No abstract

MicroRNA (miRNA) expression is frequently altered in human cancers. To search for epigenetically silenced miRNAs in nonsmall-cell lung cancer (NSCLC), we mapped human miRNAs on autosomal chromosomes and selected 55 miRNAs in silico. We treated six NSCLC cell lines with the DNA methylation inhibitor 5-aza-2 0 -deoxycytidine (5-aza-CdR) and determined the expressions of the 55 miRNAs. Fourteen miRNAs were decreased in the cancer cell lines and were induced after 5-aza-CdR treatment. After a detailed DNA methylation analysis, we found that mir-34b and mir-126 were silenced by DNA methylation. Mir-34b was silenced by the DNA methylation of its own promoter, whereas mir-126 was silenced by the DNA methylation of its host gene, EGFL7. A chromatin immunoprecipitation assay revealed H3K9me2 and H3K9me3 in mir-34b and EGFL7, and H3K27me3 in EGFL7. The overexpression of mir-34b and mir-126 decreased the expression of c-Met and Crk, respectively. The 5-aza-CdR treatment of lung cancer cell line resulted in increased mir-34b expression and decreased c-Met protein. We next analyzed the DNA methylation status of these miRNAs using 99 primary NSCLCs. Mir-34b and mir-126 were methylated in 41 and 7% of all the cases, respectively. The DNA methylation of mir-34b was not associated with c-Met expression determined by immunohistochemistry, but both mir-34b methylation (p 5 0.007) and c-Met expression (p 5 0.005) were significantly associated with lymphatic invasion in a multivariate analysis. The DNA methylation of mir-34b can be used as a biomarker for an invasive phenotype of lung cancer.MicroRNAs (miRNAs) are broadly conserved small noncoding RNA that regulate gene expression by binding to the 3 0 UTR of target mRNAs in a complementary manner. 1Through the posttranscriptional regulation of many target genes, miRNAs are involved in many biological processes, such as development and human carcinogenesis. MicroRNA expression is altered in human cancers, and some miRNAs have oncogenic or tumor suppressive functions in human malignancies, including lung cancer. 2-5Chromosomal deletions or amplifications are important mechanisms of miRNA expression change in cancers. For example, mir-15 and mir-16 are frequently deleted and downregulated in chronic lymphocytic leukemia.2 The mir-17-92 miRNA cluster is amplified and overexpressed in B-cell lymphoma 6 and lung cancer. 4 However, the precise mechanisms responsible for changes in miRNA expression in cancer remain largely unknown.DNA methylation plays an important role in inactivating tumor suppressor genes in many types of human cancers. 7,8 Recently, DNA methylation in cancerous tissue has been shown to cause the silencing of miRNAs located in the vicinity of CpG islands. 9,10 As the epigenetic silencing of tumor suppressor genes is a common event in lung carcinogenesis 11-14 and miRNA expression is altered in lung cancer, 5 we decided to search for epigenetically silenced miRNAs in lung cancer.In our study, we selected 55 candidate miRNAs in silico based on the genome structure and tre...

Patients with short bowel syndrome lack sufficient functional intestine to sustain themselves with enteral intake alone. Transplantable vascularized bioengineered intestine could restore nutrient absorption. Here we report the engineering of humanized intestinal grafts by repopulating decellularized rat intestinal matrix with human induced pluripotent stem cell-derived intestinal epithelium and human endothelium. After 28 days of in vitro culture, hiPSC-derived progenitor cells differentiate into a monolayer of polarized intestinal epithelium. Human endothelial cells seeded via native vasculature restore perfusability. Ex vivo isolated perfusion testing confirms transfer of glucose and medium-chain fatty acids from lumen to venous effluent. Four weeks after transplantation to RNU rats, grafts show survival and maturation of regenerated epithelium. Systemic venous sampling and positron emission tomography confirm uptake of glucose and fatty acids in vivo. Bioengineering intestine on vascularized native scaffolds could bridge the gap between cell/tissue-scale regeneration and whole organ-scale technology needed to treat intestinal failure patients.

Engineering and transplantation of viable lung grafts based on decellularized porcine lung scaffolds and human endothelial and epithelial cells is technically feasible. Further graft maturation will be necessary to enable higher-level functions such as mucociliary clearance, and ventilation-perfusion matching.

A data mining method is proposed to discover association rules related to protein-protein interactions. To evaluate the detected rules by the method, a new scoring measure of the rules is introduced. The method allowed us to detect popular interaction rules such as "An SH3 domain binds to a proline-rich region." These results indicate that the method may detect novel knowledge on protein-protein interactions.

Pulmonary metastasectomy for HCC in selected patients resulted in relatively good outcomes with regard to OS. History of recurrence and serum DCP levels were shown to be candidates of prognostic factors for OS.

VATS lobectomy is less invasive than open lobectomy, but in terms of survival outcomes, VATS lobectomy was oncologically equivalent to open lobectomy. The oncological benefit of VATS reported by retrospective studies might be overestimated.

We investigated whether the CpG island methylation of certain microRNAs was associated with the clinicopathological features and the prognosis of non-small-cell lung cancer. The methylation of mir-152, -9-3, -124-1, -124-2, and -124-3 was analyzed in 96 nonsmall-cell lung cancer specimens using a combined bisulfite restriction analysis. The median observation period was 49.5 months. The methylation of mir-9-3, -124-2, and -124-3 was individually associated with an advanced T factor independent of age, sex, and smoking habit. Moreover, the methylation of multiple microRNA loci was associated with a poorer progression-free survival in a univariate analysis. Our result enlightens the accumulation of aberrant DNA methylation which occurs in concordance with the tumor progression. (Cancer Sci 2011; 102: 2126-2131 L ung cancer is the leading cause of cancer-related mortality in the world,(1) and non-small-cell lung cancer (NSCLC) is the most common type. Surgical resection remains the only curative treatment for NSCLC. Identifying factors that are associated with aggressive disease may lead to the development of novel biomarkers and the identification of therapeutic targets that can help reduce the burden of this disease.MicroRNAs (miRNAs) are a class of small non-coding RNAs that negatively regulate target gene expression by accelerating the degradation of mRNA and translational inhibition, with potentially hundreds of target mRNAs.(2) They influence a variety of cellular functions including proliferation, differentiation, and apoptosis.(3) Specific miRNAs can behave as either tumor suppressor genes or oncogenes, depending on the tissue type and the presence of specific targets. (4,5) More than 100 species of known miRNAs are embedded within or near the CpG islands of the human genome and are potentially subject to control by epigenetic alterations such as DNA methylation and histone modification. Systematic assessments of miRNA expression and epigenetic modifications among cell lines and primary tumor specimens have revealed the existence of the epigenetic regulation of miRNAs in multiple tumor types. (6)(7)(8)(9) The goals of this study were to explore possible relationships between the methylation profiles of miRNAs and the clinicopathological characteristics of NSCLC patients and to identify new specific methylation markers capable of detecting advanced pathological features.In the present study, the methylation status of five miRNA loci within five separate CpG islands was determined in 96 NSCLC tissue specimens. The choice of the miRNAs was based on our previous study (9) as well as other published reports. (10,11) Our data show that the CpG island methylation of miRNAs is common in NSCLC, and that the methylation of multiple miR-NA loci is associated with an advanced T status as well as the progression-free survival (PFS) of patients with NSCLC. Materials and MethodsPatients. We collected cancer tissues and normal lung tissues from NSCLC patients who underwent surgical resection at the University of Tokyo Hosp...