Translational research : the journal of laboratory and clinical medicine
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Despite significant investments in basic science by the US National Institutes of Health, there is a concern that the return on this investment has been limited in terms of clinical utility. In the field of biomarkers, translational research is used to bridge the gap between the results of basic research that identify biomolecules involved in or the consequence of carcinogenesis and their incorporation into medical application. ⋯ The field of biomarker research requires extensive interactions between academic researchers and industrial developers, and clinicians are needed to help shape the research direction that can be addressed only by a multidisciplinary, multi-institutional approach. In this article, we provide our perspective on the relatively slow pace of cancer biomarker translation, especially those for early detection and screening.
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The approach to molecular genetic studies of complex phenotypes evolved considerably during the recent years. The candidate gene approach, which is restricted to an analysis of a few single-nucleotide polymorphisms (SNPs) in a modest number of cases and controls, has been supplanted by the unbiased approach of genome-wide association studies (GWAS), wherein a large number of tagger SNPs are typed in many individuals. GWAS, which are designed on the common disease-common variant hypothesis (CD-CV), identified several SNPs and loci for complex phenotypes. ⋯ Robust phenotyping and large-scale sequencing studies are essential to extract the information content of the vast number of DNA sequence variants (DSVs) in the genome. To garner meaningful clinical information and link the genotype to a phenotype, the identification and characterization of a large number of causal fields beyond the information content of DNA sequence variants would be necessary. This review provides an update on the current progress and limitations in identifying DSVs that are associated with phenotypic effects.
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MicroRNAs (miRNAs) are a class of small RNAs that regulate gene expression. Expression profiles of specific miRNAs have improved cancer diagnosis and classification as well as provided prognostic information in many human cancers, including lung cancer. Tumor-suppressive and oncogenic miRNAs were uncovered in lung carcinogenesis. ⋯ Tumor-suppressive and oncogenic miRNAs that were identified in lung cancer will be reviewed here. Emphasis is placed on highlighting those functionally validated miRNAs that are not only biomarkers of lung carcinogenesis but also candidate pharmacologic targets. How these miRNA findings advance an understanding of lung cancer biology and how they could improve lung cancer therapy are discussed in this article.
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In this review, we describe the recent advances in the understanding of the role of microRNAs in idiopathic pulmonary fibrosis (IPF), a chronic progressive and lethal fibrotic lung disease. Approximately 10% of the microRNAs are significantly changed in IPF lungs. Among the significantly downregulated microRNAs are members of let-7, mir-29, and mir-30 families as well as miR-17∼92 cluster among the upregulated mir-155 and mir-21. ⋯ As a result, their aberrant expression leads to a release of inhibitions on the TGFβ1 pathway and to the creation of feed-forward loops. Coanalysis of published microRNA and gene expression microarray data in IPF reveals enrichment of the TGFβ1, Wnt, sonic hedgehog, p53, and vascular endothelial growth factor pathways and complex regulatory networks. The changes in microRNA expression in the IPF lung and the evidence for their role in the fibrosis suggest that microRNAs should be evaluated as therapeutic targets in IPF.
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Acute lung injury (ALI), including the ventilator-induced lung injury (VILI) and the more severe acute respiratory distress syndrome (ARDS), are common and complex inflammatory lung diseases potentially affected by various genetic and nongenetic factors. Using the candidate gene approach, genetic variants associated with immune response and inflammatory pathways have been identified and implicated in ALI. Because gene expression is an intermediate phenotype that resides between the DNA sequence variation and the higher level cellular or whole-body phenotypes, the illustration of gene expression regulatory networks potentially could enhance understanding of disease susceptibility and the development of inflammatory lung syndromes. ⋯ Therefore, via regulation of target genes in these biological processes and pathways, miRNAs potentially contribute to the development of ALI. Although this line of inquiry exists at a nascent stage, miRNAs have the potential to be critical components of a comprehensive model for inflammatory lung disease built by a systems biology approach that integrates genetic, genomic, proteomic, epigenetic as well as environmental stimuli information. Given their particularly recognized role in regulation of immune and inflammatory responses, miRNAs also serve as novel therapeutic targets and biomarkers for ALI/ARDS or VILI, thus facilitating the realization of personalized medicine for individuals with acute inflammatory lung disease.