Integrated Analyses of Copy Number Variations and Gene Expression in Lung Adenocarcinoma

Numerous efforts have been made to elucidate the etiology and improve the treatment of lung cancer, but the overall five-year survival rate is still only 15%. Identification of prognostic biomarkers for lung cancer using gene expression microarrays poses a major challenge in that very few overlapping genes have been reported among different studies. To address this issue, we have performed concurrent genome-wide analyses of copy number variation and gene expression to identify genes reproducibly associated with tumorigenesis and survival in non-smoking female lung adenocarcinoma. The genomic landscape of frequent copy number variable regions (CNVRs) in at least 30% of samples was revealed, and their aberration patterns were highly similar to several studies reported previously. Further statistical analysis for genes located in the CNVRs identified 475 genes differentially expressed between tumor and normal tissues (p<10−5). We demonstrated the reproducibility of these genes in another lung cancer study (p = 0.0034, Fisher's exact test), and showed the concordance between copy number variations and gene expression changes by elevated Pearson correlation coefficients. Pathway analysis revealed two major dysregulated functions in lung tumorigenesis: survival regulation via AKT signaling and cytoskeleton reorganization. Further validation of these enriched pathways using three independent cohorts demonstrated effective prediction of survival. In conclusion, by integrating gene expression profiles and copy number variations, we identified genes/pathways that may serve as prognostic biomarkers for lung tumorigenesis

The role of peptides in bone healing and regeneration: A systematic review

Background: Bone tissue engineering and the research surrounding peptides has expanded significantly over the last few decades. Several peptides have been shown to support and stimulate the bone healing response and have been proposed as therapeutic vehicles for clinical use. The aim of this comprehensive review is to present the clinical and experimental studies analysing the potential role of peptides for bone healing and bone regeneration. Methods: A systematic review according to PRISMA guidelines was conducted. Articles presenting peptides capable of exerting an upregulatory effect on osteoprogenitor cells and bone healing were included in the study. Results: Based on the available literature, a significant amount of experimental in vitro and in vivo evidence exists. Several peptides were found to upregulate the bone healing response in experimental models and could act as potential candidates for future clinical applications. However, from the available peptides that reached the level of clinical trials, the presented results are limited. Conclusion: Further research is desirable to shed more light into the processes governing the osteoprogenitor cellular responses. With further advances in the field of biomimetic materials and scaffolds, new treatment modalities for bone repair will emerge

Use and efficacy of bone morphogenetic proteins in fracture healing

Signal transduction in aging related disease

The effect of application time of two types of bone cement on the cement-bone interface strength.

The aim of this study was to investigate whether the application time of bone cement would have an effect on the cement-bone interface strength in two types of commercially available bone cements. CMW1 Radiopaque(®) (CMW1) and SmartSetHV(®) (SmartSet) were applied to bovine cancellous bone specimens at 2 and at 4 min. Specimens were loaded to failure and the shear strength of the cement-bone interface was calculated. The mean shear strength (±standard deviation) of the cement-bone interface was 2.79 ± 1.29 MPa for CMW1 applied at 2 min; 1.35 ± 0.89 MPa for CMW1 applied at 4 min; 2.93 ± 1.21 MPa for SmartSet applied at 2 min and 3.00 ± 1.11 MPa for SmartSet applied at 4 min. Compared to all other groups, the cement-bone interface strength was significantly lower when CMW1 was applied to the bone specimens at 4 min (p < 0.05). There was no significant difference in the cement-bone interface strength when SmartSet was applied to bone at 2 and at 4 min. Under these testing conditions, the cement-bone interface strength was not affected by the time of application of SmartSet to bone. However, it was significantly lower when CMW1 was applied to bone at 4 min

Microsatellite instability and loss of heterozygosity at the MEN1 locus in lung carcinoid tumors: A novel approach using real-time PCR with melting curve analysis in histopathologic material

The possible causes and genetic mechanisms of pulmonary carcinoid tumor development are unclear. In this study, we examined genetic alterations at the MEN1 locus in archival material from 15 pulmonary carcinoids. We employed, for the first time in this setting, real-time PCR with melting curve analysis in order to identify loss of heterozygosity (LOH) or microsatellite instability (MI) in two polymorphic markers (PYGM, D11S449) at the MEN1 locus and one additional marker (D11S906) of a putative oncosuppressive region distal to the MEN1 gene. Sequencing data were available in a selected subset of tumors in order to verify the reliability of real-time PCR analysis. We observed LOH at PYGM in 38% of the cases and MI in 13.3% of the cases. Our data indicate that real-time PCR with melting curve analysis is a reliable technique for LOH and MI detection and indicate that genetic errors at the MEN1 locus but also distal to it may be involved in the development of sporadic pulmonary carcinoid tumors

hMSH2 and hMLH1 gene expression patterns differ between lung adenocarcinoma and squamous cell carcinoma: correlation with patient survival and response to adjuvant chemotherapy treatment

Background: We recently showed that the mRNA levels of mismatch repair (MMR) proteins in non-small cell lung carcinoma (NSCLC) tissue specimens and the phenotypic translation of molecular MMR data refines the biology of the MMR system with consequent diagnostic implications in the clinical assessment of lung cancer patients. Methods: hMLH1 and hMSH2 mRNA expression was previously evaluated by qPCR for 29 NSCLC patients (13 with squamous cell carcinoma [SQC] and 16 with adenocarcinoma [ADC]) and MMR mRNA levels were converted into clinically distinct phenotypic entities. In this study, we evaluated the correlation of the hMSH2 and hMLH1 mRNA phenotypes with patient survival and their response to adjuvant chemotherapy. Results: hMSH2 and hMLH1 mRNA phenotypic distribution differed between SQC and ADC. The MMR phenotypes differed also between advanced and early stage SQC. SQC patients with an increased hMSH2 expression had a better outcome than patients with a reduced hMSH2 expression. However, ADC patients with an increased hMSH2 expression had a poor outcome compared to those with low hMSH2 levels. SQC patients with a high hMSH2 expression exhibited a better response to adjuvant chemotherapy, whereas ADC patients with high hMSH2 levels had a poor response. ADC patients with low hMSH2 levels showed good response to adjuvant chemotherapy compared to SQC patients bearing the same phenotypic profile. Conclusions: Our findings show that MMR mRNA phenotypes may be added to the known biological differences between SQC and ADC. hMLH1 and hMSH2 phenotypes distributed differently according to the NSCLC stage. Distinct MMR mRNA phenotypes in SQC and ADC corresponded to patient response to adjuvant chemotherapy

Phenotypic mismatch repair hMSH2 and hMLH1 gene expression profiles in primary non-small cell lung carcinomas

Background: Defects in the human DNA mismatch repair genes (MMR) hMSH2 and hMLH1 arc responsible for the development of sporadic and hereditary colorectal cancers. The role of MMR genes in the pathogenesis of lung cancer has not been elucidated. The aim of this study was to address the phenotypic mRNA expression profiles of mismatch DNA repair system in lung cancer. Materials and methods: We evaluated the mRNA levels of the hMSH2 and hMLH1 components of the mismatch DNA repair (MMR) system in 29 unselected frozen pairs of primary non-small cell lung carcinomas (NSCLCs) and their adjacent normal tissue (ANTs) specimens by quantitative real-time PCR analysis relative to housekeeping Porphobilinogen deaminase (hPBGD) mRNA. To simplify and potentially improve the analysis of data, we defined for each individual MMR mRNA two possible phenotypes: a regular (R(2): hMSH2/hPBGD mRNAs >= 1 and R(1): hMLH1/hPBGD mRNAs >= 1) and a reduced (r(2): hMSH2/hPBGD mRNAs < 1 and r(1): hMLH1/hPBGD mRNAs < 1). The presence of MMR gene expression was evaluated after conversion of the molecular mRNA levels into clinically distinct phenotypic entities by these working criteria, based on the hypothesis that reduced mRNA and protein levels result in lower or non-functional MMR. Results: Phenotyping defined four distinct MMR system expression profiles, R(2)R(1), r(2)R(1), R(2)r(1) and r(2)r(1) by ascending tumor progression rate and identified a previously unrecognized disease-associated phenotypic entity (r(2)r(1)). The phenotype-based biological aspects of the MMR system suggested that its two components: (1) function independently and (2) are not directly involved in the onset of the transformation process, since healthy lung tissue was devoid of r(2)r(1) phenotypes. Conclusion: These findings link MMR mRNA levels of paired lung tissue specimens to patients' clinical condition and suggest that phenotypic translation of molecular MMR data refines the biology of the MMR system with consequent diagnostic implications in the clinical assessment of lung cancer patients. (C) 2008 Elsevier Ireland Ltd. All rights reserved