Fibroblast growth factor-21 (FGF21) is a hormone secreted by the liver during fasting that elicits diverse aspects of the adaptive starvation response. Among its effects, FGF21 induces hepatic fatty acid oxidation and ketogenesis, increases insulin sensitivity, blocks somatic growth and causes bone loss. Here we show that transgenic overexpression of FGF21 markedly extends lifespan in mice without reducing food intake or affecting markers of NAD+ metabolism or AMP kinase and mTOR signaling. Transcriptomic analysis suggests that FGF21 acts primarily by blunting the growth hormone/insulin-like growth factor-1 signaling pathway in liver. These findings raise the possibility that FGF21 can be used to extend lifespan in other species.
<div>Abstract<p>Cytoglobin (<i>CYGB)</i> is a recently discovered vertebrate globin distantly related to myoglobin with unknown function. <i>CYGB</i> is assigned to chromosomal region 17q25, which is frequently lost in multiple malignancies. Previous studies failed to detect evidence for mutations in the <i>CYGB</i> gene. Recent studies provided preliminary evidence for increased methylation of the gene in lung cancer. Our study was aimed at investigating the role of <i>CYGB</i> as a tumor suppressor gene. By nested methylation-specific DNA sequencing analysis of lung and breast cancer cell lines and bronchial and mammary epithelial cell lines, we identified that methylation of a 110-bp CpG-rich segment of the <i>CYGB</i> promoter was correlated with gene silencing. We specifically targeted this sequence and developed a quantitative methylation-specific PCR assay, suitable for high-throughput analysis. We showed that the tumor specificity of <i>CYGB</i> methylation in discriminating patients with and without lung cancer, using biopsies and sputum samples. We further showed the tumor specificity of this assay with multiple other epithelial and hematologic malignancies. To show tumor suppressor activity of <i>CYGB</i>, we performed the following: (<i>a</i>) RNA interference–mediated knockdown of <i>CYGB</i> gene on colony formation in a <i>CYGB</i> expression–positive lung cancer cell line, resulting in increased colony formation; (<i>b</i>) enforced gene expression in <i>CYGB</i> expression–negative lung and breast cancer cell lines, reducing colony formation; and (<i>c</i>) identification of potential proximate targets down-stream of the <i>CYGB</i> genes. Our data constitute the first direct functional evidence for <i>CYGB</i>, the newest member of the globin family, as a tumor suppressor gene. [Cancer Res 2008;68(18):7448–56]</p></div>
Background Non-small cell lung cancer (NSCLC) represents the majority (85%) of lung cancers and is comprised mainly of adenocarcinomas and squamous cell carcinomas (SCCs). The sequential pathogenesis of lung adenocarcinomas and SCCs occurs through dissimilar phases as the former tumors typically arise in the lung periphery whereas the latter normally arise near the central airway. Methodology/Principal Findings We assessed the expression of SOX2, an embryonic stem cell transcriptional factor that also plays important roles in the proliferation of basal tracheal cells and whose expression is restricted to the main and central airways and bronchioles of the developing and adult mouse lung, in NSCLC by various methodologies. Here, we found that SOX2 mRNA levels, from various published datasets, were significantly elevated in lung SCCs compared to adenocarcinomas (all p<0.001). Moreover, a previously characterized OCT4/SOX2/NANOG signature effectively separated lung SCCs from adenocarcinomas in two independent publicly available datasets which correlated with increased SOX2 mRNA in SCCs. Immunohistochemical analysis of various histological lung tissue specimens demonstrated marked nuclear SOX2 protein expression in all normal bronchial epithelia, alveolar bronchiolization structures and premalignant lesions in SCC development (hyperplasia, dysplasia and carcinoma in situ) and absence of expression in all normal alveoli and atypical adenomatous hyperplasias. Moreover, SOX2 protein expression was greatly higher in lung SCCs compared to adenocarcinomas following analyses in two independent large TMA sets (TMA set I, n = 287; TMA set II, n = 511 both p<0.001). Furthermore, amplification of SOX2 DNA was detected in 20% of lung SCCs tested (n = 40) and in none of the adenocarcinomas (n = 17). Conclusions/Significance Our findings highlight a cell-lineage gene expression pattern for the stem cell transcriptional factor SOX2 in the pathogenesis of lung SCCs and suggest a differential activation of stem cell-related pathways between squamous cell carcinomas and adenocarcinomas of the lung.
Supplementary Figures 1-3, Tables 1-3 from Steroid Receptor Coactivator-3 Expression in Lung Cancer and Its Role in the Regulation of Cancer Cell Survival and Proliferation
Background: Current treatment guidelines for stage IV non-small cell lung cancer (NSCLC) with brain metastases recommend brain treatments, including surgical resection and radiotherapy (RT), in addition to resection of the primary lung tumor. Here, we investigate the less-studied impact of treatment sequence on the overall survival. Methods: The National Cancer Database was queried for NSCLC patients with brain metastases who underwent surgical resection of the primary lung tumor (n = 776). Kaplan-Meier survival curves with log-rank test and propensity score stratified Cox regression with Wald test were used to evaluate the associations between various treatment plans and overall survival (OS). Results: Compared to patients who did not receive any brain treatment (median OS = 6.05 months), significantly better survival was observed for those who received brain surgery plus RT (median OS = 26.25 months, p < 0.0001) and for those who received brain RT alone (median OS = 14.49 months, p < 0.001). Patients who received one upfront brain treatment (surgery or RT) before lung surgery were associated with better survival than those who received lung surgery first (p < 0.05). The best survival outcome (median OS 27.1 months) was associated with the sequence of brain surgery plus postoperative brain RT followed by lung surgery. Conclusions: This study shows the value of performing upfront brain treatments followed by primary lung tumor resection for NSCLC patients with brain metastases, especially the procedure of brain surgery plus postoperative brain RT followed by lung surgery.
Background: The effectiveness of breathing exercises in the treatment of chronic obstructive pulmonary disease (COPD) has been demonstrated in several systematic reviews (SRs), but a comprehensive review is still lacking. The aim of this study was to synthesize evidence from SRs, to summarise the effects of breathing exercises interventions for COPD patients. Methods: We conducted an overview of the SRs of breathing exercises in the treatment of COPD. We include Systematic Reviews of randomized-controlled clinical trials. In the included COPD, control of breathing exercises alone was the only variable and no restriction was placed on relevant outcome measures. The SRs were screened by computer retrieval from the Chinese National Knowledge Infrastructure (CNKI), WanFang database, Chinese Science and Technology Journal Database (CSTJ), Chinese Biological Medicine (CBM), MEDLINE (PubMed), Embase, Cochrane library, and Web of Science. The Risk of Bias in Systematic reviews (ROBIS) tool, the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement, a Measure Tool to Assess Systematic Reviews (AMSTAR) 2, and the Grades of Recommendations, Assessment, Development and Evaluation (GRADE) were used to evaluate the risk of bias, reporting quality, methodology quality, and evidence quality. Results: Nine SRs met the inclusion criteria and were included in the overview, 4 SRs in Chinese, and 3 SRs in English. All the SRs were published between 2015– 2021. According to the ROBIS tool, 4 SRs (57.14%) were rated as low risk of bias. The PRISMA scale showed that 5 SRs had some defects, and 2 SRs were relatively complete. Reporting deficiencies exist primarily in protocol and registration (28.6%), search (42.9%), risk of bias across studies (0%), additional analyses (42.9%), and funding (28.6%). Based on the AMSTAR-2 scale, 3 SRs were low quality, and the other 4 SRs were very low. The result of evidence quality assessment showed that among the 34 outcomes involved in the 7 studies, 19 were low-level outcomes, 15 were very low-level outcomes, and there were no moderate and high-level quality outcomes. Limitations and publication bias were two major factors that reduced the quality of evidence. Conclusion: Breathing exercises in certain can improve pulmonary function, exercise endurance, dyspnea, quality of life, and respiratory muscle strength of COPD patients. However, there is an urgent need for high-quality studies to guide clinical practice due to certain deficiencies in reporting quality and the low quality of methodology and outcomes. Keywords: breathing exercises, chronic obstructive pulmonary disease, overview, systematic reviews
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