parkin knockout (PKO) and wild-type (WT) mice were treated with IL-13 or allergen (house dust mite, HDM) in the presence or absence of mtDNA isolated from normal mouse lungs. Results Parkin mRNA expression in asthmatic airway epithelium was upregulated, which positively correlated with the levels of released mtDNA in BALF. IL-13-stimulated HTBE cells increased Parkin expression. Moreover, IL-13 induced mtDNA release in Parkin-sufficient, but not in Parkin-deficient HTBE cells. PKO (vs WT) mice attenuated airway mtDNA release and inflammation following IL-13 or HDM treatments. mtDNA amplified airway inflammation in mice treated with IL-13 or HDM. Notably, Parkin also mediated mtDNA-induced exacerbation of airway inflammation. Conclusion Our research findings suggest that Parkin promotes mtDNA release and inflammation in airways, thus improving our understanding of the complex role of Parkin and mitochondrial dysfunction in asthma pathogenesis.

JMJD5 couples with CDK9 to release the paused RNA polymerase II

Abstract: More than 30% of genes in higher eukaryotes are regulated by RNA polymerase II (Pol II) promoter proximal pausing. Pausing is released by the positive transcription elongation factor complex (P-TEFb). However, the exact mechanism by which this occurs and whether phosphorylation of the carboxyl-terminal domain of Pol II is involved in the process remains unknown. We previously reported that JMJD5 could generate tailless nucleosomes at position +1 from transcription start sites (TSS), thus perhaps enable progression of Pol II. Here we find that knockout of JMJD5 leads to accumulation of nucleosomes at position +1. Absence of JMJD5 also results in loss of or lowered transcription of a large number of genes. Interestingly, we found that phosphorylation, by CDK9, of Ser2 within two neighboring heptad repeats in the carboxyl-terminal domain of Pol II, together with phosphorylation of Ser5 within the second repeat, HR-Ser2p (1, 2)-Ser5p (2) for short, allows Pol II to bind JMJD5 via engagement of the N-terminal domain of JMJD5. We suggest that these events bring JMJD5 near the nucleosome at position +1, thus allowing JMJD5 to clip histones on this nucleosome, a phenomenon that may contribute to release of Pol II pausing.

Impact of Proactive Integrated Care on Chronic Obstructive Pulmonary Disease

Abstract: Background. Up to 50% of COPD patients do not receive recommended care for COPD. To address this important issue, we developed Proactive Integrated Care (Proactive iCare), a healthcare delivery model that couples integrated care with remote monitoring. Methods. We conducted a prospective, quasi-randomized clinical trial in 511 patients with advanced COPD, or a recent COPD exacerbation, to test whether Proactive iCare impacts patient- centered outcomes and healthcare utilization. Patients were allocated to Proactive iCare (n =352) or Usual Care (n = 159), and were examined for changes in quality of life using the St. Georges Respiratory Questionnaire (SGRQ), symptoms, guideline-based care, and healthcare utilization. Findings. Proactive iCare improved the total SGRQ by 7-9 units (p<0.0001), symptom SGRQ by 9 units (p<0.0001), activity SGRQ by 6-7 units (p<0.001) and impact SGRQ by 7-11 units (p<0.0001) at 3, 6 and 9 months, compared with Usual Care. Proactive iCare increased the 6-minute walk distance by 40 m (p<0.001), reduced COPD-related urgent office visits by 76 visits per 100 subjects (p<0.0001), identified unreported exacerbations, and decreased smoking (p = 0.01). Proactive iCare also improved cough, sputum, shortness of breath, the BODE index and oxygen titration (p<0.05). Mortality in the Proactive iCare group (1.1%) was not significantly different than mortality in the Usual Care group (3.8%; p = 0.08). Interpretation. Results suggest that linking integrated care with remote monitoring improves the lives of people with advanced COPD.

Single-cell RNA transcriptomics identifies Hivep3 as essential in regulating the development of innate-like T lymphocytes

Abstract: Most T lymphocytes leave the thymus as naive cells with limited functionality. However, unique populations of T cells, commonly known as innate-like T cells, differentiate into functionally distinct effector subsets during thymic development under the influence of the transcription factor PLZF. Here, we profiled >10,000 differentiating thymic iNKT cells using single-cell RNA sequencing to provide a comprehensive transcriptional landscape of their maturation, function, and fate decision in steady state. We identified Hivep3, a zinc finger transcription factor and adaptor protein, as a key factor that is expressed in early precursors and regulates the post-selection proliferative burst, differentiation and functions of iNKT cells. Importantly, we extended these results to other PLZF+ innate-like T cell populations, highlighting the unique and common requirement of Hivep3 to the development of all innate-like T cells.

Identification of Influential Variants in Significant Aggregate Rare Variant Tests

Abstract: Introduction: Studies that examine the role of rare variants in both simple and complex disease are increasingly common. Though the usual approach of testing rare variants in aggregate sets is more powerful than testing individual variants, it is of interest to identify the variants that are plausible drivers of the association. We present a novel method for prioritization of rare variants after a significant aggregate test by quantifying the influence of the variant on the aggregate test of association. Methods: In addition to providing a measure used to rank variants, we use outlier detection methods to present the computationally efficient Rare Variant Influential Filtering Tool (RIFT) to identify a subset of variants that influence the disease association. We evaluated several outlier detection methods that vary based on the underlying variance measure: interquartile range (Tukey fences), median absolute deviation and standard deviation. We performed 1000 simulations for 50 regions of size 3kb and compared the true and false positive rates. We compared RIFT using the Inner Tukey to two existing methods: adaptive combination of p-values (ADA) and a Bayesian hierarchical model (BeviMed). Finally, we applied this method to data from our targeted resequencing study in idiopathic pulmonary fibrosis (IPF). Results: All outlier detection methods observed higher sensitivity to detect uncommon variants (0.001 0.03) compared to very rare variants (MAF < 0.001). For uncommon variants, RIFT had a lower median false positive rate compared to the ADA. ADA and RIFT had significantly higher true positive rates than that observed for BeviMed. When applied to two regions found previously associated with IPF including 100 rare variants, we identified six polymorphisms with the greatest evidence for influencing the association with IPF. Discussion: In summary, RIFT has a high true positive rate while maintaining a low false positive rate for identifying polymorphisms influencing rare variant association tests. This work provides an approach to obtain greater resolution of the rare variant signals within significant aggregate sets; this information can provide an objective measure to prioritize variants for follow-up experimental studies and insight into the biological pathways involved.

Methods of Identifying Atopic Dermatitis and Food Allergies

Abstract: The invention relates to skin tape stripping methods to identify a subject at risk of having atopic dermatitis, or a subject having atopic dermatitis who is at risk of developing a food allergy, or a subject at risk of developing a food allergy in the absence of the subject having atopic dermatitis.

Tolerance induction in memory CD4 T cells is partial and reversible

Abstract: Memory T cells respond rapidly in part because they are less reliant on heightened levels of costimulatory molecules. This presents challenges to silencing memory T cells in tolerance strategies for autoimmunity or allergy. We find that memory CD4 T cells generated by infection or immunisation survive secondary activation with antigen delivered without adjuvant, regardless of their location in secondary lymphoid organs or peripheral tissues. These cells were, however, functionally altered following a tertiary immunisation with antigen and adjuvant, proliferating poorly but maintaining their ability to produce inflammatory cytokines. Transcriptional and cell cycle analysis of these memory CD4 T cells suggest they are unable to commit fully to cell division potentially because of low expression of DNA repair enzymes. In contrast, these memory CD4 T cells could proliferate following tertiary reactivation by viral re-infection. These data suggest that tolerance induction in memory CD4 T cells is partial and can be reversed.

Methods for detection of emphysema

Abstract: Disclosed are methods of identifying, predicting and treating subjects at risk for exacerbation or the presence of a respiratory disease, by detecting expression levels of one or more proteins associated with the respiratory disease.