The DsbA-L gene is associated with respiratory function of the elderly via its adiponectin multimeric or antioxidant properties

Oxidative stress and inflammation play a key role in the age-related decline in the respiratory function. Adipokine in relation to the metabolic and inflammatory systems is attracting growing interest in the field of respiratory dysfunction. The present clinical and experimental studies investigated the role of the disulfide bond-forming oxidoreductase A-like protein (DsbA-L) gene, which has antioxidant and adiponectin multimeric (i.e. activation) properties, on the respiratory function of the elderly. We performed a retrospective longitudinal genotype-phenotype relationship analysis of 318 Japanese relatively elderly participants (mean age ± standard deviation: 67.0 ± 5.8 years) during a health screening program and an in vitro DsbA-L knock-down evaluation using 16HBE14o-cells, a commonly evaluated human airway epithelial cell line. The DsbA-L rs1917760 polymorphism was associated with a reduction in the ratio of forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) and %FEV1 and with the elevation of the prevalence of FEV1/FVC < 70%. We also confirmed that the polymorphism was associated with a decreased respiratory function in relation to a decrease in the ratio of high-molecular-weight adiponectin/total adiponectin (as a marker of adiponectin multimerization) and an increase in the oxidized human serum albumin (as an oxidative stress marker). Furthermore, we clarified that DsbA-L knock-down induced oxidative stress and up-regulated the mucus production in human airway epithelial cells. These findings suggest that the DsbA-L gene may play a role in protecting the respiratory function of the elderly, possibly via increased systemic adiponectin functions secreted from adipocytes or through systemic and/or local pulmonary antioxidant properties

Discovery of a good responder subtype of esophageal squamous cell carcinoma with cytotoxic T-lymphocyte signatures activated by chemoradiotherapy

Definitive chemoradiotherapy (CRT) is a less invasive therapy for esophageal squamous cell carcinoma (ESCC). Five-year survival rate of locally advanced ESCC patients by definitive CRT were 37%. We previously reported that tumor-specific cytotoxic T-lymphocyte (CTL) activation signatures were preferentially found in long-Term survivors. However, it is unknown whether the CTL activation is actually driven by CRT. We compared gene expression profiles among pre-and post-Treatment biopsy specimens of 30 ESCC patients and 121 pre-Treatment ESCC biopsy specimens. In the complete response (CR) cases, 999 overexpressed genes including at least 234 tumor-specific CTL-Activation associated genes such as IFNG, PRF1, and GZMB, were found in post-Treatment biopsy specimens. Clustering analysis using expression profiles of these 234 genes allowed us to distinguish the immune-Activated cases, designating them as I-Type, from other cases. However, despite the better CR rate in the I-Type, overall survival was not significantly better in both these 30 cases and another 121 cases. Further comparative study identified a series of epithelial to mesenchymal transition-related genes overexpressed in the early relapse cases. Importantly, the clinical outcome of CDH2-negative cases in the I-Type was significantly better than that of the CDH2-positive cases in the I-Type. Furthermore, NK cells, which were activated by neutrophils-producing S100A8/S100A9, and CTLs were suggested tocooperatively enhance the effect of CRT in the CDH2-negative I-Type. These results suggested that CTL gene activation may provide a prognostic advantage in ESCCs with epithelial characteristics

Unsupervised clustering analysis with expression data of the processed 2,854 genes in the 60 ESCC samples treated with definitive CRT.

<p>Expression data in all of the 60 samples (A: 30 pre-treatment biopsy samples, B: 30 post-treatment biopsy samples) were analyzed by the Cluster and Treeview programs. Three patient clusters (box) were identified. Among them, one cluster (red) was a good responder with 73% CR.</p

Supervised clustering analysis with expression data of the 999 genes induced by CRT in a good responder cluster.

<p>(A) In accordance with the unsupervised clustering analysis with expression data of the processed 2,854 genes, the dendrograms reproducibly showed the presence of a good responder cluster (CR: 56% and 68%) in both pre- and post- treatment samples. (B) Comparison of immune-related gene expression levels between pre- and post- treatment samples. Key genes (<i>PRF1</i>, <i>GZMB</i>, <i>IFNG</i>, <i>CASPs</i>, <i>TNFs</i>) for the CTL activation, which were included in 234 immune-related genes of the above 999 genes, were upregulated in post-treatment samples especially with CR cases. Pre-treatment samples (blue), post-treatment samples (red). CR: cases with complete response, non CR: cases with non CR (partial response, PR). * <i>p</i><0.05, **<i>p</i><0.01, ***<i>p</i><0.001.</p

Overall survival in the I-type cases and non I-type cases in 117 cases of the second cohort.

<p>The I-type cases did not show better overall survival in both all of the 117 cases (A) and the 59 CR cases (B).</p

Overall survival in the <i>CDH2</i>-negative epithelial-type cases and <i>CDH2</i>-positive mesenchymal-type cases in 117 cases of the second cohort.

<p>(A) In all of the 117 cases, 82 <i>CDH2</i>-negative cases showed better overall survival (OS) compared with 35 <i>CDH2</i>-positive cases (56% vs 21% in 5 year OS rate). (B) Especially, in 33 I-type cases, 15 <i>CDH2</i>-negative cases showed much better OS compared with 18 <i>CDH2</i>-positive cases (64% vs 12% in 5 year OS rate). (C) In 84 non I-type cases, 67 <i>CDH2</i>-negative cases showed better OS compared with 17 <i>CDH2</i>-positive cases (54% vs 31% in 5 year OS rate).</p

Supervised clustering analysis with expression data of the 234 immune-related genes in the 60 ESCC samples.

<p>In accordance with supervised clustering analyses with expression data of the 999 genes (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0143804#pone.0143804.g001" target="_blank">Fig 1A</a>), the dendrograms reproducibly showed the presence of a good responder cluster (CR: 56% and 68%) in each pre- and post- treatment samples. We designated the immune-activated ESCC subtype as I-type. </p