Cancer-specific functional profiling in microsatellite-unstable (MSI) colon and endometrial cancers using combined differentially expressed genes and biclustering analysis.

Microsatellite-unstable (MSI) cancers have distinct genetic and clinical features from microsatellite-stable cancers, but the molecular functional differences between MSI cancers originating from different tissues or organs have not been well studied because the application of usual differentially expressed gene (DEG) analysis is error-prone, producing too many noncancer-specific normally functioning genes. To maximize therapeutic efficacy, biomarkers reflecting cancer-specific differences between MSI cancers of different tissue origins should be identified. To identify functional differences between MSI colon and endometrial cancers, we combined DEG analysis and biclustering instead of DEG analysis alone and refined functionally relevant biclusters reflecting genuine functional differences between the 2 tumors. Specifically, using The Cancer Genome Atlas and genome-tissue expression as data sources, gene ontology (GO) enrichment tests were performed after routinely identifying DEGs between the 2 tumors with the exclusion of DEGs identified in their normal counterparts. Cancer-specific biclusters and associated enriched GO terms were obtained by biclustering with enrichment tests for the preferences for cancer type (either colon or endometrium) and GO enrichment tests for each cancer-specific bicluster, respectively. A novel childness score was developed to select functionally relevant biclusters among cancer-specific biclusters based on the extent to which the enriched GO terms of the biclusters tended to be child terms of the enriched GO terms in DEGs. The selected biclusters were tested using survival analysis to validate their clinical significance. We performed multiple sequential analyses to produce functionally relevant biclusters from the RNA sequencing data of MSI colon and endometrial cancer samples and their normal counterparts. We identified 3066 cancer-specific DEGs. Biclustering analysis revealed 153 biclusters and 41 cancer-specific biclusters were selected using Fisher exact test. A mean childness score over 0.6 was applied as the threshold and yielded 8 functionally relevant biclusters from cancer-specific biclusters. Functional differences appear to include gland cavitation and the TGF-ß receptor, G protein, and cytokine pathways. In the survival analysis, 6 of the 8 functionally relevant biclusters were statistically significant. By attenuating noise and applying a synergistic contribution of DEG results, we refined candidate biomarkers to complement tissue-specific features of MSI tumors.

STAT3 mediates RCP-induced cancer cell invasion through the NF-κB/Slug/MT1-MMP signaling cascade.

Rab coupling protein (RCP) has been known to induce cancer invasion and metastasis, and STAT3 is one of major oncogenic factors. In the present study, we identify the critical role of STAT3 in RCP-induced cancer cell invasion. Immunohistochemical data of ovarian cancer tissues presented that levels of RCP expression are closely correlated with those of phospho-STAT3 (p-STAT3). In addition, ovarian cancer patients with high expression of both RCP and p-STAT3 had significantly lower progress-free and overall survival rates compared to those with low either RCP or p-STAT3 expression. Mechanistically, RCP induced STAT3 phosphorylation in both ovarian and breast cancer cells. Silencing or pharmacological inhibition of STAT3 significantly inhibited RCP-induced cancer cell invasion. In addition, we provide evidence that the ß1 integrin/EGFR axis is important for RCP-induced STAT3 phosphorylation. Furthermore, STAT3 activated NF-κB for Slug expression that in turn upregulated MT1-MMP expression for cancer cell invasion. Collectively, our present data demonstrate that STAT3 is located downstream of the ß1 integrin/EGFR axis and induces Slug and MT1-MMP expression for cancer cell invasion.

Enhancing the landscape of colorectal cancer using targeted deep sequencing.

Targeted next-generation sequencing (NGS) technology detects specific mutations that can provide treatment opportunities for colorectal cancer (CRC) patients. We included 145 CRC patients who underwent surgery. We analyzed the mutation frequencies of common actionable genes and their association with clinicopathological characteristics and oncologic outcomes using targeted NGS. Approximately 97.9% (142) of patients showed somatic mutations. Frequent mutations were observed in TP53 (70%), APC (60%), and KRAS (49%). TP53 mutations were significantly linked to higher overall stage (p = 0.038) and lower disease-free survival (DFS) (p = 0.039). ATM mutation was significantly associated with higher tumor stage (p = 0.012) and shorter overall survival (OS) (p = 0.041). Stage 3 and 4 patients with ATM mutations (p = 0.023) had shorter OS, and FBXW7 mutation was significantly associated with shorter DFS (p = 0.002). However, the OS of patients with or without TP53, RAS, APC, PIK3CA, and SMAD4 mutations did not differ significantly (p = 0.59, 0.72, 0.059, 0.25, and 0.12, respectively). Similarly, the DFS between patients with RAS, APC, PIK3CA, and SMAD4 mutations and those with wild-type were not statistically different (p = 0.3, 0.79, 0.13, and 0.59, respectively). In multivariate Cox regression analysis, ATM mutation was an independent biomarker for poor prognosis of OS (p = 0.043). A comprehensive analysis of the molecular markers for CRC can provide insights into the mechanisms underlying disease progression and help optimize a personalized therapy.

Mutation Analysis of Colorectal and Gastric Carcinomas Originating from Adenomas: Insights into Genomic Evolution Associated with Malignant Progression.

Small malignant tumor foci arising from benign lesions are rare but offer a unique opportunity to investigate the genomic evolution that occurs during malignant transformation. In this study, we analyzed 11 colorectal and 10 gastric adenoma-carcinoma pairs, each of which represented malignant tumors (carcinomas) embedded in benign lesions (adenomas) found in the same patient. Whole-exome sequencing revealed that mutation abundance was variable across different cases, but comparable between adenoma-carcinoma pairs. When mutations were classified as adenoma-specific, carcinoma-specific, or common, adenoma-specific mutations were more enriched with subclonal mutations than were carcinoma-specific mutations, indicative of a perturbation in mutational subclonal architecture (such as selective sweep) during malignant transformation. Among the recurrent mutations in colorectal cancers, APC and KRAS mutations were common between adenomas and carcinomas, indicative of their early occurrence during genomic evolution. TP53 mutations were often observed as adenoma-specific and therefore likely not associated with the emergence of malignant clones. Clonality-based enrichment analysis revealed that subclonal mutations of extracellular matrix genes in adenomas are more likely to be clonal in carcinomas, indicating potential roles for these genes in malignant transformation. Compared with colorectal cancers, gastric cancers showed more lesion-specific mutations than common mutations and higher levels of discordance in copy number profiles between matched adenomas and carcinomas, which may explain the elevated evolutionary dynamics and heterogeneity of gastric cancers compared to colorectal cancers. Taken together, this study demonstrates that co-existing benign and malignant lesions enable the evolution-based categorization of genomic alterations that may reveal clinically important biomarkers in colorectal and gastric cancers.

Bach2 deficiency leads autoreactive B cells to produce IgG autoantibodies and induce lupus through a T cell-dependent extrafollicular pathway.

Class-switched IgG autoantibodies but not unswitched IgM autoantibodies play a crucial role in the development of systemic lupus erythematosus (SLE). Bach2 is known to be essential for class switch recombination of Ig genes, but recent genomic and clinical studies have suggested an association of Bach2 deficiency with SLE. This study was undertaken to examine the mechanism by which Bach2 regulates the development of SLE. Despite defects in Ig class switch recombination and germinal center formation when actively immunized, Bach2-/- mice spontaneously accumulated IgG autoantibody-secreting cells without germinal center reactions in a regulatory T cell-independent manner, and this phenomenon was accompanied by manifestations akin to SLE. Transcriptome analyses revealed that Bach2 regulated the expression of genes related to germinal center formation and SLE pathogenesis in B cells. B cell-specific deletion of Bach2 was sufficient to impair the development of germinal center B cells but insufficient to promote the production of IgG autoantibodies. Bach2 deficiency caused CD4+ T cells to overexpress Icos and differentiate into extrafollicular helper T cells in a cell-autonomous manner. These findings suggest that Bach2-deficient autoreactive B cells preferentially react at extrafollicular sites to give rise to IgG class-switched pathogenic plasma cells and that this effect requires the help of Bach2-Icoshi helper T cells. Thus, the cell-autonomous roles of Bach2 in B cells and in their cognate CD4+ T cells are required to maintain self-tolerance against SLE.

Clinical MetaData ontology: a simple classification scheme for data elements of clinical data based on semantics.

BACKGROUND: The increasing use of common data elements (CDEs) in numerous research projects and clinical applications has made it imperative to create an effective classification scheme for the efficient management of these data elements. We applied high-level integrative modeling of entire clinical documents from real-world practice to create the Clinical MetaData Ontology (CMDO) for the appropriate classification and integration of CDEs that are in practical use in current clinical documents. METHODS: CMDO was developed using the General Formal Ontology method with a manual iterative process comprising five steps: (1) defining the scope of CMDO by conceptualizing its first-level terms based on an analysis of clinical-practice procedures, (2) identifying CMDO concepts for representing clinical data of general CDEs by examining how and what clinical data are generated with flows of clinical care practices, (3) assigning hierarchical relationships for CMDO concepts, (4) developing CMDO properties (e.g., synonyms, preferred terms, and definitions) for each CMDO concept, and (5) evaluating the utility of CMDO. RESULTS: We created CMDO comprising 189 concepts under the 4 first-level classes of Description, Event, Finding, and Procedure. CMDO has 256 definitions that cover the 189 CMDO concepts, with 459 synonyms for 139 (74.0%) of the concepts. All of the CDEs extracted from 6 HL7 templates, 25 clinical documents of 5 teaching hospitals, and 1 personal health record specification were successfully annotated by 41 (21.9%), 89 (47.6%), and 13 (7.0%) of the CMDO concepts, respectively. We created a CMDO Browser to facilitate navigation of the CMDO concept hierarchy and a CMDO-enabled CDE Browser for displaying the relationships between CMDO concepts and the CDEs extracted from the clinical documents that are used in current practice. CONCLUSIONS: CMDO is an ontology and classification scheme for CDEs used in clinical documents. Given the increasing use of CDEs in many studies and real-world clinical documentation, CMDO will be a useful tool for integrating numerous CDEs from different research projects and clinical documents. The CMDO Browser and CMDO-enabled CDE Browser make it easy to search, share, and reuse CDEs, and also effectively integrate and manage CDEs from different studies and clinical documents.

Low Estimated Glomerular Filtration Rate Is Prevalent among North Korean Refugees in South Korea.

BACKGROUND: The number of North Korean refugees entering South Korea is rising. Few studies have investigated the risk of non-communicable disease in North Korean refugees. Moreover, kidney insufficiency, a risk factor for cardiovascular disease, has not been studied in this population. We compared the prevalence of non-communicable disease and kidney function in North Korean refugees and South Koreans. METHODS: Our study was conducted using a case-control design. We enrolled 118 North Korean refugees from the Hana Center and selected 472 randomly sampled South Korean individuals as controls, who were age- and sex-matched with the North Korean refugees in a ratio of 1:4, from the 2014 Korea National Health and Nutrition Examination Survey database. RESULTS: The prevalence of non-communicable disease did not differ significantly between the groups; however, a low estimated glomerular filtration rate (eGFR; <90 mL/min per 1.73 m2) was more prevalent in the North Korean refugees than in the South Korean population (52.1% vs. 29.9%, P<0.001). After adjusting for covariates and weight gain after escape, the prevalence of a low eGFR was associated with the length of residence in South Korea (odds ratio, 2.84; 95% confidence interval, 1.02-7.89). CONCLUSION: The prevalence of non-communicable disease did not differ between North Korean refugees and the South Korean population, while a low eGFR was more prevalent in North Korean refugees than in South Koreans. Moreover, after adjusting for other covariates, the prevalence of a low eGFR in North Korean refugees was associated with the length of residence in South Korea.

Dissecting the relationships of IgG subclasses and complements in membranous lupus nephritis and idiopathic membranous nephropathy.

Membranous lupus nephritis (MLN) and idiopathic membranous nephropathy (IMN) are kidney diseases with similar morphology, but distinct etiologies, both producing glomeruli with immune deposits. Immunoglobulins and complements, the main components of the deposits, can be detected by immunofluorescence (IF) microscopy. Previous researches characterized the immune deposits only individually, but not the interactions between them. To study these relationships we analyzed an IF profile of IgG subclasses and complements (IgG1, IgG2, IgG3, IgG4, C3, C1q, and C4) in 53 and 95 cases of biopsy-confirmed MLNs and IMNs, respectively, mainly using information theory and Bayesian networks. We identified significant entropy differences between MLN and IMN for all markers except C3 and IgG1, but mutual information (a measure of mutual dependence) were not significantly different for all the pairs of markers. The entropy differences between MLN and IMN, therefore, were not attributable to the mutual information. These findings suggest that disease type directly and/or indirectly influences the glomerular deposits of most of IgG subclasses and complements, and that the interactions between any pair of the markers were similar between the two diseases. A Markov chain of IgG subclasses was derived from the mutual information about each pair of IgG subclass. Finally we developed an integrated disease model, consistent with the previous findings, describing the glomerular immune deposits of the IgG subclasses and complements based on a Bayesian network using the Markov chain of IgG subclasses as seed. The relationships between the markers were effectively explored by information theory and Bayesian network. Although deposits of IgG subclasses and complements depended on both disease type and the other markers, the interaction between the markers appears conserved, independent from the disease type. The disease model provided an integrated and intuitive representation of the relationships of the IgG subclasses and complements in MLN and IMN.

Clinicopathologic Correlations of E-cadherin and Prrx-1 Expression Loss in Hepatocellular Carcinoma.

BACKGROUND: Developing predictive markers for hepatocellular carcinoma (HCC) is important, because many patients experience recurrence and metastasis. Epithelial to mesenchymal transition (EMT) is a developmental process that plays an important role during embryogenesis and also during cancer metastasis. Paired-related homeobox protein 1 (Prrx-1) is an EMT inducer that has recently been introduced, and its prognostic significance in HCC is largely unknown. METHODS: Tissue microarray was constructed using surgically resected primary HCCs from 244 cases. Immunohistochemical staining of E-cadherin and Prrx-1 was performed. The correlation between E-cadherin loss and Prrx-1 expression, as well as other clinicopathologic factors, was evaluated. RESULTS: E-cadherin expression was decreased in 96 cases (39.4%). Loss of E-cadherin correlated with a higher recurrence rate (p < .001) but was not correlated with patient's survival. Thirty-two cases (13.3%) showed at least focal nuclear Prrx-1 immunoreactivity while all non-neoplastic livers (n = 22) were negative. Prrx-1 expression was not associated with E-cadherin loss, survival or recurrence rates, pathologic factors, or the Ki-67 labeling index. Twenty tumors that were positive for E-cadherin and Prrx-1 had significantly higher nuclear grades than the rest of the cohort (p = .037). In Cox proportional hazard models, E-cadherin loss and large vessel invasion were independent prognostic factors for shorter disease-free survival. Cirrhosis and high Ki-67 index (> 40%) were independent prognostic factors for shorter overall survival. CONCLUSIONS: Prrx-1 was expressed in small portions of HCCs but not in normal livers. Additional studies with a large number of Prrx-1-positive cases are required to confirm the results of this study.

MicroRNA Expression Signatures Associated With BRAF-Mutated Versus KRAS-Mutated Colorectal Cancers.

BRAF and KRAS genes are known to play a similar role in the activation of RAS-RAF-MEK-ERK signaling pathway in colorectal tumorigenesis. However, BRAF-mutated colorectal cancers (CRCs) have distinct clinicopathologic characteristics different from those of the KRAS mutated ones as in comparison the BRAF-mutated CRCs are associated with a much worse prognosis for the afflicted patients. This study aimed to determine the different miRNA expression signatures associated with BRAF-mutated CRCs in comparison to KRAS-mutated ones, and to identify the specific miRNAs possibly mediating the aggressive phenotype of the BRAF-mutated CRCs. We screened 535 formalin-fixed paraffin-embedded CRC tissue samples for the BRAF V600E mutation, and selected 7 BRAF-mutated and 7 KRAS-mutated CRCs that were tumor size, stage, and microsatellite status-matched. Affymetrix GeneChip® miRNA 4.0 Array was used for detection of miRNA expression differences in the selected samples. We validated the array results by quantitative reverse transcription polymerase chain reaction (qRT-PCR) for selected miRNAs. A total of 10 differentially expressed (DE) miRNAs associated with BRAF-mutated CRCs were obtained, including miR-31-5p, miR-877-5p, miR-362-5p, and miR-425-3p. miR-31-5p showed the highest fold change (8.3-fold) among all of the miRNAs analyzed. From the analyses of GO biological processes, the DE-miRNAs were functionally relevant to cellular proliferation such as positive regulation of gene expression (P = 1.26 × 10(-10)), transcription (P = 9.70 × 10(-10)), and RNA metabolic process (P = 1.97 × 10(-9)). Bioinformatics analysis showed that the DE-miRNAs were significantly enriched in cancer-associated pathways including neutrophin signaling (P = 6.84 × 10(-5)), pathways in cancer (P = 0.0016), Wnt signaling (P = 0.0027), and MAPK signaling pathway (P = 0.0036). Our results suggest that the DE-miRNAs in BRAF-mutated CRCs in comparison to KRAS-mutated CRCs are implicated in the aggressive phenotype of the BRAF-mutated CRCs. Further experimental validation is required to confirm these results.

Significance of the Extracapsular Spread of Metastatic Lymph Nodes in Papillary Thyroid Carcinoma.

OBJECTIVES: The extracapsular spread (ECS) of metastatic lymph nodes is associated with aggressive tumor behavior, and is regarded as a major risk factor for local recurrence in patients with head and neck squamous cell carcinoma. However, the significance of ECS of metastatic lymph nodes has not been well established in well-differentiated thyroid carcinoma. The purpose of this study was to examine this question. METHODS: A retrospective review was performed of 335 patients with papillary thyroid carcinoma who underwent total thyroidectomy with lymph node dissection from April 2001 to December 2009. We analyzed various clinical characteristics, pathologic factors, and the size, number, and ECS of foci in metastatic lymph nodes. RESULTS: On pathologic review, 201 of the patients (56.6%) had lymph node metastasis. This was significantly related to age and tumor size. ECS was noted in 64 of these 201 patients (31.8%), and was significantly related to male gender, tumor size, presence of extrathyroidal extension, metastatic lymph node size, and focus size. Recurrence occurred in 13 patients (3.9%), and the presence of ECS was significantly related to recurrence. CONCLUSION: ECS of metastatic lymph nodes is an important prognostic factor for loco-regional recurrence in papillary thyroid carcinoma.

DOT1L cooperates with the c-Myc-p300 complex to epigenetically derepress CDH1 transcription factors in breast cancer progression.

DOT1L has emerged as an anticancer target for MLL-associated leukaemias; however, its functional role in solid tumours is largely unknown. Here we identify that DOT1L cooperates with c-Myc and p300 acetyltransferase to epigenetically activate epithelial-mesenchymal transition (EMT) regulators in breast cancer progression. DOT1L recognizes SNAIL, ZEB1 and ZEB2 promoters via interacting with the c-Myc-p300 complex and facilitates lysine-79 methylation and acetylation towards histone H3, leading to the dissociation of HDAC1 and DNMT1 in the regions. The upregulation of these EMT regulators by the DOT1L-c-Myc-p300 complex enhances EMT-induced breast cancer stem cell (CSC)-like properties. Furthermore, in vivo orthotopic xenograft models show that DOT1L is required for malignant transformation of breast epithelial cells and breast tumour initiation and metastasis. Clinically, DOT1L expression is associated with poorer survival and aggressiveness of breast cancers. Collectively, we suggest that cooperative effect of DOT1L and c-Myc-p300 is critical for acquisition of aggressive phenotype of breast cancer by promoting EMT/CSC.

High MicroRNA-370 Expression Correlates with Tumor Progression and Poor Prognosis in Breast Cancer.

PURPOSE: Deregulation of microRNA-370 (miR-370) has been reported in various cancers, in which it can act as either an oncogene or a tumor suppressor gene. However, the clinicopathologic significance of miR-370 expression in breast cancer has not been studied. METHODS: The expression of miR-370 was determined with quantitative real-time polymerase chain reaction in 60 formalin-fixed, paraffin-embedded primary breast cancer tissues. Additionally, the protein expression levels of previously known targets of miR-370, such as FOXM1, FOXO1, and FOXO3a, were detected using immunohistochemistry. Finally, we analyzed its correlation with target protein expression, clinicopathologic features, and clinical outcome. RESULTS: High levels of miR-370 expression correlated with lymph node metastasis (p=0.009), advanced stage (p=0.002), and frequent perineural invasion (p=0.042). Moreover, patients with high miR-370 expression had poor disease-free survival compared with the low-expression group. However, no correlation was observed between miR-370 and its target protein expression. CONCLUSION: Our results indicate that upregulation of miR-370 in breast cancer is correlated with breast cancer progression and that it might be a potential biomarker for predicting clinical outcomes.

Tumor necrosis factor-α produced in the kidney contributes to angiotensin II-dependent hypertension.

Immune system activation contributes to the pathogenesis of hypertension and the resulting progression of chronic kidney disease. In this regard, we recently identified a role for proinflammatory Th1 T-lymphocyte responses in hypertensive kidney injury. Because Th1 cells generate interferon-γ and tumor necrosis factor-α (TNF-α), we hypothesized that interferon-γ and TNF-α propagate renal damage during hypertension induced by activation of the renin-angiotensin system. Therefore, after confirming that mice genetically deficient of Th1 immunity were protected from kidney glomerular injury despite a preserved hypertensive response, we subjected mice lacking interferon-γ or TNF-α to our model of hypertensive chronic kidney disease. Interferon deficiency had no impact on blood pressure elevation or urinary albumin excretion during chronic angiotensin II infusion. By contrast, TNF-deficient (knockout) mice had blunted hypertensive responses and reduced end-organ damage in our model. As angiotensin II-infused TNF knockout mice had exaggerated endothelial nitric oxide synthase expression in the kidney and enhanced nitric oxide bioavailability, we examined the actions of TNF-α generated from renal parenchymal cells in hypertension by transplanting wild-type or TNF knockout kidneys into wild-type recipients before the induction of hypertension. Transplant recipients lacking TNF solely in the kidney had blunted hypertensive responses to angiotensin II and augmented renal endothelial nitric oxide synthase expression, confirming a role for kidney-derived TNF-α to promote angiotensin II-induced blood pressure elevation by limiting renal nitric oxide generation.

Time-lapse electrical resistivity investigations for imaging the grouting injection in shallow subsurface cavities.

The highway of Yongweol-ri, Muan-gun, south-western part of the South Korean Peninsula, is underlain by the abandoned of subsurface cavities, which were discovered in 2005. These cavities lie at shallow depths with the range of 5∼15 meters below the ground surface. Numerous subsidence events have repeatedly occurred in the past few years, damaging infrastructure and highway. As a result of continuing subsidence issues, the Korean Institute of Geosciences and Mineral Resources (KIGAM) was requested by local administration to resolve the issue. The KIGAM used geophysical methods to delineate subsurface cavities and improve more refined understanding of the cavities network in the study area. Cement based grouting has been widely employed in the construction industry to reinforce subsurface ground. In this research work, time-lapse electrical resistivity surveys were accomplished to monitor the grouting injection in the subsurface cavities beneath the highway, which have provided a quasi-real-time monitoring for modifying the subsurface cavities related to ground reinforcement, which would be difficult with direct methods. The results obtained from time-lapse electrical resistivity technique have satisfactory imaged the grouting injection experiment in the subsurface cavities beneath the highway. Furthermore, the borehole camera confirmed the presence of grouting material in the subsurface cavities, and hence this procedure increases the mechanical resistance of subsurface cavities below the highway.

Differential diagnosis of lupus and primary membranous nephropathies by IgG subclass analysis.

BACKGROUND AND OBJECTIVES: Previous studies showed that the accuracy of IgG subclasses (ISs) in differentiating membranous lupus nephritis (MLN) from primary membranous nephropathy (PMN) is <80%. This study hypothesized that diagnostic accuracy of ISs would be increased if renal compartment measurements and decision tree analysis are applied. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Renal biopsy specimens from 41 patients with MLN and 59 patients with PMN between October 2004 and March 2010 were examined, and immunofluorescence staining against IgG1, IgG2, IgG3, and IgG4 as well as C3, C1q, and C4 was evaluated in five different renal compartments (glomerular capillary walls, mesangium, tubules, interstitium, and blood vessels). From IS data, a decision tree to differentiate MLN from PMN was produced (IS decision tree) and its accuracy was compared with that of previous studies. Diagnostic accuracy of the IS decision tree was also compared with that of the complement decision tree as a reference. RESULTS: The demographic information and patterns of IS deposition were similar to those of previous studies. The IS decision tree had, as decision markers, IgG1 in the mesangium and IgG2 and IgG4 along the glomerular capillary wall. The IS decision tree showed higher accuracy (88%) than that of previous studies (<80%) and also that of the complement decision tree (81%). CONCLUSIONS: Accuracy of ISs was increased due to the study methods, but the same methodology was less effective using complement measurements. Appropriate data analysis may enhance diagnostic value, but the analysis alone cannot achieve the ideal diagnostic value.

Synergistic effect of different levels of genomic data for cancer clinical outcome prediction.

There have been many attempts in cancer clinical-type classification by using a dataset from a number of molecular layers of biological system. Despite these efforts, however, it still remains difficult to elucidate the cancer phenotypes because the cancer genome is neither simple nor independent but rather complicated and dysregulated by multiple molecular mechanisms. Recently, heterogeneous types of data, generated from all molecular levels of 'omic' dimensions from genome to phenome, for instance, copy number variants at the genome level, DNA methylation at the epigenome level, and gene expression and microRNA at the transcriptome level, have become available. In this paper, we propose an integrated framework that uses multi-level genomic data for prediction of clinical outcomes in brain cancer (glioblastoma multiforme, GBM) and ovarian cancer (serous cystadenocarcinoma, OV). From empirical comparison results on individual genomic data, we provide some preliminary insights about which level of data is more informative to a given clinical-type classification problem and justify these perceptions with the corresponding biological implications for each type of cancer. For GBM, all clinical outcomes had a better the area under the curve (AUC) of receiver operating characteristic when integrating multi-layers of genomic data, 0.876 for survival to 0.832 for recurrence. Moreover, the better AUCs were achieved from the integration approach for all clinical outcomes in OV as well, ranging from 0.787 to 0.893. We found that the opportunity for success in prediction of clinical outcomes in cancer was increased when the prediction was based on the integration of multi-layers of genomic data. This study is expecting to improve comprehension of the molecular pathogenesis and underlying biology of both cancer types.

A novel role for type 1 angiotensin receptors on T lymphocytes to limit target organ damage in hypertension.

RATIONALE: Human clinical trials using type 1 angiotensin (AT(1)) receptor antagonists indicate that angiotensin II is a critical mediator of cardiovascular and renal disease. However, recent studies have suggested that individual tissue pools of AT(1) receptors may have divergent effects on target organ damage in hypertension. OBJECTIVE: We examined the role of AT(1) receptors on T lymphocytes in the pathogenesis of hypertension and its complications. METHODS AND RESULTS: Deficiency of AT(1) receptors on T cells potentiated kidney injury during hypertension with exaggerated renal expression of chemokines and enhanced accumulation of T cells in the kidney. Kidneys and purified CD4(+) T cells from "T cell knockout" mice lacking AT(1) receptors on T lymphocytes had augmented expression of Th1-associated cytokines including interferon-γ and tumor necrosis factor-α. Within T lymphocytes, the transcription factors T-bet and GATA-3 promote differentiation toward the Th1 and Th2 lineages, respectively, and AT(1) receptor-deficient CD4(+) T cells had enhanced T-bet/GATA-3 expression ratios favoring induction of the Th1 response. Inversely, mice that were unable to mount a Th1 response due to T-bet deficiency were protected from kidney injury in our hypertension model. CONCLUSIONS: The current studies identify an unexpected role for AT(1) receptors on T lymphocytes to protect the kidney in the setting of hypertension by favorably modulating CD4(+) T helper cell differentiation.

Semantically enabled and statistically supported biological hypothesis testing with tissue microarray databases.

BACKGROUND: Although many biological databases are applying semantic web technologies, meaningful biological hypothesis testing cannot be easily achieved. Database-driven high throughput genomic hypothesis testing requires both of the capabilities of obtaining semantically relevant experimental data and of performing relevant statistical testing for the retrieved data. Tissue Microarray (TMA) data are semantically rich and contains many biologically important hypotheses waiting for high throughput conclusions. METHODS: An application-specific ontology was developed for managing TMA and DNA microarray databases by semantic web technologies. Data were represented as Resource Description Framework (RDF) according to the framework of the ontology. Applications for hypothesis testing (Xperanto-RDF) for TMA data were designed and implemented by (1) formulating the syntactic and semantic structures of the hypotheses derived from TMA experiments, (2) formulating SPARQLs to reflect the semantic structures of the hypotheses, and (3) performing statistical test with the result sets returned by the SPARQLs. RESULTS: When a user designs a hypothesis in Xperanto-RDF and submits it, the hypothesis can be tested against TMA experimental data stored in Xperanto-RDF. When we evaluated four previously validated hypotheses as an illustration, all the hypotheses were supported by Xperanto-RDF. CONCLUSIONS: We demonstrated the utility of high throughput biological hypothesis testing. We believe that preliminary investigation before performing highly controlled experiment can be benefited.