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Can Treatment of Obstructive Sleep Apnea with CPAP Still Improve Kidney Outcomes?
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Can Treatment of Obstructive Sleep Apnea with CPAP Still Improve Kidney Outcomes?

Am J Respir Crit Care Med. 2017 Aug 16;:

Authors: Ahmed SB

PMID: 28813163 [PubMed - as supplied by publisher]




Through the Looking Glass and What was Found There: Imaging Biomarkers of COPD.
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Through the Looking Glass and What was Found There: Imaging Biomarkers of COPD.

Am J Respir Crit Care Med. 2017 Aug 16;:

Authors: Capaldi DPI, Parraga G

PMID: 28813162 [PubMed - as supplied by publisher]




Circulating mtDNA as a Mechanism-based, Prognostic Biomarker for Idiopathic Pulmonary Fibrosis.
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Circulating mtDNA as a Mechanism-based, Prognostic Biomarker for Idiopathic Pulmonary Fibrosis.

Am J Respir Crit Care Med. 2017 Aug 16;:

Authors: Cloonan SM

PMID: 28813161 [PubMed - as supplied by publisher]




Recommended Reading from University Hospital Cleveland Fellows.
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Recommended Reading from University Hospital Cleveland Fellows.

Am J Respir Crit Care Med. 2017 Aug 16;:

Authors: Attaway A, Ayache M, Velani S, McKell J

Abstract
We review three recent and very interesting articles that have come out in the literature that made us reconsider certain aspects of asthma. These studies ask us whether a biologic is emerging that can be used in patients with normal IgE and no evidence of eosinophilia, if late onset asthma is associated with cardiovascular disease, and finally how different types of environmental exposures can influence the development of asthma in farming cultures.

PMID: 28812907 [PubMed - as supplied by publisher]




miR-542 Promotes Mitochondrial Dysfunction and SMAD Activity and is Raised in ICU Acquired Weakness.
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miR-542 Promotes Mitochondrial Dysfunction and SMAD Activity and is Raised in ICU Acquired Weakness.

Am J Respir Crit Care Med. 2017 Aug 15;:

Authors: Farre Garros R, Paul R, Connolly M, Lewis A, Garfield BE, Natanek SA, Bloch S, Mouly V, Griffiths MJ, Polkey MI, Kemp PR

Abstract
RATIONALE: Loss of skeletal muscle mass and function is a common consequence of critical illness and a range of chronic diseases but the mechanisms by which this occurs are unclear.
OBJECTIVES: We aimed to identify miRNAs that were increased in the quadriceps of patients with muscle wasting and to determine the molecular pathways by which they contributed to muscle dysfunction.
METHODS: miR-542-3p/-5p were quantified in the quadriceps of patients with COPD and intensive care unit acquired weakness (ICUAW). The effect of miR-542-3p/5p was determined on mitochondrial function and TGF-β signaling in vitro and in vivo.
MEASUREMENTS AND MAIN RESULTS: miR-542-3p/5p were elevated in patients with COPD but more markedly in patients with ICUAW. In vitro, miR-542-3p suppressed the expression of the mitochondrial ribosomal protein MRPS10, and reduced 12S rRNA expression suggesting mitochondrial ribosomal stress. miR-542-5p increased nuclear phospho-SMAD2/3 and suppressed expression of SMAD7, SMURF1 and PPP2CA, proteins that inhibit or reduce SMAD2/3 phosphorylation suggesting that miR-542-5p increased TGF-β signaling. In mice, miR-542 over-expression caused muscle wasting, reduced mitochondrial function, 12S rRNA expression and SMAD7 expression, consistent with the effects of the miRNAs in vitro. Similarly, in patients with ICUAW, the expression of 12S rRNA and of the inhibitors of SMAD2/3 phosphorylation were reduced, indicative of mitochondrial ribosomal stress and increased TGF-β signaling. In patients undergoing aortic surgery, pre-operative levels of miR-542-3p/5p were positively correlated with muscle loss following surgery. Conclusion; Elevated miR-542-3p/5p may cause muscle atrophy in ICU patients through the promotion of mitochondrial dysfunction and activation of SMAD2/3 phosphorylation.  .

PMID: 28809518 [PubMed - as supplied by publisher]




Simultaneously Mounted Pro- and Anti-inflammatory Host Response Relates to the Development of Secondary Infections in Patients with Sepsis.
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Simultaneously Mounted Pro- and Anti-inflammatory Host Response Relates to the Development of Secondary Infections in Patients with Sepsis.

Am J Respir Crit Care Med. 2017 Aug 15;196(4):406-407

Authors: Pickkers P

PMID: 28809516 [PubMed - in process]




A Biosignature Predicting Complicated Course in Children Presenting with Septic Shock. Why PERSEVERE?
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A Biosignature Predicting Complicated Course in Children Presenting with Septic Shock. Why PERSEVERE?

Am J Respir Crit Care Med. 2017 Aug 15;196(4):411-413

Authors: Randolph AG

PMID: 28809515 [PubMed - in process]




Individualization of Positive End-Expiratory Pressure Setting in Patients with Acute Respiratory Distress Syndrome under Extracorporeal Membrane Oxygenation. Inputs from Electrical Impedance Tomography.
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Individualization of Positive End-Expiratory Pressure Setting in Patients with Acute Respiratory Distress Syndrome under Extracorporeal Membrane Oxygenation. Inputs from Electrical Impedance Tomography.

Am J Respir Crit Care Med. 2017 Aug 15;196(4):404-406

Authors: Guérin C

PMID: 28809514 [PubMed - in process]




Vascular Endothelial Growth Factor in Idiopathic Pulmonary Fibrosis. An Imbalancing Act.
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Vascular Endothelial Growth Factor in Idiopathic Pulmonary Fibrosis. An Imbalancing Act.

Am J Respir Crit Care Med. 2017 Aug 15;196(4):409-411

Authors: Atamas SP

PMID: 28809513 [PubMed - in process]




Triple Therapy for Chronic Obstructive Pulmonary Disease Management. Are Our Expectations Fulfilled?
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Triple Therapy for Chronic Obstructive Pulmonary Disease Management. Are Our Expectations Fulfilled?

Am J Respir Crit Care Med. 2017 Aug 15;196(4):402-404

Authors: Tashkin DP, Taube C

PMID: 28809512 [PubMed - in process]




Vascular Stiffness and Mechanotransduction: Back in the Limelight.
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Vascular Stiffness and Mechanotransduction: Back in the Limelight.

Am J Respir Crit Care Med. 2017 Aug 15;196(4):527-530

Authors: Dabral S, Pullamsetti SS

PMID: 28809511 [PubMed - in process]




Why Do I Smoke and Why Do I Keep Smoking?
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Why Do I Smoke and Why Do I Keep Smoking?

Am J Respir Crit Care Med. 2017 Aug 15;196(4):P7-P8

Authors:

PMID: 28809510 [PubMed - in process]




American Thoracic Society/National Heart, Lung, and Blood Institute Asthma-Chronic Obstructive Pulmonary Disease Overlap Workshop Report.
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American Thoracic Society/National Heart, Lung, and Blood Institute Asthma-Chronic Obstructive Pulmonary Disease Overlap Workshop Report.

Am J Respir Crit Care Med. 2017 Aug 01;196(3):375-381

Authors: Woodruff PG, van den Berge M, Boucher RC, Brightling C, Burchard EG, Christenson SA, Han MK, Holtzman MJ, Kraft M, Lynch DA, Martinez FD, Reddel HK, Sin DD, Washko GR, Wenzel SE, Punturieri A, Freemer MM, Wise RA

Abstract
Asthma and chronic obstructive pulmonary disease (COPD) are highly prevalent chronic obstructive lung diseases with an associated high burden of disease. Asthma, which is often allergic in origin, frequently begins in infancy or childhood with variable airflow obstruction and intermittent wheezing, cough, and dyspnea. Patients with COPD, in contrast, are usually current or former smokers who present after the age of 40 years with symptoms (often persistent) including dyspnea and a productive cough. On the basis of age and smoking history, it is often easy to distinguish between asthma and COPD. However, some patients have features compatible with both diseases. Because clinical studies typically exclude these patients, their underlying disease mechanisms and appropriate treatment remain largely uncertain. To explore the status of and opportunities for research in this area, the NHLBI, in partnership with the American Thoracic Society, convened a workshop of investigators in San Francisco, California on May 14, 2016. At the workshop, current understanding of asthma-COPD overlap was discussed among clinicians, pathologists, radiologists, epidemiologists, and investigators with expertise in asthma and COPD. They considered knowledge gaps in our understanding of asthma-COPD overlap and identified strategies and research priorities that will advance its understanding. This report summarizes those discussions.

PMID: 28636425 [PubMed - indexed for MEDLINE]




Macrophage Elastase Induces TRAIL-mediated Tumor Cell Death through Its Carboxy-Terminal Domain.
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Macrophage Elastase Induces TRAIL-mediated Tumor Cell Death through Its Carboxy-Terminal Domain.

Am J Respir Crit Care Med. 2017 Aug 01;196(3):353-363

Authors: Dandachi N, Kelly NJ, Wood JP, Burton CL, Radder JE, Leme AS, Gregory AD, Shapiro SD

Abstract
RATIONALE: Macrophage elastase (matrix metalloproteinase [MMP]-12) is a potent protease that contributes to the lung destruction that accompanies cigarette smoking; it simultaneously inhibits lung tumor angiogenesis and metastasis by catalyzing the formation of antiangiogenic peptides. Recent studies have revealed novel nonproteolytic functions of MMP12, including antimicrobial activity through a peptide within its C-terminal domain (CTD).
OBJECTIVES: To determine whether the MMP12 CTD contributes to its antitumor activity in lung cancer.
METHODS: We used recombinant MMP12 peptide fragments, including its catalytic domain, CTD, and a 20 amino acid peptide within the CTD (SR20), in an in vitro system to delineate their effects on non-small cell lung cancer cell proliferation and apoptosis. We translated our findings to two murine models of lung cancer, including orthotopic human xenograft and Kras(LSL/G12D) mouse models of lung cancer.
MEASUREMENTS AND MAIN RESULTS: We show that SR20 triggers tumor apoptosis by up-regulation of gene expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptor, death receptor 4, sensitizing cells to an autocrine loop of TRAIL-mediated cell death. We then demonstrate the therapeutic efficacy of SR20 against two murine models of lung cancer.
CONCLUSIONS: The MMP12 CTD initiates TRAIL-mediated tumor cell death through its conserved SR20 peptide.

PMID: 28345958 [PubMed - indexed for MEDLINE]




Smoking-Dependent Distal-to-Proximal Repatterning of the Adult Human Small Airway Epithelium.
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Smoking-Dependent Distal-to-Proximal Repatterning of the Adult Human Small Airway Epithelium.

Am J Respir Crit Care Med. 2017 Aug 01;196(3):340-352

Authors: Yang J, Zuo WL, Fukui T, Chao I, Gomi K, Lee B, Staudt MR, Kaner RJ, Strulovici-Barel Y, Salit J, Crystal RG, Shaykhiev R

Abstract
RATIONALE: Small airways are the primary site of pathologic changes in chronic obstructive pulmonary disease (COPD), the major smoking-induced lung disorder.
OBJECTIVES: On the basis of the concept of proximal-distal patterning that determines regional specialization of the airway epithelium during lung development, we hypothesized that a similar program operates in the adult human lung being altered by smoking, leading to decreased regional identity of the small airway epithelium (SAE).
METHODS: The proximal and distal airway signatures were identified by comparing the transcriptomes of large and small airway epithelium samples obtained by bronchoscopy from healthy nonsmokers. The expression of these signatures was evaluated in the SAE of healthy smokers and smokers with COPD compared with that of healthy nonsmokers. The capacity of airway basal stem cells (BCs) to maintain region-associated phenotypes was evaluated using the air-liquid interface model.
MEASUREMENTS AND MAIN RESULTS: The distal and proximal airway signatures, containing 134 and 233 genes, respectively, were identified. These signatures included known developmental regulators of airway patterning, as well as novel regulators such as epidermal growth factor receptor, which was associated with the proximal airway phenotype. In the SAE of smokers with COPD, there was a dramatic smoking-dependent loss of the regional transcriptome identity with concomitant proximalization. This repatterning phenotype was reproduced by stimulating SAE BCs with epidermal growth factor, which was up-regulated in the SAE of smokers, during differentiation of SAE BCs in vitro.
CONCLUSIONS: Smoking-induced global distal-to-proximal reprogramming of the SAE represents a novel pathologic feature of COPD and is mediated by exaggerated epidermal growth factor/epidermal growth factor receptor signaling in SAE BCs.

PMID: 28345955 [PubMed - indexed for MEDLINE]




Fifty Years of Research in ARDS. Cell-based Therapy for Acute Respiratory Distress Syndrome. Biology and Potential Therapeutic Value.
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Fifty Years of Research in ARDS. Cell-based Therapy for Acute Respiratory Distress Syndrome. Biology and Potential Therapeutic Value.

Am J Respir Crit Care Med. 2017 Aug 01;196(3):266-273

Authors: Laffey JG, Matthay MA

Abstract
On the basis of several preclinical studies, cell-based therapy has emerged as a potential new therapeutic for acute respiratory distress syndrome (ARDS). Of the various cell-based therapy options, mesenchymal stem/stromal cells (MSCs) from bone marrow, adipose tissue, and umbilical cord have the most experimental data to support their potential efficacy for lung injury from both infectious and noninfectious causes. Mechanistically, MSCs exert their beneficial effects by release of paracrine factors, microvesicles, and transfer of mitochondria, all of which have antiinflammatory and pro-resolving effects on injured lung endothelium and alveolar epithelium, including enhancing the resolution of pulmonary edema by up-regulating sodium-dependent alveolar fluid clearance. MSCs also have antimicrobial effects mediated by release of antimicrobial factors and by up-regulating monocyte/macrophage phagocytosis. Phase 2a clinical trials to establish safety in ARDS are in progress, and two phase 1 trials did not report any serious adverse events. Several issues need further study, including: determining the optimal methods for large-scale production, reconstitution of cryopreserved cells for clinical use, defining cell potency assays, and determining the therapeutic potential of conditioned media derived from MSCs. Because ARDS is a heterogeneous syndrome, targeting MSCs to patients with ARDS with a more hyperinflammatory endotype may further enhance their potential for efficacy.

PMID: 28306336 [PubMed - indexed for MEDLINE]




Classification of Airflow Limitation Based on z-Score Underestimates Mortality in Patients with Chronic Obstructive Pulmonary Disease.
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Classification of Airflow Limitation Based on z-Score Underestimates Mortality in Patients with Chronic Obstructive Pulmonary Disease.

Am J Respir Crit Care Med. 2017 Aug 01;196(3):298-305

Authors: Tejero E, Prats E, Casitas R, Galera R, Pardo P, Gavilán A, Martínez-Cerón E, Cubillos-Zapata C, Del Peso L, García-Río F

Abstract
RATIONALE: Global Lung Function Initiative recommends reporting lung function measures as z-score, and a classification of airflow limitation (AL) based on this parameter has recently been proposed.
OBJECTIVES: To evaluate the prognostic capacity of the AL classifications based on z-score or percentage predicted of FEV1 in patients with chronic obstructive pulmonary disease (COPD).
METHODS: A cohort of 2,614 patients with COPD recruited outside the hospital setting was examined after a mean (± SD) of 57 ± 13 months of follow-up, totaling 10,322 person-years. All-cause mortality was analyzed, evaluating the predictive capacity of several AL staging systems.
MEASUREMENTS AND MAIN RESULTS: Based on Global Initiative for Chronic Obstructive Lung Disease guidelines, 461 patients (17.6%) had mild, 1,452 (55.5%) moderate, 590 (22.6%) severe, and 111 (4.2%) very severe AL. According to z-score classification, 66.3% of patients remained with the same severity, whereas 23.7% worsened and 10.0% improved. Unlike other staging systems, patients with severe AL according to z-score had higher mortality than those with very severe AL (increase of risk by 5.2 and 3.9 times compared with mild AL, respectively). The predictive capacity for 5-year survival was slightly higher for FEV1 expressed as percentage of predicted than as z-score (area under the curve: 0.714-0.760 vs. 0.649-0.708, respectively). A severity-dependent relationship between AL grades by z-score and mortality was only detected in patients younger than age 60 years.
CONCLUSIONS: In patients with COPD, the AL classification based on z-score predicts worse mortality than those based on percentage of predicted. It is possible that the z-score underestimates AL severity in patients older than 60 years of age with severe functional impairment.

PMID: 28306326 [PubMed - indexed for MEDLINE]




Diagnostic Instability and Reversals of Chronic Obstructive Pulmonary Disease Diagnosis in Individuals with Mild to Moderate Airflow Obstruction.
Related Articles

Diagnostic Instability and Reversals of Chronic Obstructive Pulmonary Disease Diagnosis in Individuals with Mild to Moderate Airflow Obstruction.

Am J Respir Crit Care Med. 2017 Aug 01;196(3):306-314

Authors: Aaron SD, Tan WC, Bourbeau J, Sin DD, Loves RH, MacNeil J, Whitmore GA, Canadian Respiratory Research Network

Abstract
RATIONALE: Chronic obstructive pulmonary disease (COPD) is a chronic, progressive disease, and reversal of COPD diagnosis is thought to be uncommon.
OBJECTIVES: To determine whether a spirometric diagnosis of mild or moderate COPD is subject to variability and potential error.
METHODS: We examined two prospective cohort studies that enrolled subjects with mild to moderate post-bronchodilator airflow obstruction. The Lung Health Study (n = 5,861 subjects; study duration, 5 yr) and the Canadian Cohort of Obstructive Lung Disease (CanCOLD) study (n = 1,551 subjects; study duration, 4 yr) were examined to determine frequencies of (1) diagnostic instability, represented by how often patients initially met criteria for a spirometric diagnosis of COPD but then crossed the diagnostic threshold to normal and then crossed back to COPD over a series of annual visits, or vice versa; and (2) diagnostic reversals, defined as how often an individual's COPD diagnosis at the study outset reversed to normal by the end of the study.
MEASUREMENTS AND MAIN RESULTS: Diagnostic instability was common and occurred in 19.5% of the Lung Health Study subjects and 6.4% of the CanCOLD subjects. Diagnostic reversals of COPD from the beginning to the end of the study period occurred in 12.6% and 27.2% of subjects in the Lung Health Study and CanCOLD study, respectively. The risk of diagnostic instability was greatest for subjects whose baseline FEV1/FVC value was closest to the diagnostic threshold, and the risk of diagnostic reversal was greatest for subjects who quit smoking during the study.
CONCLUSIONS: A single post-bronchodilator spirometric assessment may not be reliable for diagnosing COPD in patients with mild to moderate airflow obstruction at baseline.

PMID: 28267373 [PubMed - indexed for MEDLINE]




Role for NLRP3 Inflammasome-mediated, IL-1β-Dependent Responses in Severe, Steroid-Resistant Asthma.
Related Articles

Role for NLRP3 Inflammasome-mediated, IL-1β-Dependent Responses in Severe, Steroid-Resistant Asthma.

Am J Respir Crit Care Med. 2017 Aug 01;196(3):283-297

Authors: Kim RY, Pinkerton JW, Essilfie AT, Robertson AAB, Baines KJ, Brown AC, Mayall JR, Ali MK, Starkey MR, Hansbro NG, Hirota JA, Wood LG, Simpson JL, Knight DA, Wark PA, Gibson PG, O'Neill LAJ, Cooper MA, Horvat JC, Hansbro PM

Abstract
RATIONALE: Severe, steroid-resistant asthma is the major unmet need in asthma therapy. Disease heterogeneity and poor understanding of pathogenic mechanisms hampers the identification of therapeutic targets. Excessive nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome and concomitant IL-1β responses occur in chronic obstructive pulmonary disease, respiratory infections, and neutrophilic asthma. However, the direct contributions to pathogenesis, mechanisms involved, and potential for therapeutic targeting remain poorly understood, and are unknown in severe, steroid-resistant asthma.
OBJECTIVES: To investigate the roles and therapeutic targeting of the NLRP3 inflammasome and IL-1β in severe, steroid-resistant asthma.
METHODS: We developed mouse models of Chlamydia and Haemophilus respiratory infection-mediated, ovalbumin-induced severe, steroid-resistant allergic airway disease. These models share the hallmark features of human disease, including elevated airway neutrophils, and NLRP3 inflammasome and IL-1β responses. The roles and potential for targeting of NLRP3 inflammasome, caspase-1, and IL-1β responses in experimental severe, steroid-resistant asthma were examined using a highly selective NLRP3 inhibitor, MCC950; the specific caspase-1 inhibitor Ac-YVAD-cho; and neutralizing anti-IL-1β antibody. Roles for IL-1β-induced neutrophilic inflammation were examined using IL-1β and anti-Ly6G.
MEASUREMENTS AND MAIN RESULTS: Chlamydia and Haemophilus infections increase NLRP3, caspase-1, IL-1β responses that drive steroid-resistant neutrophilic inflammation and airway hyperresponsiveness. Neutrophilic airway inflammation, disease severity, and steroid resistance in human asthma correlate with NLRP3 and IL-1β expression. Treatment with anti-IL-1β, Ac-YVAD-cho, and MCC950 suppressed IL-1β responses and the important steroid-resistant features of disease in mice, whereas IL-1β administration recapitulated these features. Neutrophil depletion suppressed IL-1β-induced steroid-resistant airway hyperresponsiveness.
CONCLUSIONS: NLRP3 inflammasome responses drive experimental severe, steroid-resistant asthma and are potential therapeutic targets in this disease.

PMID: 28252317 [PubMed - indexed for MEDLINE]




Checkpoint Blockade in Lung Cancer and Mesothelioma.
Related Articles

Checkpoint Blockade in Lung Cancer and Mesothelioma.

Am J Respir Crit Care Med. 2017 Aug 01;196(3):274-282

Authors: Lievense LA, Sterman DH, Cornelissen R, Aerts JG

Abstract
In the last decade, immunotherapy has emerged as a new treatment modality in cancer. The most success has been achieved with the class of checkpoint inhibitors (CPIs), antibodies that unleash the antitumor immune response. After the success in melanoma, numerous clinical trials are being conducted investigating CPIs in lung cancer and mesothelioma. The programmed death protein (PD) 1-PD ligand 1/2 pathway and cytotoxic T lymphocyte-associated protein 4 are currently the most studied immunotherapeutic targets in these malignancies. In non-small cell lung cancer, anti-PD-1 antibodies have become part of the approved treatment arsenal. In small cell lung cancer and mesothelioma, the efficacy of checkpoint inhibition has not yet been proven. In this Concise Clinical Review, an overview of the landmark clinical trials investigating checkpoint blockade in lung cancer and mesothelioma is provided. Because response rates are around 20% in the majority of clinical trials, there is much room for improvement. Predictive biomarkers are therefore essential to fully develop the potential of CPIs. To increase efficacy, multiple clinical trials investigating the combination of cytotoxic T lymphocyte-associated protein 4 inhibitors and PD-1/PD ligand 1 blockade in lung cancer and mesothelioma are being conducted. Given the potential benefit of immunotherapy, implementation of current and new knowledge in trial designs and interpretation of results is essential for moving forward.

PMID: 28252315 [PubMed - indexed for MEDLINE]




Antenatal Determinants of Bronchopulmonary Dysplasia and Late Respiratory Disease in Preterm Infants.
Related Articles

Antenatal Determinants of Bronchopulmonary Dysplasia and Late Respiratory Disease in Preterm Infants.

Am J Respir Crit Care Med. 2017 Aug 01;196(3):364-374

Authors: Morrow LA, Wagner BD, Ingram DA, Poindexter BB, Schibler K, Cotten CM, Dagle J, Sontag MK, Mourani PM, Abman SH

Abstract
RATIONALE: Mechanisms contributing to chronic lung disease after preterm birth are incompletely understood.
OBJECTIVES: To identify antenatal risk factors associated with increased risk for bronchopulmonary dysplasia (BPD) and respiratory disease during early childhood after preterm birth, we performed a prospective, longitudinal study of 587 preterm infants with gestational age less than 34 weeks and birth weights between 500 and 1,250 g.
METHODS: Data collected included perinatal information and assessments during the neonatal intensive care unit admission and longitudinal follow-up by questionnaire until 2 years of age.
MEASUREMENTS AND MAIN RESULTS: After adjusting for covariates, we found that maternal smoking prior to preterm birth increased the odds of having an infant with BPD by twofold (P = 0.02). Maternal smoking was associated with prolonged mechanical ventilation and respiratory support during the neonatal intensive care unit admission. Preexisting hypertension was associated with a twofold (P = 0.04) increase in odds for BPD. Lower gestational age and birth weight z-scores were associated with BPD. Preterm infants who were exposed to maternal smoking had higher rates of late respiratory disease during childhood. Twenty-two percent of infants diagnosed with BPD and 34% of preterm infants without BPD had no clinical signs of late respiratory disease during early childhood.
CONCLUSIONS: We conclude that maternal smoking and hypertension increase the odds for developing BPD after preterm birth, and that maternal smoking is strongly associated with increased odds for late respiratory morbidities during early childhood. These findings suggest that in addition to the BPD diagnosis at 36 weeks, other factors modulate late respiratory outcomes during childhood. We speculate that measures to reduce maternal smoking not only will lower the risk for preterm birth but also will improve late respiratory morbidities after preterm birth.

PMID: 28249118 [PubMed - indexed for MEDLINE]




Early Expansion of Circulating Granulocytic Myeloid-derived Suppressor Cells Predicts Development of Nosocomial Infections in Patients with Sepsis.
Related Articles

Early Expansion of Circulating Granulocytic Myeloid-derived Suppressor Cells Predicts Development of Nosocomial Infections in Patients with Sepsis.

Am J Respir Crit Care Med. 2017 Aug 01;196(3):315-327

Authors: Uhel F, Azzaoui I, Grégoire M, Pangault C, Dulong J, Tadié JM, Gacouin A, Camus C, Cynober L, Fest T, Le Tulzo Y, Roussel M, Tarte K

Abstract
RATIONALE: Sepsis induces a sustained immune dysfunction responsible for poor outcome and nosocomial infections. Myeloid-derived suppressor cells (MDSCs) described in cancer and inflammatory processes may be involved in sepsis-induced immune suppression, but their clinical impact remains poorly defined.
OBJECTIVES: To clarify phenotype, suppressive activity, origin, and clinical impact of MDSCs in patients with sepsis.
METHODS: Peripheral blood transcriptomic analysis was performed on 29 patients with sepsis and 15 healthy donors. A second cohort of 94 consecutive patients with sepsis, 11 severity-matched intensive care patients, and 67 healthy donors was prospectively enrolled for flow cytometry and functional experiments.
MEASUREMENTS AND MAIN RESULTS: Genes involved in MDSC suppressive functions, including S100A12, S100A9, MMP8, and ARG1, were up-regulated in the peripheral blood of patients with sepsis. CD14(pos)HLA-DR(low/neg) monocytic (M)-MDSCs were expanded in intensive care unit patients with and without sepsis and CD14(neg)CD15(pos) low-density granulocytes/granulocytic (G)-MDSCs were more specifically expanded in patients with sepsis (P < 0.001). Plasma levels of MDSC mediators S100A8/A9, S100A12, and arginase 1 were significantly increased. In vitro, CD14(pos)- and CD15(pos)-cell depletion increased T-cell proliferation in patients with sepsis. G-MDSCs, made of immature and mature granulocytes expressing high levels of degranulation markers, were specifically responsible for arginase 1 activity. High initial levels of G-MDSCs, arginase 1, and S100A12 but not M-MDSCs were associated with subsequent occurrence of nosocomial infections.
CONCLUSIONS: M-MDSCs and G-MDSCs strongly contribute to T-cell dysfunction in patients with sepsis. More specifically, G-MDSCs producing arginase 1 are associated with a higher incidence of nosocomial infections and seem to be major actors of sepsis-induced immune suppression.

PMID: 28146645 [PubMed - indexed for MEDLINE]




Shared and Distinct Aspects of the Sepsis Transcriptomic Response to Fecal Peritonitis and Pneumonia.
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Shared and Distinct Aspects of the Sepsis Transcriptomic Response to Fecal Peritonitis and Pneumonia.

Am J Respir Crit Care Med. 2017 Aug 01;196(3):328-339

Authors: Burnham KL, Davenport EE, Radhakrishnan J, Humburg P, Gordon AC, Hutton P, Svoren-Jabalera E, Garrard C, Hill AVS, Hinds CJ, Knight JC

Abstract
RATIONALE: Heterogeneity in the septic response has hindered efforts to understand pathophysiology and develop targeted therapies. Source of infection, with different causative organisms and temporal changes, might influence this heterogeneity.
OBJECTIVES: To investigate individual and temporal variations in the transcriptomic response to sepsis due to fecal peritonitis, and to compare these with the same parameters in community-acquired pneumonia.
METHODS: We performed genome-wide gene expression profiling in peripheral blood leukocytes of adult patients admitted to intensive care with sepsis due to fecal peritonitis (n = 117) or community-acquired pneumonia (n = 126), and of control subjects without sepsis (n = 10).
MEASUREMENTS AND MAIN RESULTS: A substantial portion of the transcribed genome (18%) was differentially expressed compared with that of control subjects, independent of source of infection, with eukaryotic initiation factor 2 signaling being the most enriched canonical pathway. We identified two sepsis response signature (SRS) subgroups in fecal peritonitis associated with early mortality (P = 0.01; hazard ratio, 4.78). We defined gene sets predictive of SRS group, and serial sampling demonstrated that subgroup membership is dynamic during intensive care unit admission. We found that SRS is the major predictor of transcriptomic variation; a small number of genes (n = 263) were differentially regulated according to the source of infection, enriched for IFN signaling and antigen presentation. We define temporal changes in gene expression from disease onset involving phagosome formation as well as natural killer cell and IL-3 signaling.
CONCLUSIONS: The majority of the sepsis transcriptomic response is independent of the source of infection and includes signatures reflecting immune response state and prognosis. A modest number of genes show evidence of specificity. Our findings highlight opportunities for patient stratification and precision medicine in sepsis.

PMID: 28036233 [PubMed - indexed for MEDLINE]