ResearchPad - pneumonitis https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Identification of miRNA signatures associated with radiation-induced late lung injury in mice]]> https://www.researchpad.co/article/elastic_article_7641 Acute radiation exposure of the thorax can lead to late serious, and even life-threatening, pulmonary and cardiac damage. Sporadic in nature, late complications tend to be difficult to predict, which prompted this investigation into identifying non-invasive, tissue-specific biomarkers for the early detection of late radiation injury. Levels of circulating microRNA (miRNA) were measured in C3H and C57Bl/6 mice after whole thorax irradiation at doses yielding approximately 70% mortality in 120 or 180 days, respectively (LD70/120 or 180). Within the first two weeks after exposure, weight gain slowed compared to sham treated mice along with a temporary drop in white blood cell counts. 52% of C3H (33 of 64) and 72% of C57Bl/6 (46 of 64) irradiated mice died due to late radiation injury. Lung and heart damage, as assessed by computed tomography (CT) and histology at 150 (C3H mice) and 180 (C57Bl/6 mice) days, correlated well with the appearance of a local, miRNA signature in the lung and heart tissue of irradiated animals, consistent with inherent differences in the C3H and C57Bl/6 strains in their propensity for developing radiation-induced pneumonitis or fibrosis, respectively. Radiation-induced changes in the circulating miRNA profile were most prominent within the first 30 days after exposure and included miRNA known to regulate inflammation and fibrosis. Importantly, early changes in plasma miRNA expression predicted survival with reasonable accuracy (88–92%). The miRNA signature that predicted survival in C3H mice, including miR-34a-5p, -100-5p, and -150-5p, were associated with pro-inflammatory NF-κB-mediated signaling pathways, whereas the signature identified in C57Bl/6 mice (miR-34b-3p, -96-5p, and -802-5p) was associated with TGF-β/SMAD signaling. This study supports the hypothesis that plasma miRNA profiles could be used to identify individuals at high risk of organ-specific late radiation damage, with applications for radiation oncology clinical practice or in the context of a radiological incident.

]]>
<![CDATA[Podocalyxin Regulates Murine Lung Vascular Permeability by Altering Endothelial Cell Adhesion]]> https://www.researchpad.co/article/5989da21ab0ee8fa60b7f156

Despite the widespread use of CD34-family sialomucins (CD34, podocalyxin and endoglycan) as vascular endothelial cell markers, there is remarkably little known of their vascular function. Podocalyxin (gene name Podxl), in particular, has been difficult to study in adult vasculature as germ-line deletion of podocalyxin in mice leads to kidney malformations and perinatal death. We generated mice that conditionally delete podocalyxin in vascular endothelial cells (PodxlΔEC mice) to study the homeostatic role of podocalyxin in adult mouse vessels. Although PodxlΔEC adult mice are viable, their lungs display increased lung volume and changes to the matrix composition. Intriguingly, this was associated with increased basal and inflammation-induced pulmonary vascular permeability. To further investigate the etiology of these defects, we isolated mouse pulmonary endothelial cells. PodxlΔEC endothelial cells display mildly enhanced static adhesion to fibronectin but spread normally when plated on fibronectin-coated transwells. In contrast, PodxlΔEC endothelial cells exhibit a severely impaired ability to spread on laminin and, to a lesser extent, collagen I coated transwells. The data suggest that, in endothelial cells, podocalyxin plays a previously unrecognized role in maintaining vascular integrity, likely through orchestrating interactions with extracellular matrix components and basement membranes, and that this influences downstream epithelial architecture.

]]>
<![CDATA[Is IMRT Superior or Inferior to 3DCRT in Radiotherapy for NSCLC? A Meta-Analysis]]> https://www.researchpad.co/article/5989d9d2ab0ee8fa60b64a12

Introduction

There are no adequate data to determine whether intensity-modulated radiotherapy (IMRT) is superior to three-dimensional conformal radiotherapy (3DCRT) in the treatment of non-small cell lung cancer (NSCLC). This meta-analysis was conducted to compare the clinical outcomes of IMRT and 3DCRT in the treatment of NSCLC.

Methods

No exclusions were made based on types of study design. We performed a literature search in PubMed, EMBASE and the Cochrane library databases from their inceptions to April 30, 2015. The overall survival (OS) and relative risk (RR) of radiation pneumonitis and radiation oesophagitis were evaluated. Two authors independently assessed the methodological quality and extracted data. Publication bias was evaluated by funnel plot using Egger’s test results.

Results

From the literature search, 10 retrospective studies were collected, and of those, 5 (12,896 patients) were selected for OS analysis, 4 (981 patients) were selected for radiation pneumonitis analysis, and 4 (1339 patients) were selected for radiation oesophagitis analysis. Cox multivariate proportional hazards models revealed that 3DCRT and IMRT had similar OS (HR = 0.96, P = 0.477) but that IMRT reduced the incidence of grade 2 radiation pneumonitis (RR = 0.74, P = 0.009) and increased the incidence of grade 3 radiation oesophagitis (RR = 2.47, P = 0.000).

Conclusions

OS of IMRT for NSCLC is not inferior to that of 3DCRT, but IMRT significantly reduces the risk of radiation pneumonitis and increases the risk of radiation oesophagitis compared to 3DCRT.

]]>
<![CDATA[MiRNA-Related Genetic Variations Associated with Radiotherapy-Induced Toxicities in Patients with Locally Advanced Non–Small Cell Lung Cancer]]> https://www.researchpad.co/article/5989db0bab0ee8fa60bca566

Severe radiation-induced toxicities limit treatment efficacy and compromise outcomes of lung cancer. We aimed to identify microRNA-related genetic variations as biomarkers for the prediction of radiotherapy-induced acute toxicities. We genotyped 233 SNPs (161 in microRNA binding site and 72 in processing gene) and analyzed their associations with pneumonitis and esophagitis in 167 stage III NSCLC patients received definitive radiation therapy. Sixteen and 11 SNPs were associated with esophagitis and pneumonitis, respectively. After multiple comparison correction, RPS6KB2:rs10274, SMO:rs1061280, SMO:rs1061285 remained significantly associated with esophagitis, while processing gene DGCR8:rs720014, DGCR8:rs3757, DGCR8:rs1633445 remained significantly associated with pneumonitis. Patients with the AA genotype of RPS6KB2:rs10274 had an 81% reduced risk of developing esophagitis (OR: 0.19, 95% CI: 0.07–0.51, p = 0.001, q = 0.06). Patients with the AG+GG genotype of SMO:rs1061280 had an 81% reduced risk of developing esophagitis (OR: 0.19, 95% CI: 0.07–0.53, p = 0.001, q = 0.06). Patients with the GG+GA genotype of DGCR8:rs720014 had a 3.54-fold increased risk of pneumonitis (OR: 3.54, 95% CI: 1.65–7.61, p <0.05, q <0.1). Significantly cumulative effects of the top SNPs were observed for both toxicities (P-trend <0.001). Using bioinformatics tools, we found that the genotype of rs10274 was associated with altered expression of the RPS6KB2 gene. Gene-based analysis showed DGCR8 (p = 0.010) and GEMIN4 (p = 0.039) were the top genes associated with the risk of developing pneumonitis. Our results provide strong evidence that microRNA-related genetic variations contribute to the development of radiotherapy-induced acute esophagitis and pneumonitis and could thus serve as biomarkers to help accurately predict radiotherapy-induced toxicity in NSCLC patients.

]]>
<![CDATA[External Validation of the A2DS2 Score to Predict Stroke-Associated Pneumonia in a Chinese Population: A Prospective Cohort Study]]> https://www.researchpad.co/article/5989da2cab0ee8fa60b82c0a

Background and Purpose

The A2DS2 score was recently developed from the Berlin Stroke Registry for predicting in-hospital pneumonia after acute ischemic stroke and performed well in an external validation in the North-west Germany Stroke Registry. It could be a useful tool for risk stratification in clinical practice or stroke trials. We aimed to prospectively validate the predictive value of A2DS2 score in a Chinese stroke population.

Methods

The prognostic model was used to predict stroke-associated pneumonia (SAP) from Henan Province Stroke Registry (HNSR) in which data were prospectively collected. The receiver-operating characteristic curves were plotted, and the C statistics were calculated to assess the discrimination ability. The Hosmer–Lemeshow goodness-of-fit test and the plot of observed versus predicted SAP risk were used to assess model calibration.

Results

Among 1142 eligible patients, the overall in-hospital SAP was 18.8%, which ranged from 9.0% in patients with lower A2DS2 scores (0–4) to 65.0% in those with higher scores of 5 to 10 (P for trend <0.001). The C statistic was 0.836 (95% confidence interval, 0.803–0.868) through the A2DS2 score, suggesting excellent discrimination in the HNSR. The A2DS2 score also showed excellent calibration (Cox and Snell R2 = 0.243) in the external validation sample from the HNSR.

Conclusions

The A2DS2 score could reliably predict in-hospital SAP in Chinese stroke patients. It might be helpful for the assessment of increased risk monitoring and prophylactic treatment in identified high-risk patients for SAP in clinical routine.

]]>
<![CDATA[Associations of Adverse Clinical Course and Ingested Substances among Patients with Deliberate Drug Poisoning: A Cohort Study from an Intensive Care Unit in Japan]]> https://www.researchpad.co/article/5989da9aab0ee8fa60ba35df

Objectives

Some patients with deliberate drug poisoning subsequently have an adverse clinical course. The present study aimed to examine whether the type of drugs ingested and psychiatric diagnoses were related to an adverse clinical course.

Methods

We conducted a cohort study of patients with deliberate drug poisoning admitted to the intensive care unit of a university hospital located in Tokyo, Japan, between September 2006 and June 2013. Intensive care unit (ICU) stay of ≥4 days was used as a primary outcome measure, while the incidence of aspiration pneumonitis was used as a secondary outcome measure. Ingested substances and psychiatric diagnoses were used as explanatory variables.

Results

Of the 676 patients with deliberate drug poisoning, 88% had a history of psychiatric treatment and 82% had ingested psychotropic drugs. Chlorpromazine-promethazine-phenobarbital combination drug (Vegetamin®) ranked fifth among the most frequently ingested substances in cases of deliberate drug poisoning and had the highest incidence of prolonged ICU stay (20%) and aspiration pneumonitis (29%). The top three major classes consisted of benzodiazepines (79%), new-generation antidepressants (25%), and barbiturates/non-barbiturates (23%). Barbiturate overdose was independently associated with increased odds of both prolonged ICU stay (8% vs. 17%; odds ratio [OR], 2.97; 95% confidence interval [CI], 1.60–5.55) and aspiration pneumonitis (8% vs. 24%; OR, 3.83; 95% CI, 2.18–6.79) relative to those associated with overdose of only other sedative-hypnotics (i.e., benzodiazepines).

Conclusion

These results suggest that judicious prescribing of barbiturates by psychiatrists could reduce the risk of an adverse clinical course when a patient attempts an overdose.

]]>
<![CDATA[Characteristics and Prognostic Impact of Pneumonitis during Systemic Anti-Cancer Therapy in Patients with Advanced Non-Small-Cell Lung Cancer]]> https://www.researchpad.co/article/5989daafab0ee8fa60baab68

Background

Data on characteristics, outcomes, and prognosis of advanced non-small-cell lung cancer (NSCLC) patients who develop pneumonitis during systemic anti-cancer therapy (pneumonitis) are currently lacking.

Methods

We conducted a retrospective cohort study of 910 consecutive patients diagnosed with advanced NSCLC between January 2004 and January 2014. Of these, 140 patients were excluded because they did not receive systemic anti-cancer therapy at this hospital.

Results

A total of 770 patients were included in the study, of whom 44 (6%) were diagnosed with pneumonitis. The mortality rate of pneumonitis was 36%. The incidence of pneumonitis was independently associated with pre-existing ILD (adjusted odds ratio, 2.99, P = 0.008), and survivors were significantly associated with younger age (P = 0.003) and radiographic non-acute interstitial pneumonia pattern (P = 0.004). In all patients, pneumonitis was identified as an independent predictor of overall survival (OS) (adjusted hazard ratio 1.53, 95% CI, 1.09–2.09, P = 0.015). Performance status was poor in 82% of survivors of pneumonitis; in 62% of survivors, the PS worsened after the pneumonitis improved. Additionally, 54% of survivors received no further systemic anti-cancer therapy after pneumonitis. The median survival time of survivors after pneumonitis was 3.5 months (95% CI, 2.3–7.2 months).

Conclusions

Our study indicated that 6% of patients with advanced NSCLC developed pneumonitis during systemic anti-cancer therapy. The early mortality rate of pneumonitis is high, and the survival and PS after pneumonitis is extremely poor. Additionally, pneumonitis has an adverse impact on the survival of patients with advanced NSCLC. These data should be considered for the management of pneumonitis, and we recommend that future work focuses on pneumonitis particularly to improve the survival of patients with advanced NSCLC.

]]>
<![CDATA[iTRAQ-Based Proteomics Reveals Novel Biomarkers for Idiopathic Pulmonary Fibrosis]]> https://www.researchpad.co/article/5989db53ab0ee8fa60bdc9ff

Idiopathic pulmonary fibrosis (IPF) is a gradual lung disease with a survival of less than 5 years post-diagnosis for most patients. Poor molecular description of IPF has led to unsatisfactory interpretation of the pathogenesis of this disease, resulting in the lack of successful treatments. The objective of this study was to discover novel noninvasive biomarkers for the diagnosis of IPF. We employed a coupled isobaric tag for relative and absolute quantitation (iTRAQ)-liquid chromatography–tandem mass spectrometry (LC–MS/MS) approach to examine protein expression in patients with IPF. A total of 97 differentially expressed proteins (38 upregulated proteins and 59 downregulated proteins) were identified in the serum of IPF patients. Using String software, a regulatory network containing 87 nodes and 244 edges was built, and the functional enrichment showed that differentially expressed proteins were predominantly involved in protein activation cascade, regulation of response to wounding and extracellular components. A set of three most significantly upregulated proteins (HBB, CRP and SERPINA1) and four most significantly downregulated proteins (APOA2, AHSG, KNG1 and AMBP) were selected for validation in an independent cohort of IPF and other lung diseases using ELISA test. The results confirmed the iTRAQ profiling results and AHSG, AMBP, CRP and KNG1 were found as specific IPF biomarkers. ROC analysis indicated the diagnosis potential of the validated biomarkers. The findings of this study will contribute in understanding the pathogenesis of IPF and facilitate the development of therapeutic targets.

]]>
<![CDATA[Hypersensitivity pneumonitis onset and severity is regulated by CD103 dendritic cell expression]]> https://www.researchpad.co/article/5989db5fab0ee8fa60be114e

Background

Pulmonary dendritic cells drive lung responses to foreign antigens, including Saccharopolyspora rectivirgula, a causative agent of hypersensitivity pneumonitis. While the airway inflammatory mechanisms involved in hypersensitivity pneumonitis are well described, the mechanisms leading to the break in homeostasis and hypersensitivity pneumonitis onset are not well-described, and could involve CD103+ dendritic cells, which are found at baseline and during inflammatory responses in the lung. However, recent demonstration of the ability of CD103+ dendritic cells to induce inflammatory responses starkly contrasts with their classically described role as regulatory cells. These discrepancies may be attributable to the lack of current information on the importance of CD103 expression and modulation on these cells during inflammatory episodes.

Methods

To verify the importance of CD103 expression in the regulation of hypersensitivity pneumonitis, wild-type and Cd103-/- mice were exposed intranasally to S. rectivirgula and airway inflammation was quantified. Surface expression of CD103 in response to S. rectivirgula exposure was studied and cell transfers were used to determine the relative importance of CD103 expression on dendritic cells and T cells in regulating the inflammation in hypersensitivity pneumonitis.

Results

Cd103-/- mice developed an exacerbated inflammatory response as early as 18h following S. rectivirgula exposure. CD103 expression on dendritic cells was downregulated quickly following S. rectivirgula exposure, and cell transfers demonstrated that CD103 expression on dendritic cells specifically (and not T cells) regulates the onset and severity of this response.

Conclusion

All in all, we demonstrate that CD103 expression by dendritic cells, but not T cells, is crucial for homeostasis maintenance and the regulation of the TH17 airway inflammatory response in hypersensitivity pneumonitis.

]]>
<![CDATA[Aspiration-Related Deaths in 57 Consecutive Patients: Autopsy Study]]> https://www.researchpad.co/article/5989da35ab0ee8fa60b86132

Background

Aspiration can cause a diverse spectrum of pulmonary disorders some of which can lead to death but can be difficult to diagnose.

Patients and Methods

The medical records and autopsy findings of 57 consecutive patients in whom aspiration was the immediate cause of death at Mayo Clinic (Rochester, MN, USA) over a 9-yr period, from January 1 2004 to December 31 2012 were analyzed.

Results

The median age at death was 72 years (range, 13–95 years) and included 39 (68%) males. The most common symptom before death was dyspnea (63%) and chest radiography revealed bilateral infiltrates in the majority (81%). Most common precipitating factors for aspiration were depressed consciousness (46%) and dysphagia (44%). Aspiration-related syndromes leading to death were aspiration pneumonia in 26 (46%), aspiration pneumonitis in 25 (44%), and large airway obstruction in 6 patients (11%). Aspiration was clinically unsuspected in 19 (33%) patients. Antimicrobial therapy had been empirically administered to most patients (90%) with aspiration pneumonia and aspiration pneumonitis.

Conclusion

We conclude aspiration-related deaths occur most commonly in the elderly with identifiable risks and presenting bilateral pulmonary infiltrates. One-third of these aspiration-related pulmonary syndromes were clinically unsuspected at the time of death.

]]>
<![CDATA[Absence of Detectable Influenza RNA Transmitted via Aerosol during Various Human Respiratory Activities – Experiments from Singapore and Hong Kong]]> https://www.researchpad.co/article/5989dab8ab0ee8fa60bad8d9

Two independent studies by two separate research teams (from Hong Kong and Singapore) failed to detect any influenza RNA landing on, or inhaled by, a life-like, human manikin target, after exposure to naturally influenza-infected volunteers. For the Hong Kong experiments, 9 influenza-infected volunteers were recruited to breathe, talk/count and cough, from 0.1 m and 0.5 m distance, onto a mouth-breathing manikin. Aerosolised droplets exhaled from the volunteers and entering the manikin’s mouth were collected with PTFE filters and an aerosol sampler, in separate experiments. Virus detection was performed using an in-house influenza RNA reverse-transcription polymerase chain reaction (RT-PCR) assay. No influenza RNA was detected from any of the PTFE filters or air samples. For the Singapore experiments, 6 influenza-infected volunteers were asked to breathe (nasal/mouth breathing), talk (counting in English/second language), cough (from 1 m/0.1 m away) and laugh, onto a thermal, breathing manikin. The manikin’s face was swabbed at specific points (around both eyes, the nostrils and the mouth) before and after exposure to each of these respiratory activities, and was cleaned between each activity with medical grade alcohol swabs. Shadowgraph imaging was used to record the generation of these respiratory aerosols from the infected volunteers and their impact onto the target manikin. No influenza RNA was detected from any of these swabs with either team’s in-house diagnostic influenza assays. All the influenza-infected volunteers had diagnostic swabs taken at recruitment that confirmed influenza (A/H1, A/H3 or B) infection with high viral loads, ranging from 105-108 copies/mL (Hong Kong volunteers/assay) and 104–107 copies/mL influenza viral RNA (Singapore volunteers/assay). These findings suggest that influenza RNA may not be readily transmitted from naturally-infected human source to susceptible recipients via these natural respiratory activities, within these exposure time-frames. Various reasons are discussed in an attempt to explain these findings.

]]>