How to Get the Most from Microarray Data: Advice from Reverse Genomics

Whole-genome profiling of gene expression is a powerful tool for identifying cancer-associated genes. Genes differentially expressed between normal and tumorous tissues are usually considered to be cancer associated. We recently demonstrated that the analysis of interindividual variation in gene expression can be useful for identifying cancer associated genes. The goal of this study was to identify the best microarray data–derived predictor of known cancer associated genes. We found that the traditional approach of identifying cancer genes—identifying differentially expressed genes—is not very efficient. The analysis of interindividual variation of gene expression in tumor samples identifies cancer-associated genes more effectively. The results were consistent across 4 major types of cancer: breast, colorectal, lung, and prostate. We used recently reported cancer-associated genes (2011–2012) for validation and found that novel cancer-associated genes can be best identified by elevated variance of the gene expression in tumor samples

Heterogeneous nuclear ribonucleoprotein (hnRNP) L promotes DNA damage-induced cell apoptosis by enhancing the translation of p53

The tumor suppressor p53 is an essential gene in the induction of cell cycle arrest, DNA repair, and apoptosis. p53 protein is induced under cellular stress, blocking cell cycle progression and inducing DNA repair. Under DNA damage conditions, it has been reported that post-transcriptional regulation of p53 mRNA contributes to the increase in p53 protein level. Here we demonstrate that heterogeneous nuclear ribonucleoprotein (hnRNP) L enhances p53 mRNA translation. We found that hnRNP L is increased and binds to the 5' UTR of p53 mRNA in response to DNA damage. Increased hnRNP L caused enhancement of p53 mRNA translation. Conversely, p53 protein levels were decreased following hnRNP L knock-down, rendering them resistant to apoptosis and arrest in the G2/M phase after DNA damage. Thus, our findings suggest that hnRNP L functions as a positive regulator of p53 translation and promotes cell cycle arrest and apoptosis.11Ysciescopu

A scientometric study of the limnological societies: inferences of research collaboration and core topics based on publication networks

Scientometric analysis of limnological societies and related publications revealed complex relationships among research topics and research collaborations. We applied scientometric analysis, word networks, bibliographic coupling, and author networks analysis, to 34 777 publications related to limnology and monsoon research. We analyzed usage frequencies of limnology-related words in a Google corpus and found that usage frequencies of most limnological terms peaked during the 1980s. Social interest in the term “limnology” showed a gradually decreasing trend after the late 1990s. Monsoon research was focused in the Asian–Indian region but not in the European, African, and American regions. Word networks of limnological studies related to monsoons were mainly grouped into 3 clusters (Indian monsoons, East Asian monsoons, and monsoon assessment clusters). In the citation network of limnology journals, water quality, plankton, and invertebrate research groups generally showed strong internal citation networks. An author connection map of the limnological societies revealed strong modulators in the international societies, whereas research collaboration was rather limited to small groups within the entire network. This retrospective analysis will provide meaningful information to further develop and enhance international collaboration within limnological studies

Development of a Spirometry \u3cem\u3eT\u3c/em\u3e-score in the General Population

Background and objective: Spirometry values may be expressed as T-scores in standard deviation units relative to a reference in a young, normal population as an analogy to the T-score for bone mineral density. This study was performed to develop the spirometry T-score. Methods: T-scores were calculated from lambda-mu-sigma-derived Z-scores using a young, normal age reference. Three outcomes of all-cause death, respiratory death, and COPD death were evaluated in 9,101 US subjects followed for 10 years; an outcome of COPD-related health care utilization (COPD utilization) was evaluated in 1,894 Korean subjects followed for 4 years. Results: The probability of all-cause death appeared to remain nearly zero until -1 of forced expiratory volume in 1 second (FEV1) T-score but increased steeply where FEV1 T-score reached below -2.5. Survival curves for all-cause death, respiratory death, COPD death, and COPD utilization differed significantly among the groups when stratified by FEV1 T-score (P \u3c 0.001). The adjusted hazard ratios of the FEV1 T-score for the four outcomes were 0.54 (95% confidence interval, 0.48–0.60), 0.43 (95% CI: 0.37–0.50), 0.30 (95% CI: 0.24–0.37), and 0.69 (95% CI: 0.59–0.81), respectively, adjusting for covariates (P \u3c 0.001). Conclusion: The spirometry T-score could predict all-cause death, respiratory death, COPD death, and COPD utilization

Favorable response to doxorubicin combination chemotherapy does not yield good clinical outcome in patients with metastatic breast cancer with triple-negative phenotype

<p>Abstract</p> <p>Background</p> <p>We analyzed the responses to first line treatment and clinical outcomes of metastatic breast cancer patients treated with palliative doxorubicin/cyclophosphamide (AC) according to molecular cancer subtype.</p> <p>Methods</p> <p>A retrospective analysis was performed for 110 metastatic breast cancer patients selected on the basis of palliative AC treatment and the availability of immunohistochemical data for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER-2/neu) status.</p> <p>Results</p> <p>Of the 110 patients analyzed, 71 (64.5%) were hormone receptor positive (HR+), 14 (12.7%) were HER2+, and 25 (22.7%) were triple negative (TN). There were no differences in age, stage at diagnosis, total number of cycles of palliative chemotherapy, incidence of visceral metastasis, and metastatic sites with the exception of liver among breast cancer subtypes. The overall response rates to AC were 55.9% for the HR+ subgroup, 42.9% for the HER2+ subgroup, and 56.5% for the TN subgroup. The progression-free survival (PFS) in patients with HER2+ and TN were significantly shorter than in the HR+ (median PFS, 9.1 <it>vs </it>8.1 <it>vs </it>11.5 months, respectively; p = 0.0002). The overall survival (OS) was 25.4 months in the TN subgroup and 27.3 months in HER2+ subgroup. The median OS for these two groups was significantly shorter than for patients in the HR+ subgroup (median, 38.5 months; 95% CI, 30.1-46.9 months; p < 0.0001).</p> <p>Conclusions</p> <p>The response to palliative AC chemotherapy did not differ among breast cancer subtypes. Despite chemosensitivity for palliative AC, the TN subtype has a shorter overall survival than non-TN subtypes. Innovative treatment strategies should be developed to slow the course of disease.</p

Pyruvate Dehydrogenase Kinase 4 Promotes Vascular Calcification via SMAD1/5/8 Phosphorylation

Vascular calcification, a pathologic response to defective calcium and phosphate homeostasis, is strongly associated with cardiovascular mortality and morbidity. In this study, we have observed that pyruvate dehydrogenase kinase 4 (PDK4) is upregulated and pyruvate dehydrogenase complex phosphorylation is increased in calcifying vascular smooth muscle cells (VSMCs) and in calcified vessels of patients with atherosclerosis, suggesting that PDK4 plays an important role in vascular calcification. Both genetic and pharmacological inhibition of PDK4 ameliorated the calcification in phosphate-treated VSMCs and aortic rings and in vitamin D3-treated mice. PDK4 augmented the osteogenic differentiation of VSMCs by phosphorylating SMAD1/5/8 via direct interaction, which enhances BMP2 signaling. Furthermore, increased expression of PDK4 in phosphate-treated VSMCs induced mitochondrial dysfunction followed by apoptosis. Taken together, our results show that upregulation of PDK4 promotes vascular calcification by increasing osteogenic markers with no adverse effect on bone formation, demonstrating that PDK4 is a therapeutic target for vascular calcification