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Motivation: Genes are typically expressed in modular manners in biological processes. Recent studies reflect such features in analyzing gene expression patterns by directly scoring gene sets. Gene annotations have been used to define the gene sets, which have served to reveal specific biological themes from expression data. However, current annotations have limited analytical power, because they are classified by single categories providing only unary information for the gene sets. Results: Here we propose a method for discovering composite biological themes from expression data. We intersected two annotated gene sets from different categories of Gene Ontology (GO). We then scored the expression changes of all the single and intersected sets. In this way, we were able to uncover, for example, a gene set with the molecular function F and the cellular component C that showed significant expression change, while the changes in individual gene sets were not significant. We provided an exemplary analysis for HIV-1 immune response. In addition, we tested the method on 20 public datasets where we found many ‘filtered’ composite terms the number of which reached ∼34% (a strong criterion, 5% significance) of the number of significant unary terms on average. By using composite annotation, we can derive new and improved information about disease and biological processes from expression data. Availability: We provide a web application (ADGO: ) for the analysis of differentially expressed gene sets with composite GO annotations. The user can analyze Affymetrix and dual channel array (spotted cDNA and spotted oligo microarray) data for four species: human, mouse, rat and yeast. Contact: chu@kribb.re.kr Supplementary information

Sampled grating has been used to enlarge the allowed range of coupling coefficient for high spatial hole-burning corrected single-frequency yield in conventional index-coupled DFB lasers with 1%-80% mirror combination. Theoretical calculation using an effective-index transfer matrix method shows that the allowed range of coupling coefficient increases approximately by 20% in the proposed sampled grating distributed-feedback lasers (DFB) lasers compared with conventional ones. Thus, the tolerance to the coupling coefficient variation improves to the level typically achieved in grating fabrication. The improvement is attributed to the flattened axial photon distribution of gap modes, and therefore stability in other lasing characteristics can be expected.

Combined effects of residual facet reflection and spatial hole-burning on the front-rear correlation and nonlinearity in L-I characteristics of quarter-wavelength-shifted DFB lasers have been studied by using an effective index transfer matrix method and rate equations. Changes in front-to-rear power ratio, caused by the spatial hole-burning and asymmetric facet-reflection due to the different grating end phases at the two facets, are shown to be responsible for both the correlation and the linearity problems, while the threshold gain change causes the linearity problem only. The problems are serious even in the cases of low facet reflectivity of 0.3%.

The validity of the method of estimating nonuniformity in axial photon distribution from front-to-rear output power ratio has been studied by an effective index transfer matrix method. The correlation between the front-to-rear output power ratio and the maximum-to-minimum photon density ratio is shown to be good over the whole useful range of the grating coupling coefficient in uniform grating DFB laser with low-reflection/high-reflection facets, and an accurate estimation is possible. However, the correlation becomes poor as the reflectivity of the high-reflection facet decreases and the coupling coefficient increases, resulting in poor estimation.

An analytical model for calculating the minimum drift region length of SOI RESURF diodes is presented with an expression for the maximum breakdown voltage of the device. The minimum drift region length is determined from the condition that the maximum breakdown voltage due to the one-dimensional field along the vertical path equals that of the lateral electric field along the surface. Analytical results agree well with the simulations using PISCES II, and qualitatively with the experimental results.

In the workflow technology literature, so far, very-large scale workflow architectures, systems and applications have been looking for distributed computing infrastructures maximizing their performance and efficiency, but using minimal resources. Almost all conventional workflow systems are based upon the client-server and clustering computing environments. However, according to that Grid/P2P is hot-issued as a very feasible infrastructure for very-large scale information systems, we need to explore some reasonable approaches for applying the Grid/P2P as an infrastructure of very-large scale workflow systems. This paper ought to be one of those trials for seeking the-how that is fitted very well into the nature of the Grid/P2P. This paper proposes a scheme to generate a Grid/P2P configuration for implementing resource management and scheduling functionality, which gives best performance in enacting a workflow process. The scheme's essential idea is on the peer-to-peer workflow model that is automatically generated from the workflow process (represented by ICN) by an algorithm conceived in this paper. Eventually, the peer-to-peer workflow model becomes a Grid/P2P resource configuration for enacting the workflow process on runtime. In this paper, we describe about the peer-to-peer workflow model that provides a theoretical basis for peer-to-peer workflow distribution and enactment over Grid/P2P.

Purpose: To investigate the clinical significance of activation of YAP1, a newly identified oncogene in colorectal cancer (CRC). Patients and Methods: A gene expression signature reflecting YAP1 activation was identified in CRC cells, and CRC patients were stratified into two groups according to this signature: activated YAP1 CRC (AYCC) or inactivated YAP1 CRC (IYCC). Stratified patients in six test cohorts were evaluated to determine the effect of the signature on CRC prognosis and response to treatment with cetuximab. Results: The activated YAP1 signature was associated with poor prognosis for CRC in four independent patient cohorts with stage I-III disease (total n = 1,028). In a multivariate analysis, the impact of the YAP1 signature on the disease-free survival rate was independent of other clinical variables [hazard ratio (HR), 1.63; 95% confidence interval (CI), 1.25-2.13; P < .001]. In patients with stage IV CRC, AYCC patients had a poorer disease control rate and progression-free survival duration after cetuximab-based monotherapy than did IYCC patients (HR, 1.82; 95% CI, 1.05-3.16; P = .03). In multivariate analysis, the effect of YAP1 activation on PFS was independent of KRAS mutation status and cetuximab-based therapy was effective only in IYCC patients without KRAS mutations. Conclusion: Activation of YAP1 is highly associated with poor prognosis for CRC and may be useful in identifying patients with CRC resistant to treatment with cetuximab. Citation Format: Keun-Wook Lee, Sung Sook Lee, Sang-Bae Kim, Yun-Yong Park, Bo Hwa Sohn, Hyun-Sung Lee, Ju-Seog Lee. Activation of yap1 is significantly associated with poor prognosis and cetuximab resistance in colorectal cancer patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4734. doi:10.1158/1538-7445.AM2014-4734

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide. Vitamin D (VD) has been implicated in the prevention of multiple cancers, some of which are characterized by inactivation of TGF-β signaling. Recently, inactivation of TGF-β signaling has been associated with development of HCC. We examined the potential role of VD in HCC chemoprevention in the context of TGF-β inactivation in a mouse model. Methods: Wild type, Sptbn1+/- and Smad3+/- male mice were treated with 50 mg/kg of the chemical carcinogen diethylnitrosamine (DEN) via i.p. injection at 14 days of age. At 8 months, the animals were changed from regular chow (2,200 IU/kg VD) to one of two diets: lower than normal VD (200 IU/kg) or high VD (10,000 IU/kg). At one year of age, the livers were harvested for tissue analysis. Several metrics were assessed including expression levels of 164 proteins from liver tumors by Reverse Phase Protein Array (RPPA). Results: Twenty three mice were treated with lower than normal dose VD while 26 received high dose VD. We did not find significant differences in blood calcium levels in animals on either diet. As expected, high VD intervention after 8 months of DEN injection did not affect the total number of tumors the mice developed; however, the lower than normal VD regimen promoted tumor growth in the context of Smad3 disruption (liver-to-body weight ratio 18.37% in Smad3+/- mice treated with low dose VD vs. 6.25% in Smad3+/- animals treated with high dose, p=0.028). Furthermore, RPPA data revealed that the lower than normal VD intake in DEN-treated Smad3 heterozygous null mice results in repression of tumor suppressing genes such as PDCD4 and concomitant up-regulation of tumor promoting genes like Stat5A, Bcl2-XL, PDGFRB and PEA15. Conclusions: Remarkably, lower than normal VD in the context of Smad3 disruption promotes tumor growth possibly through repression of tumor suppressing genes such as PDCD4 and up-regulation of oncogenes like Stat5A, Bcl2-XL, PDGFRB and PEA15. These results suggest that VD treatment strategies could potentially be significant for chemoprevention and treatment of HCC in the context of inactivation of TGF-β signaling in patient populations with underlying deficiency of VD. Citation Format: Nina M. Muñoz, Lior H. Katz, Keigo Machida, Hidekazu Tsukamoto, Kirty Shetty, Aiwu R. He, Lynt B. Johnson, Asif Rashid, Sang Bae Kim, Ju-Seog Lee, Lopa Mishra. Vitamin D deficiency promotes hepatocellular carcinoma tumor growth in TGF-β impaired mice by Smad3 heterozygous deletion. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 248. doi:10.1158/1538-7445.AM2014-248

Identification of recurrent leukemia-associated mutations in genes encoding regulators of DNA methylation such as DNMT3A and TET2 have underscored the critical importance of DNA methylation in maintenance of normal physiology. To gain insight into how DNA methylation exerts the central role, we sought to determine the genome-wide pattern of DNA methylation in the normal precursors of leukemia cells: the hematopoietic stem cell (HSC), and investigate the factors that affect alterations in DNA methylation and gene expression. We performed whole genome bisulfite sequencing (WGBS) on purified murine HSCs achieving a total of 1,121M reads, resulting in a combined average of 40X coverage. Using Hidden Markov Model we identified 32,325 under-methylated regions (UMRs) with average proportion of methylation ≤ 10% and by inspecting the UMR size distribution, we discovered exceptionally large “methylation Canyons” which span highly conserved domains frequently containing transcription factors and are quite distinct from CpG islands and shores. Methylation Canyons are a distinct genomic feature that is stable, albeit with subtle differences, across cell-types and species. Canyon-associated genes showed a striking pattern of enrichment for genes involved in transcriptional regulation (318 genes, P=6.2 x 10-123), as well as genes containing a homeobox domain (111 genes, P=3.9 x 10-85). We compared Canyons with TF binding sites as identified from more than 150 ChIP-seq data sets across a variety of blood lineages (>10)19 and found that TF binding peaks for 10 HSC pluripotency TFs are significantly enriched in entirety of Canyons compared with their surrounding regions. Low DNA methylation is usually associated with active gene expression. However, half of Canyon genes associated with H3K27me3 showed low or no expression regardless of their H3K4me3 association while H3K4me3-only Canyon genes were highly expressed. Because DNMT3A is mutated in a high frequency of human leukemias24, we examined the impact of loss of Dnmt3a on Canyon size. Upon knockout of Dnmt3a, the edges of the Canyons are hotspots of differential methylation while regions inside of Canyon are relatively resistant. The methylation loss in Dnmt3a KO HSCs led Canyon edge erosion, Canyon size expansion and addition of 861 new Canyons for a total of 1787 Canyons. Canyons marked with H3K4me3 only were most likely to expand after Dnmt3a KO and the canyons marked only with H3K27me3 or with both marks were more likely to contract. This suggests Dnmt3a specifically is acting to restrain Canyon size where active histone marks (and active transcription) are already present. WGBS cannot distinguish between 5mC and 5hmC, so we determined the genome-wide distribution of 5hmC in WT and Dnmt3a KO HSCs using the cytosine-5-methylenesulphonate (CMS)-Seq method in which sodium bisulfate treatment convert 5hmC to CMS; CMS-containing DNA fragments are then immunoprecipitated using a CMS specific antiserum. Strikingly, 5hmC peaks were enriched specifically at the borders of Canyons. In particular, expanding Canyons, typically associated with highest H3K4me3 marking, were highly enriched at the edges for the 5hmC signal suggesting a model in which Tet proteins and Dnmt3a act concomitantly on Canyon borders opposing each other in alternately effacing and restoring methylation at the edges, particularly at sites of active chromatin marks. Using Oncomine data, we tested whether Canyon-associated genes were likely to be associated with hematologic malignancy development and found Canyon genes were highly enriched in seven signatures of genes over-expressed in Leukemia patients compared to normal bone marrow; in contrast, four sets of control genes were not similarly enriched. Further using TCGA data, we found that expressed canyon genes are significantly enriched for differentially expressed genes between patients with and without DNMT3A mutation (p value Disclosures: No relevant conflicts of interest to declare.

BackgroundAlthough several prognostic genomic predictors have been identified from independent studies, it remains unclear whether these predictors are actually concordant with respect to their predictions for individual patients and which predictor performs best. We compared five prognostic genomic predictors, the V7RHS, the ColoGuideEx, the Meta163, the OncoDX, and the MDA114, in terms of predicting disease-free survival in two independent cohorts of patients with colorectal cancer.Study designUsing original classification algorithms, we tested the predictions of five genomic predictors for disease-free survival in two cohorts of patients with colorectal cancer (n = 229 and n = 168) and evaluated concordance of predictors in predicting outcomes for individual patients.ResultsWe found that only two predictors, OncoDX and MDA114, demonstrated robust performance in identifying patients with poor prognosis in 2 independent cohorts. These two predictors also had modest but significant concordance of predicted outcome (r>0.3, PConclusionsFurther validation of developed genomic predictors is necessary. Despite the limited number of genes shared by OncoDX and MDA114, individual-patient outcomes predicted by these two predictors were significantly concordant.

Metabolic changes are common features of many cancer cells and are frequently associated with the clinical outcome of patients with various cancers including hepatocellular carcinoma (HCC). Thus, aberrant metabolic pathways in cancer cells are attractive targets for cancer therapy. However, our understanding of cancer-specific regulatory mechanisms of cell metabolism is still very limited. We found that Tat activating regulatory DNA-binding protein (TARDBP) is a novel regulator of glycolysis in HCC cells. TARDBP regulates expression of the platelet isoform of phosphofructokinase (PFKP), the rate-limiting enzyme of glycolysis that catalyzes the irreversible conversion of fructose-6-phosphate to fructose-1,6-bisphosphate. Silencing of TARDBP expression in multiple HCC cell lines leads to impaired glucose metabolism and inhibition of in vitro and in vivo growth of HCC cells. Notably, the miR-520 family is an intermediate regulator of TARDBP-mediated regulation of glycolysis. Mechanistically, TARDBP suppressed expression of the miR-520 family, which in turn inhibited expression of PFKP. We further showed that expression of PFKP is significantly associated with the overall survival of patients with HCC. Our study provides new mechanistic insights into the regulation of glycolysis in HCC cells and reveals TARDBP as a potential therapeutic target for HCC. Citation Format: Yun-Yong Park, Sang Bae Kim, Hee Dong Han, Bo-Hwa Sohn, Jiyong Liang, Yiling Lu, Gordon Mills, Anil Sood, Ju-Seog Lee. TARDBP regulates glycolysis in hepatocellular carcinoma by regulating PFKP through miR-520. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5398. doi:10.1158/1538-7445.AM2013-5398

Effects of the systematic epi-layer thickness errors on the optical reflection spectra have been studied in epitaxial wafers for 850 nm vertical-cavity surface-emitting lasers (VCSELs), and a procedure of estimating the error layer and magnitude is proposed. The experimentally confirmed procedure is based on the finding that the overall shape of the reflection spectra depends mainly on a newly defined parameter, the effective error.

Transcription factors (TFs) are direct effectors of altered signaling pathways in cancer. To uncover new TFs that would determine clinical outcomes in breast cancer patients, we systematically analyzed gene expression data from breast cancer patients. Our results revealed that forkhead box protein M1 (FOXM1) is the top-ranked survival-associated TF with triple-negative breast cancer. Surprisingly, silencing FOXM1 expression led breast cancer cells to become more sensitive to doxorubicin (Dox). We found that FOXM1-dependent resistance to Dox is mediated by regulating DNA repair genes. We further demonstrated that NF-κB1 interacts with FOXM1 in the presence of Dox to protect breast cancer cells from DNA damage. Finally, silencing FOXM1 expression in a mouse xenograft model significantly sensitized the cells to Dox. Our systematic approaches identified an unexpected role of FOXM1 in Dox resistance by regulating DNA repair genes and FOXM1 may be a promising therapeutic target for sensitizing breast cancer cells to Dox. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2962. doi:1538-7445.AM2012-2962

Although the importance of the cellular microenvironment (soil) during invasion and metastasis of cancer cells (seed) has been well-recognized, technical challenges have limited the ability to assess the influence of the microenvironment on cancer cells at the molecular level. Here, we show that an experimental strategy, competitive cross-species hybridization of microarray experiments, can characterize the influence of different microenvironments on cancer cells by independently extracting gene expression data of cancer and host cells when human cancer cells were xenografted into different organ sites of immunocompromised mice. Surprisingly, the analysis of gene expression data showed that the brain microenvironment induces complete reprogramming of metastasized cancer cells, resulting in a gain of neuronal cell characteristics and mimicking neurogenesis during development. We also show that epigenetic changes coincide with transcriptional reprogramming in cancer cells. These observations provide proof of principle for competitive cross-species hybridization of microarray experiments to characterize the effect of the microenvironment on tumor cell behavior Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4283. doi:1538-7445.AM2012-4283

Wnt/β-catenin signaling has been known to be involved in many cellular processes including cell proliferation, migration, and survival. Aberrant activation of Wnt/β-catenin signaling has been widely reported in many cancers and associated with poor outcome after treatments. However, activation of Wnt/β-catenin signaling in hepatocellular carcinoma (HCC) has been known to be significantly associated with favorable outcome. In this study, we identified 82 genes as a β-catenin signature by analyzing expression data from tumor tissues of patients with HCC and liver tissues from active β-catenin mutant transgenic mice. HCC patients with the β-catenin signature have significantly better prognosis in both overall survival and recurrence-free survival than those without the signature. Further analysis of β-catenin signature revealed over-expression of glutamine synthetase (GS), liver-specific β-catenin target gene, and shift of glutamine metabolism. Cell growth rate were highly dependent on GS expression levels. Cell proliferation rate was increased by GS knockdown using shRNAs but decreased by GS overexpression in HCC cell lines. Intracellular glutamate concentrations were severely decreased by GS overexpression. GS overexpression in HCC cells also led to decrease intracellular α-ketoglutarate levels impeding TCA cycle, and intracellular glutathione levels accumulating high reactive oxygen species (ROS). In conclusion, we found GS up-regulation in HCC cells inhibited cell growth by glutamate depletion and thereby lower anaplerotic metabolic activity and higher ROS levels. Our results present molecular mechanisms for the favorable outcome in HCC patients with CTNNB1 mutations and importance of glutamine metabolism in cancer cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5142. doi:1538-7445.AM2012-5142

MicroRNAs (miRNAs) are single-stranded, non-coding RNA molecules and on average only 22 nucleotides long that regulate gene expression at the post-transcriptional level. The current approaches with miRNA-mRNA association were not enough to verify real functional targets at protein level, which could affect on biological signaling pathway. In this study, we developed a correlation based approach (sequence-independence) to predict potential miRNA targets with genomic and proteomic data including the expression of phosphorylated proteins in NCI-60 cells. To do this we calculated the number of correlated probe-pairs between miRNA(439)-mRNA(22k) and protein(222)-mRNA probe pairs. Then, two significant output pair sets were combined by mRNA probes and then counted the number of common probes. With these count numbers, finally we generated Association score matrix between miRNA and protein probes. Using those score matrix, we evaluated the highly associated miRNAs with 36 biological pathways, which play critical roles in cell cycle, proliferation and metastasis. Among these associations, we found that miR-500 cluster is highly associated with ERK/MAPK signaling pathway through activating MEK1/2 phosphorylation in Melanoma and breast cancer cells. In conclusion, we developed a novel expression profile based approach to systematically predict potential miRNA functional targets which play critical roles in cell signaling pathways from the NCI-60 genomic and proteomic data at whole genomic scale. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 135. doi:1538-7445.AM2012-135

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor with poor prognosis due in part to drug resistance and high incidence of tumor recurrence. The drug resistant and cancer recurrence phenotype may be ascribed to the presence of cancer stem cells, which seem to reside in special stem-cell niches in vivo and require special culture conditions including certain growth factors and serum-free medium to maintain their stemness in vitro. In this study, we used several stem-like glioblastoma cell lines (GSC11, GSC23 and GBM3752) derived from patients’ tissues by typical neurosphere culture system, and showed that addition of fetal bovine serum (FBS) to the medium induced an increase of ROS, leading to aberrant differentiation and decreases of stem cell markers such as CD133. We found that exposure of glioblastoma stem cells (GSCs) to serum induces their differentiation through activation of mitochondrial respiration, leading to an increase in superoxide (O2−) generation and a profound reactive oxygen species (ROS) stress response manifested by upregulation of oxidative stress response pathway. This increase in mitochondrial ROS leads to a down-regulation of molecules including SOX2, and Olig2, and Notch1 that are important for stem cell function and an upregulation of mitochondrial superoxide dismutase SOD2 that converts O2− to H2O2. Neutralization of ROS by antioxidant N-acetylcysteine in the serum-treated GSCs suppresses the increase of superoxide and largely rescues the expression of SOX2, Olig2, and Notch1, and prevents the serum-induced differentiation phenotype. Upregulation of ROS by chemical disruption of mitochondrial electron respiration chain induced further decrease of CD133. Our study suggests that mitochondrial function and cellular redox status may profoundly affect the fates of glioblastoma stem cells, and that modulation of ROS generation may be an effective way to impact CSCs, which may provide a new basis for developing novel therapeutic approaches. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 999. doi:1538-7445.AM2012-999

Background Gastric cancer continues to be one of the deadliest cancers in the world and therefore identification of new drugs targeting this type of cancer is thus of significant importance. The purpose of this study was to identify and validate a therapeutic agent which might improve the outcomes for gastric cancer patients in the future. Methodology/Principal Findings Using microarray technology, we generated a gene expression profile of human gastric cancer–specific genes from human gastric cancer tissue samples. We used this profile in the Broad Institute's Connectivity Map analysis to identify candidate therapeutic compounds for gastric cancer. We found the histone deacetylase inhibitor vorinostat as the lead compound and thus a potential therapeutic drug for gastric cancer. Vorinostat induced both apoptosis and autophagy in gastric cancer cell lines. Pharmacological and genetic inhibition of autophagy however, increased the therapeutic efficacy of vorinostat, indicating that a combination of vorinostat with autophagy inhibitors may therapeutically be more beneficial. Moreover, gene expression analysis of gastric cancer identified a collection of genes (ITGB5, TYMS, MYB, APOC1, CBX5, PLA2G2A, and KIF20A) whose expression was elevated in gastric tumor tissue and downregulated more than 2-fold by vorinostat treatment in gastric cancer cell lines. In contrast, SCGB2A1, TCN1, CFD, APLP1, and NQO1 manifested a reversed pattern. Conclusions/Significance We showed that analysis of gene expression signature may represent an emerging approach to discover therapeutic agents for gastric cancer, such as vorinostat. The observation of altered gene expression after vorinostat treatment may provide the clue to identify the molecular mechanism of vorinostat and those patients likely to benefit from vorinostat treatment.

ESR1 is one of the most important oncogenes and therapeutic targets in breast cancer. By applying systems-level re-analysis of publicly available gene expression data, we uncovered potential regulator of ESR1. We demonstrated that orphan nuclear receptor NR2E3 regulates ESR1 via direct binding to the ESR1 promoter with concomitant recruitment of PIAS3 to promoter in breast cancer cells, and is essential for physiological cellular activity of ESR1 in estrogen receptor (ER)-positive breast cancer cells. Moreover, expression of NR2E3 was significantly associated with recurrence-free survival and favorable response to tamoxifen treatment in women with ER-positive breast cancer. Our results provide mechanistic insight into how ESR1 is regulated by NR2E3 and clinical relevance of NR2E3 in breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 356. doi:10.1158/1538-7445.AM2011-356

MicroRNAs (miRNAs) are single-stranded, non-coding RNA molecules and on average only 22 nucleotides long that regulate gene expression at the post-transcriptional level. Target predictions of miRNA based on sequence are limited due to too many candidates resulting in high false positives. To overcome this limitation functional target prediction approaches have been investigated by using mRNA and miRNA expression data. These approaches used in the computational assessment of functional miRNA-target association. However, these approaches with miRNA-mRNA association were not enough to verify real functional targets at protein level, which could affect on biological signaling pathway. Therefore, in order to overcome current limitation we developed a novel correlation-based approach (sequence-independence) that predict the association of miRNAs with signaling pathways by using genomics and proteomics data from NCI-60 cancer cell lines (mRNA, miRNA, and protein expression data). To identify miRNA-protein association, we used two correlation-based methods: direct comparison (miRNA-protein pairs) and indirect comparison (miRNA-mRNA and protein-mRNA pairs), then compared their outputs. In direct comparison, we calculated Pearson correlation coefficients for 96k probe pairs and found over 3 k significant correlated pairs (3.2 %) at the cut-off p-value < 0.005: among them 53.4 % were negative and 46.6% were positive. In indirect comparison, we ranked the number of correlated mRNA probes between miRNA-mRNA and protein-mRNA pairs, in which we calculated over 11 and 5.7 million probe pairs respectively. Then, two significant output pair sets were combined by intersection of mRNA probes and then determined the number of common probes. With these determined numbers, finally we generated association score matrix between miRNA and protein probes. Using those score matrix, we evaluated the highly associated miRNAs with 40 biological pathways, which play critical roles in cell cycle, proliferation and metastasis. In conclusion, we developed a noble expression profile-based approach to systematically predict potential miRNA functional targets which play critical roles in cell signaling pathways from the NCI-60 genomic and proteomic data at whole genomic scale. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3995. doi:10.1158/1538-7445.AM2011-3995

Voriconazole is a triazole with broad spectrum antifungal activity, and it is currently considered to be the first-line agent for the treatment of invasive aspergillosis. We report here on a case of visual and auditory hallucinations during intravenous treatment with voriconazole in association with a high trough level. A 28-year-old man with acute myelogenous leukemia was admitted for re-induction remission chemotherapy. During the persistent neutropenic fever, intravenous voriconazole was administered for the suspected invasive fungal pneumonia. He began to have visual hallucinations on the 1st day and auditory hallucinations on the 3rd day of voriconazole therapy. The plasma peak and trough concentration levels of voriconazole were 9.9 and 7.4 μg/ml, respectively, on the 3rd day. The hallucinations resolved after changing to amphotericin B deoxycholate, and the plasma concentration of voriconazole dropped to less than 0.5 μg/ml. The genotype of the CYP2C19 alleles was classified as a heterozygous extensive metabolizer. We suggest that therapeutic drug monitoring of voriconazole is indicated for a case that is suspicious for a voriconazole-related adverse event.

Esophageal adenocarcinoma (EAC) is thought to arise from the metaplastic condition known as Barrett's esophagus (BE), which is caused by chronic inflammation due to gastroesophageal reflux disease. Since the molecular mechanisms underlying the pathogenesis of EAC are unknown, understanding EAC development mechanisms and their regulation is crucial for the treatment of EAC. Comparative genomic studies of evolutionarily similar and dissimilar species have been suggested as a means of studying the evolutionary biology in the species. Thus, we performed a cross-species comparison of gene expression patterns in human and rat tissues, uncovering the evolutionarily conserved gene expression patterns during EAC progression across both species. Using a non-carcinogenic rat model that progresses from normal esophagus to BE to EAC, we were able to identify the biological mechanisms of EAC development. We analyzed gene expression data from rat specimens (15 NE, 18 BE, and 30 EAC) as well as from human tissues (28NE, 72BE, and 75EAC). Using the presence of orthologous genes in both microarray platforms and various statistical tests, we uncovered a number of genes whose expression patterns were well conserved during progression from NE to BE in humans and rats. The expression of 869 genes was commonly altered when NE progressed to BE in both humans and rats (P During BE to EAC progression in both species, 541 gene expressions were altered (P In conclusion, systems-level characterization of gene expression data from humans and a rodent model shows evolutionarily conserved genes and pathways during EAC progression, and these genes and pathways could become reliable biomarkers for early detection, or therapeutic targets for the treatment of EAC patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2005.

Prostate cancer is the most common cancer in men around the world, with a high incidence of bone metastasis, which is the major determinant of mortality in prostate cancer. The survival and proliferation of prostate cancer cells metastatic to bone result from the cross-talk between carcinoma cells and the stromal cells. In contrast to skeletal metastases resulting from breast or lung cancer that are most often osteolytic, metastases from prostate carcinoma are nearly always osteoblastic, suggesting that interactions between prostate cancer cells and stroma in bone might be different from those of lung or breast cancer cells and bone stroma. Therefore, gene expression patterns that are unique to osteoblastic prostate cancer will help to identify genes involved in the bidirectional cross-talk between prostate cancer cells and bone cells in microenvironment niche. However, because gene expression signatures from human cancer tissues are a mixture of those from carcinoma and stromal cells, it has been impossible to delineate stromal cell specific gene expression signatures from carcinoma cell signatures. Thus, we have devised a novel experimental strategy: “competitive cross-species hybridization of microarray”, which can simultaneously extract gene expression patterns of carcinoma cells and stromal cells from a single xenograft sample. In the current study, we xenografted human prostate cancer cells (PC3, PCA118b, 10A) into mouse bone and prostate and used these tissues for microarray experiments. Total RNAs were purified from three different tissue groups: normal bones (mouse RNA only), tumor-bearing bones (mixture of mouse and human RNA), and tumor-bearing prostates (mixture of mouse and human RNA). Labeled cRNA from normal bones and tumor-bearing bones were hybridized to mouse microarray slide to measure gene expression of mouse bone cells. Likewise, labeled cRNA from tumor-bearing prostate and tumor-bearing bone were hybridized to human microarray slide to measure gene expression of human prostate cancer cells. Gene expression data from mouse microarrays identified gene expression patterns unique to bone cells that interact with prostate cancer cells in bone. When same analysis applied to human data, it also uncovered prostate cancer cell gene expression signatures associated with different microenvironment (prostate vs. bone). In order to uncover gene networks involved in cross-talk between prostate cancer cells and bone cells in metastatic bone microenvironment, gene network analysis using Ingenuity Pathway Analysis (IPA) was applied to combined gene lists from human and mouse data. In conclusion, by applying novel experimental strategy, “competitive cross-species hybridization of microarray”, we uncovered critical gene network involved in bidirectional cellular communication that drives the survival of prostate cancer cells in metastatic bone microenvironment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 546.

Glioblastoma multiforme (GBM) is a common and highly aggressive primary brain tumor with poor prognosis due in part to drug resistance and high incidence of tumor recurrence. The drug resistant and cancer recurrence phenotype may be ascribed to the presence of cancer stem cells, which seem to reside in special stem-cell niches in vivo and require special culture conditions including certain growth factors and serum-free medium to maintain their stemness in vitro. In this study, we used two lines of stem-like cancer cells (GSC11 and GSC23) derived from the tumor tissues of two GBM patients by classical neurosphere culture system, and showed that addition of serum (FBS) to the medium induced an increase of ROS, leading to aberrant differentiation and eventual cell death. Although both GBM stem-like cell lines showed high percentage of CD133-positive cells (20% in GSC11 and 70% in GSC23), exposure to serum only caused a moderate decrease of CD133 expression at later time points. Several methods were used to further test the role of ROS in affecting the stemness of the GSC cells and their self-renewal capacity. Addition of 5% FBS or removal of the antioxidant supplements (B27) from the culture medium caused the spheroid GSC cells to attach to the culture surface, exhibit differentiation morphology, decrease expression of certain stem-cell markers, and eventually die within two weeks. Serum exposure also resulted in a decrease of the GSC ability to form colonies in soft agar assay and to grow tumors in a mouse xenograft model. Although an increase of general cellular ROS could be detected when GSC cells were exposed to FBS, the mitochondrial superoxide appeared to be prominent and likely to be a primary event, which led to a compensatory increase of the mitochondrial SOD2 expression and upregulation of glutathione synthesis. Interestingly, addition of the antioxidant N-Acetylcysteine to the FBS-containing medium partially blocked the FBS-induced aberrant differentiation and improved cell viability and self-renewal capacity, suggesting that ROS may play an important role in affecting stemness and differentiation status of the cancer stem cells. We postulate that during tumor development, only the progeny cells that acquire the ability to counteract the impact of ROS increase induced by serum may eventually proliferate and grow as the tumor bulk, and that proper redox-modulation may be a potential novel strategy to block tumor formation and possibly kill the stem-like cancer cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4266.

Gene-expression profiling has been applied in specific settings such as to elucidate the mechanisms of biological pathways, to classify subtypes of a disease, and to predict cancer prognosis. Furthermore, the Connectivity Map using gene-expression signature can categorize the biological responses to a large number of diverse small molecule therapeutics. To find new agents targeting gastric cancer, we analyzed global human gastric cancer gene expression profile using the Connectivity Map. From 3360 gastric cancer specific genes, it was revealed that the candidate compounds for targeting gastric cancer were histone deacetylase inhibitors (HDACi) such as vorinostat. We validated the therapeutic efficacy of vorinostat in gastric cancer cell lines. Vorinostat induced both apoptosis and autophagy in gastric cancer cell lines, but showed a different pattern in each cell line. Pharmacological or genetic inhibition of autophagy respectively by chloroquine and a siRNA against Beclin 1 increased the therapeutic efficacy of vorinostat, indicating a mechanism of drug resistance. Further transcriptome analysis will make it possible to find a predictive biomarker gene signature for vorinostat and as such can help in the future to better understand the action mechanisms of vorinostat. In conclusion, we showed that systems analysis using Connectivity Map with a human gastric cancer gene signature can be novel approach to find targeting agents for gastric cancer. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C163.

This study was conducted to beneficiation of magnesite by dry grinding and air classification. The raw ore was ground in a ball mill and pin mill controlled with grinding time and linear velocity of grinding media and fractionated in an air classifier. Pin mill is more efficient than the ball mill for liberation. As a result, the MgO grade of concentrate was 47.1% with recovery of 51.51% for classified with 3,000rpm of air classifier for ground at 13,000rpm in pin mill.

An integrated optical bent waveguide with as‐grown 45° mirror is fabricated using nearly atomically smooth facets only. These facets are grown by single‐step selective liquid‐phase epitaxy of GaAs. The mirror orientation is automatically adjusted to the optimum angles since the waveguide on {100} substrate uses only the as‐grown {111} and {100} crystal planes as waveguide walls and 45° mirrors. The technique for the mirror location control is described taking into consideration the growth rate anisotropy.

Introduction Cancer stem cells (CSCs) possess characteristics associated with normal stem cells, specifically the abilities to renew themselves and to give rise to all cell types (differentiation). It is assumed that induction of differentiation in CSCs would reduce their ability to form tumors. What triggers CSC differentiation and the role of “differentiation” in tumorigenesis remain elusive. Methods Glioma stem cell (GSC) lines and subcutaneous as well as orthotopic xenografts established from fresh surgical specimens of glioblastoma multiforme were used. Results Exposure of GSCs to serum activates mitochondrial respiration and causes an increase in mitochondrial reactive oxygen species (ROS) as well as oxidative stress responses, leading to the appearance of differentiation morphology and a deceased expression of CSC markers. Chemical perturbation of the mitochondrial electron transport chain causes ROS increase and further downregulation of stem cell markers, while antioxidant N-acetyl-cysteine reduces ROS and suppresses the differentiation of GSCs. Surprisingly, the serum-induced differentiated GSCs exhibit greater ability to form tumor in both orthotopic and subcutaneous xenograft models, which can be suppressed by N-acetyl-cysteine. Mitochondrial ROS from the serum-stimulated cells triggered the activation of nuclear factor-kappa-B (NFκB) pathway, which is a potential mechanism for the promotion of tumorigenesis. Conclusion This study suggests that ROS generated from active mitochondrial respiration in the presence of serum is critical in CSCs activation, which promotes tumor development in vivo.

4113 Background: Clinical heterogeneity in gastric cancer is likely due to biological differences among patients. Molecular subtypes and their associated biomarkers need to be established to improve treatment of this disease. We aimed to uncover subgroups of gastric cancer that have distinct biological characteristics associated with clinical outcome and to identify potential best treatments or therapeutic targets for each subgroup. Methods: We analyzed gene expression profiling data from gastric cancer cell lines and 267 patients with gastric cancer to uncover tumor subtypes and identify a gene expression signature associated with prognosis and response to adjuvant chemotherapy. The association of the signature with prognosis was validated in an independent cohort of 200 patients, and its association with response to adjuvant therapy was validated by cell culture experiments. Results: We identified an expression signature of 88 genes that specifically reflected activation of the oncogene YAP1. Compared with patients without this signature, patients with the YAP1 signature had significantly poorer prognosis. In multivariate analysis, the signature was the strongest indicator of overall survival among all demographic and clinical variables examined together (hazard ratio, 2.1; 95% confidence interval, 1.3-3.3;P = .002). Activation of YAP1 was significantly associated with resistance to adjuvant chemotherapy. We also demonstrated that the Notch pathway is a potential therapeutic target for overcoming chemoresistance mediated by YAP1. Conclusions: Activation of the oncogene YAP1 is significantly associated with poorer survival of patients with gastric cancer and induces chemoresistance to this disease. Therefore, YAP1 may be highly attractive therapeutic target for patients with gastric cancer resistant to standard chemotherapy.