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Transcription factors are direct effectors of altered signaling pathways in cancer and frequently determine clinical outcomes in cancer patients. To uncover new transcription factors that would determine clinical outcomes in breast cancer, 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 transcription factor in patients 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 NFκB1 interacts with FOXM1 in the presence of Dox to protect breast cancer cells from DNA damage. Finally, silencing FOXM1 expression in breast cancer cells 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 our findings provide mechanistic insights into how FOXM1 mediates resistance to Dox and evidence that FOXM1 may be a promising therapeutic target for sensitizing breast cancer cells to Dox.

Objective Oesophageal squamous cell carcinoma (ESCC) is a heterogeneous disease with variable outcomes that are challenging to predict. A better understanding of the biology of ESCC recurrence is needed to improve patient care. Our goal was to identify small non-coding RNAs (sncRNAs) that could predict the likelihood of recurrence after surgical resection and to uncover potential molecular mechanisms that dictate clinical heterogeneity. Design We developed a robust prediction model for recurrence based on the analysis of the expression profile data of sncRNAs from 108 fresh frozen ESCC specimens as a discovery set and assessment of the associations between sncRNAs and recurrence-free survival (RFS). We also evaluated the mechanistic and therapeutic implications of sncRNA obtained through integrated analysis from multiple datasets. Results We developed a risk assessment score (RAS) for recurrence with three sncRNAs (microRNA (miR)-223, miR-1269a and nc886) whose expression was significantly associated with RFS in the discovery cohort (n=108). RAS was validated in an independent cohort of 512 patients. In multivariable analysis, RAS was an independent predictor of recurrence (HR, 2.27; 95% CI, 1.26 to 4.09; p=0 . 007). This signature implies the expression of ΔNp63 and multiple alterations of driver genes like PIK3CA. We suggested therapeutic potentials of immune checkpoint inhibitors in low-risk patients, and Polo-like kinase inhibitors, mammalian target of rapamycin (mTOR) inhibitors, and histone deacetylase inhibitors in high-risk patients. Conclusion We developed an easy-to-use prognostic model with three sncRNAs as robust prognostic markers for postoperative recurrence of ESCC. We anticipate that such a stratified and systematic, tumour-specific biological approach will potentially contribute to significant improvement in ESCC treatment.

Background/Aims: The benefit of oral antiviral therapy in preventing hepatocellular carcinoma (HCC) in the general population is not well understood. We used a novel prediction method to estimate the risk of HCC in the Korean population based on various treatment guidelines. Methods: The 5-year risk of HCC following antiviral therapy was calculated using an HCC risk prediction model. A virtual cohort that represented Koreans (>40 years old) with chronic hepatitis B virus (HBV) infection was established using the fifth National Health and Nutrition Examination Survey. The antiviral indications tested were the Korean National Health Insurance (NHI) and European Association for the Study of the Liver (EASL) guidelines as well as a new extended indication (serum HBV DNA >2,000 IU/mL regardless of serum aminotransferase level). Results: A total of 993,872 subjects were infected with HBV in the general Korean population. Over a 5-year period, 2,725 HCC cases were predicted per 100,000 persons (0.55%/yr). When the cohort was treated based on the Korean NHI, the EASL, and the newly extended indications, HCC risks decreased to 2,531 (-7.1%), 2,089 (-23.3%), and 1,122 (-58.8%) cases per 100,000 persons, respectively (p

Hepatocellular carcinoma (HCC) is a heterogeneous disease. Mouse models are commonly used as preclinical models to study hepatocarcinogenesis, but how well these models recapitulate molecular subtypes of human HCC is unclear. Here, integration of genomic signatures from molecularly and clinically defined human HCC (n = 11) and mouse models of HCC (n = 9) identified the mouse models that best resembled subtypes of human HCC and determined the clinical relevance of each model. Mst1/2 knockout (KO), Sav1 KO, and SV40 T antigen mouse models effectively recapitulated subtypes of human HCC with a poor prognosis, whereas the Myc transgenic model best resembled human HCCs with a more favorable prognosis. The Myc model was also associated with activation of β-catenin. E2f1, E2f1/Myc, E2f1/Tgfa, and diethylnitrosamine (DEN)-induced models were heterogeneous and were unequally split into poor and favorable prognoses. Mst1/2 KO and Sav1 KO models best resemble human HCC with hepatic stem cell characteristics. Applying a genomic predictor for immunotherapy, the six-gene IFNγ score, the Mst1/2 KO, Sav1 KO, SV40, and DEN models were predicted to be the least responsive to immunotherapy. Further analysis showed that elevated expression of immune-inhibitory genes (Cd276 and Nectin2/Pvrl2) in Mst1/2 KO, Sav1 KO, and SV40 models and decreased expression of immune stimulatory gene (Cd86) in the DEN model might be accountable for the lack of predictive response to immunotherapy. Implication: The current genomic approach identified the most relevant mouse models to human liver cancer and suggests immunotherapeutic potential for the treatment of specific subtypes. Mol Cancer Res; 16(11); 1713–23. ©2018 AACR.

Several aryl hydrocarbon receptor (AhR)-active pharmaceuticals were screened as inhibitors of pancreatic cancer cell invasion and identified two compounds, omeprazole, that inhibited invasion. Inhibition of highly invasive Panc1 cell invasion by omeprazole involves an AhR-dependent non-genomic pathway, and omeprazole-mediated inhibition of Panc1 cell invasion was dependent on Jun-N-terminal kinase (JNK) and mitogen-activated kinase kinase 7 (MKK7). The failure of omeprazole to induce nuclear translocation of the AhR was not due to overexpression of cytosolic AhR partner proteins Hsp90 or XAP2, and results of DNA sequencing show that the AhR expressed in Panc1 cells was not mutated. Results of RNAseq studies indicate that omeprazole induced an AhR-dependent downregulation of several pro-invasion factors including activated leukocyte cell adhesion molecule (ALCAM), long chain fatty acid CoA-synthase (CSL4), stathmin 3 (STMN3) and neuropillin 2 (NRP2), and the specific functions of these genes are currently being investigated.

Gastric cancer is a heterogeneous cancer, making treatment responses difficult to predict. Here we show that we identify two distinct molecular subtypes, mesenchymal phenotype (MP) and epithelial phenotype (EP), by analyzing genomic and proteomic data. Molecularly, MP subtype tumors show high genomic integrity characterized by low mutation rates and microsatellite stability, whereas EP subtype tumors show low genomic integrity. Clinically, the MP subtype is associated with markedly poor survival and resistance to standard chemotherapy, whereas the EP subtype is associated with better survival rates and sensitivity to chemotherapy. Integrative analysis shows that signaling pathways driving epithelial-to-mesenchymal transition and insulin-like growth factor 1 (IGF1)/IGF1 receptor (IGF1R) pathway are highly activated in MP subtype tumors. Importantly, MP subtype cancer cells are more sensitive to inhibition of IGF1/IGF1R pathway than EP subtype. Detailed characterization of these two subtypes could identify novel therapeutic targets and useful biomarkers for prognosis and therapy response., The prognosis and treatment of gastric cancer is complicated by heterogeneity. Here, the authors reveal two molecular subtypes, the mesenchymal subtype associated with poor survival and chemoresistance, and the epithelial phenotype associated with better survival and sensitivity to chemotherapy.

Myeloid-derived suppressor cells (MDSC) are an immunosuppressive population of immature myeloid cells found in advanced-stage cancer patients and mouse tumor models. Production of inducible nitric oxide synthase (iNOS) and arginase, as well as other suppressive mechanisms, allows MDSCs to suppress T-cell–mediated tumor clearance and foster tumor progression. Using an unbiased global gene expression approach in conditional p120-catenin knockout mice (L2-cre;p120ctnf/f), a model of oral–esophageal cancer, we have identified CD38 as playing a vital role in MDSC biology, previously unknown. CD38 belongs to the ADP-ribosyl cyclase family and possesses both ectoenzyme and receptor functions. It has been described to function in lymphoid and early myeloid cell differentiation, cell activation, and neutrophil chemotaxis. We find that CD38 expression in MDSCs is evident in other mouse tumor models of esophageal carcinogenesis, and CD38high MDSCs are more immature than MDSCs lacking CD38 expression, suggesting a potential role for CD38 in the maturation halt found in MDSC populations. CD38high MDSCs also possess a greater capacity to suppress activated T cells, and promote tumor growth to a greater degree than CD38low MDSCs, likely as a result of increased iNOS production. In addition, we have identified novel tumor–derived factors, specifically IL6, IGFBP3, and CXCL16, which induce CD38 expression by MDSCs ex vivo. Finally, we have detected an expansion of CD38+ MDSCs in peripheral blood of advanced-stage cancer patients and validated targeting CD38 in vivo as a novel approach to cancer therapy. Cancer Res; 75(19); 4074–85. ©2015 AACR.

The present study aimed to examine the anti-inflammatory effects and potential mechanism of action of Artemisia asiatica Nakai (A. asiatica Nakai) extract in activated murine macrophages. A. asiatica Nakai extract showed dose-dependent suppression of lipopolysaccharide (LPS)-induced nitric oxide, inducible nitric oxide synthase, and cyclooxygenase-2 activity. It also showed dose-dependent inhibition of nuclear factor-κB (NF-κB) translocation from the cytosol to the nucleus and as an inhibitor of NF-κB-alpha phosphorylation. The extract's inhibitory effects were found to be mediated through NF-κB inhibition and phosphorylation of extracellular signal-regulated kinase 1/2 and p38 in LPS-stimulated J774A.1 murine macrophages, suggesting a potential mechanism for the anti-inflammatory activity of A. asiatica Nakai. To our knowledge, this is the first report of the anti-inflammatory effects of A. asiatica Nakai on J774A.1 murine macrophages; these results may help develop functional foods possessing an anti-inflammatory activity.

The convergence rate of a numerical procedure based on Schwarz Alternating Method(SAM) for solving elliptic boundary value problems depends on the selection of the interface conditions applied on the interior boundaries of the overlapping subdomains. It has been observed that the Robin condition (mixed interface condition), controlled by a parameter, can optimize SAM`s convergence rate. In [7], one formulated the multi-parameterized SAM and determined the optimal values of the multi-parameters to produce the best convergence rate for one-dimensional elliptic boundary value problems. Two-dimensional implementation was presented in [8]. In this paper, we present an implementation for three-dimensional problem.

DNMT3A, the gene encoding the de novo DNA methyltransferase 3A, is among the most frequently mutated genes in hematologic malignancies. However, the mechanisms through which DNMT3A normally suppresses malignancy development are unknown. Here, we show that DNMT3A loss synergizes with the FLT3 internal tandem duplication (ITD) in a dose-influenced fashion to generate rapid lethal lymphoid or myeloid leukemias similar to their human counterparts. Loss of DNMT3A leads to reduced DNA methylation, predominantly at hematopoietic enhancer regions in both mouse and human samples. Myeloid and lymphoid diseases arise from transformed murine hematopoietic stem cells. Broadly, our findings support a role for DNMT3A as a guardian of the epigenetic state at enhancer regions, critical for inhibition of leukemic transformation.

Immunotherapy has emerged as a promising anti-cancer treatment, however, little is known about the genetic characteristics that dictate response to immunotherapy. We develop a transcriptional predictor of immunotherapy response and assess its prediction in genomic data from ~10,000 human tissues across 30 different cancer types to estimate the potential response to immunotherapy. The integrative analysis reveals two distinct tumor types: the mutator type is positively associated with potential response to immunotherapy, whereas the chromosome-instable type is negatively associated with it. We identify somatic mutations and copy number alterations significantly associated with potential response to immunotherapy, in particular treatment with anti-CTLA-4 antibody. Our findings suggest that tumors may evolve through two different paths that would lead to marked differences in immunotherapy response as well as different strategies for evading immune surveillance. Our analysis provides resources to facilitate the discovery of predictive biomarkers for immunotherapy that could be tested in clinical trials., There is an urgent need to identify predictive markers for selecting responders to immunotherapy. Here, the authors describe a transcriptional predictor of immunotherapy response and assess it in genomic data from ~ 10,000 human tissues across 30 different cancer types.

Purpose: An improved understanding of the molecular pathogenesis of brain metastases, one of the most common and devastating complications of advanced melanoma, may identify and prioritize rational therapeutic approaches for this disease. In particular, the identification of molecular differences between brain and extracranial metastases would support the need for the development of organ-specific therapeutic approaches. Experimental Design: Hotspot mutations, copy number variations (CNV), global mRNA expression patterns, and quantitative analysis of protein expression and activation by reverse-phase protein array (RPPA) analysis were evaluated in pairs of melanoma brain metastases and extracranial metastases from patients who had undergone surgical resection for both types of tumors. Results: The status of 154 previously reported hotspot mutations, including driver mutations in BRAF and NRAS, were concordant in all evaluable patient-matched pairs of tumors. Overall patterns of CNV, mRNA expression, and protein expression were largely similar between the paired samples for individual patients. However, brain metastases demonstrated increased expression of several activation-specific protein markers in the PI3K/AKT pathway compared with the extracranial metastases. Conclusions: These results add to the understanding of the molecular characteristics of melanoma brain metastases and support the rationale for additional testing of the PI3K/AKT pathway as a therapeutic target in these highly aggressive tumors. Clin Cancer Res; 20(21); 5537–46. ©2014 AACR.

nc886 is a 101 nucleotide long non-coding RNA that has been designated as a precursor microRNA or a vault RNA based upon it sequence. nc886 has also been suggested to be a tumor suppressor, mainly inferred by its expression pattern as well as its genomic location at human chromosome 5q31, a locus for a tumor suppressor gene(s). However, legitimate data based on nc886's correct identity for its functional cellular roles as a tumor suppressor have not been provided yet. Here we have investigated nc886 in gastric cancer where its expression is suppressed due to CpG DNA hypermethylation at its promoter region in a cohort of paired tumor/normal tissues from 88 gastric cancer patients. CpG hypermethylation of nc886 and thus its diminished expression is significantly associated with poor survival in these cancer patients. nc886 inhibits cell proliferation when ectopically expressed in gastric cancer cells. nc886's tumor suppressive role is corroborated by the induction of well-known oncogenes such as FOS, NF-κB, and MYC upon its knockdown. All these activities of nc886 are undoubtedly independent of mature microRNA or vault RNA. Our data indicate that nc886 is a putative tumor suppressor and could potentially be used as a diagnostic marker in gastric cancer.

We have quantitatively compared the portion and temperature dependence of each current component in commercial green and blue light-emitting diodes (LEDs) using a current-component analysis method for the purpose of finding out the origin of the green-gap problem, which is a major roadblock to the next-generation solid-state lighting. The analysis results show that the loss current, which is the origin of the efficiency droop, decreases the internal quantum efficiency of the green LED significantly and is the primary origin of the green-gap problem. In addition, the loss current Iloss and the radiation current Irad that actually generates light output are approximately related as Iloss ∝ Irad1.5 almost independent of the temperature. Therefore, Iloss and Irad1.5 have the similar temperature dependence in both the green and blue LEDs, and the loss current is approximately proportional to the cube of the carrier concentration. The temperature and the carrier-concentration dependences are valuable clues to the physical origin of the green-gap problem and the efficiency droop. On the other hand, the portion and the temperature sensitivity of the Shockley-Read-Hall (SRH) nonradiative recombination current are similar in the green and blue LEDs. Therefore, in our samples, the SRH nonradiative recombination is not the origin of the green-gap problem.

NR4A1 (Nur77, TR3) is an orphan nuclear receptor that is overexpressed in pancreatic cancer and exhibits pro-oncogenic activity. RNA interference of NR4A1 expression in Panc-1 cells induced apoptosis and subsequent proteomic analysis revealed the induction of several markers of endoplasmic reticulum stress, including glucose-related protein 78 (GRP78), CCAAT/enhancer-binding protein-homologous protein (CHOP), and activating transcription factor-4 (ATF-4). Treatment of pancreatic cancer cells with the NR4A1 antagonist 1,1-bis(3′-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH) gave similar results. Moreover, both NR4A1 knockdown and DIM-C-pPhOH induced reactive oxygen species (ROS), and induction of ROS and endoplasmic reticulum stress by these agents was attenuated after cotreatment with antioxidants. Manipulation of NR4A1 expression coupled with gene expression profiling identified a number of ROS metabolism transcripts regulated by NR4A1. Knockdown of one of these transcripts, thioredoxin domain containing 5 (TXNDC5), recapitulated the elevated ROS and endoplasmic reticulum stress; thus, demonstrating that NR4A1 regulates levels of endoplasmic reticulum stress and ROS in pancreatic cancer cells to facilitate cell proliferation and survival. Finally, inactivation of NR4A1 by knockdown or DIM-C-pPhOH decreased TXNDC5, resulting in activation of the ROS/endoplasmic reticulum stress and proapoptotic pathways. Implications: The NR4A1 receptor is pro-oncogenic, regulates the ROS/endoplasmic reticulum stress pathways, and inactivation of the receptor represents a novel pathway for inducing cell death in pancreatic cancer. Mol Cancer Res; 12(4); 527–38. ©2014 AACR.

Leukemia cells are protected by various components of their microenvironment, including marrow stromal cells (MSCs). To understand the molecular mechanisms underlying this protection, we cultured acute lymphoblastic leukemia (ALL) cells with MSCs and studied the effect of the latter on the molecular profiling of ALL cells at the mRNA and protein levels. Our results indicated that activated Wnt signaling in ALL cells is involved in MSC-mediated drug resistance. Blocking the Wnt pathway sensitized the leukemia cells to chemotherapy and improved overall survival in a mouse model. Targeting the Wnt pathway may be an innovative approach to the treatment of ALL.

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 microRNA 520 (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 TARDBP is significantly associated with the overall survival of patients with HCC. Conclusion: Our study provides new mechanistic insights into the regulation of glycolysis in HCC cells and reveals TARDBP as a potential therapeutic target for HCC. (HEPATOLOGY 2013;)

Background/Aims We aim to evaluate the association between promoter polymorphism of the clusters of differentiation 14 (CD14) gene and Helicobacter pylori-induced gastric mucosal inflammation in a healthy Korean population. Methods The study population consisted of 267 healthy subjects who visited our hospital for free nationwide gastric cancer screening. Promoter polymorphism at -260 C/T of the CD14 gene was determined by polymerase chain reaction and restriction fragment length polymorphism analysis. The severity of gastric mucosal inflammation was estimated by a gastritis score based on the sum of the values of the grade and activity of the gastritis. Expression of soluble CD14 (sCD14) was assessed by quantitative sandwich ELISA. Results CD14 polymorphism was not associated with H. pylori infection. There were no significant differences in gastritis scores among the genotype subgroups, but subjects carrying the CD14 -260 CT/TT genotype had significantly higher sCD14 levels than those carrying the CC genotype. Subjects with the 260-T allele of the CD14 gene and H. pylori infection had significantly higher sCD14 levels than those with the same genotype but without infection. Conclusions In individuals with the T allele at the -260 site of the promoter region of the CD14 gene, H. pylori infection accentuates gastric mucosal inflammation.

We have decomposed the blue light-emitting diode (LED) current into the constituent components and studied the temperature dependence of each component and the internal quantum efficiency (IQE) quantitatively over the temperature range from 0°C to 80°C. The most temperature-sensitive current component is the nonradiative recombination current that increases with the temperature rise, and the component plays a dominant role in determining the temperature dependence of the IQE and luminescence output. Therefore, high-efficiency LEDs achieve high power and low temperature sensitivity simultaneously. On the other hand, the portion of the loss current that is responsible for the efficiency droop decreases with the temperature rise, resulting in lower droop at higher temperature. Some consequences and implications of the temperature dependence are also discussed.

Background Gastric cancer is supposed to be a result of inflammation induced by Helicobacter pylori (H. pylori) infection. Nucleotide-binding oligomerization domain 1 (NOD 1) is required for the innate immune response to H. pylori. We aim to investigate whether single nucleotide polymorphism (SNP) in NOD 1 gene is associated with H. pylori-induced gastric mucosal inflammation in a healthy Korean population. Methods The study was conducted on 412 adults who visited two different healthcare centers for health examinations. The G796A (E266K) NOD 1 SNP was detected by using polymerase chain reaction/restriction fragment length polymorphism. A gastritis score was calculated by the summed values of the grade and the activity of gastritis scored according to the updated Sydney system. The expression of IL-8 and COX-2 mRNA was assessed by quantitative reverse transcription polymerase chain reaction. In the group with H. pylori infection, the complete screening of the genes comprising the cag PAI was performed. Results The genotype frequencies were 26.7% (AA type), 58.3% (GA), and 15.0% (GG). In H. pylori-positive patients, gastritis score of the AA genotype was significantly higher than those of the others (p = .04). Also, the IL-8 and COX-2 mRNA levels increased in the AA genotype. In the group with H. pylori infection, 31.9% were found to carry the complete cag PAI. When the subjects were infected with intact cag PAI, the IL-8 and COX-2 mRNA levels were significantly high in AA genotype. Conclusion G796A (E266K) NOD 1 polymorphism is closely correlated with H. pylori-associated gastric mucosal inflammation in the Korean population.

Disruption of the TGF-β pathway is associated with liver fibrosis and suppression of liver tumorigenesis, conditions associated with low Vitamin D (VD) levels. However, potential contributions of VD to liver tumor progression in the context of TGF-β signaling remain unexplored. Our analyses of VD deprivation (VDD) in in vivo models of liver tumor formation revealed striking three-fold increases in tumor burden in Smad3+/− mice, with a three-fold increase in TLR7 expression compared to controls. ChIP and transcriptional assays confirm Smad3 binding at two TLR7 promoter SBE sites. Molecular interactions between TGF-β pathway and VDD were validated clinically, where an absence of VD supplementation was associated with low TGF-β pathway member expression levels and β-catenin activation in fibrotic/cirrhotic human liver tissues. Subsequent supplementing VD led to restoration of TGF-β member expression with lower β-catenin levels. Bioinformatics analysis provides positive supportive correlation between somatic mutations for VD-related genes and the TGF-β pathway. We conclude that VDD promotes tumor growth in the context of Smad3 disruption, potentially through regulation of TLR7 expression and β-catenin activation. VD could therefore be a strong candidate for liver cancer prevention in the context of aberrant Smad3 signaling.

We have quantitatively analyzed the short-term aging behavior of blue light-emitting diodes using the current-component analysis method. The internal quantum efficiency and luminescence output decrease monotonically with the aging time and are stabilized at low operation current, owing to the increase and subsequent stabilization in the tunneling and nonradiative currents, while they show complicated behavior at high operation current due to the interplay of different changing rates in the radiative and nonradiative recombination current components. The current-component analysis enables both the quantitative understanding of the aging behavior and the identification of the aging mechanisms. Also shown is that the loss current, which is responsible for the efficiency droop, is approximately proportional to the cube of the injected carrier concentration. This suggests that the origin of the efficiency droop is a three-carrier process.

HOTAIR is a long intervening non-coding RNA (lincRNA) that associates with the Polycomb Repressive Complex 2 (PRC2) and overexpression is correlated with poor survival for breast, colon and liver cancer patients. In this study, we show that HOTAIR expression is increased in pancreatic tumors compared with non-tumor tissue and is associated with more aggressive tumors. Knockdown of HOTAIR (siHOTAIR) by RNA interference shows that HOTAIR has an important role in pancreatic cancer cell invasion, as reported in other cancer cell lines. In contrast, HOTAIR knockdown in Panc1 and L3.6pL pancreatic cancer cells that overexpress this lincRNA decreased cell proliferation, altered cell cycle progression and induced apoptosis, demonstrating an expanded function of HOTAIR in pancreatic cancer cells compared with other cancer cell lines. Results of gene array studies showed that there was minimal overlap between HOTAIR-regulated genes in pancreatic cells and breast cancer cells, and HOTAIR uniquely suppressed several interferon-related genes and gene sets related to cell cycle progression in pancreatic cancer cells and tumors. Analysis of selected genes suppressed by HOTAIR in Panc1 and L3.6pL cells showed by knockdown of EZH2 and chromatin immunoprecipitation assays that HOTAIR-mediated gene repression was both PRC2-dependent and -independent. HOTAIR knockdown in L3.6pL cells inhibited tumor growth in mouse xenograft model, further demonstrating the pro-oncogenic function of HOTAIR in pancreatic cancer.

Clinical application of the prognostic gene expression signature has been delayed due to the large number of genes and complexity of prediction algorithms. In the current study we aimed to develop an easy-to-use risk score with a limited number of genes that can robustly predict prognosis of patients with hepatocellular carcinoma (HCC). The risk score was developed using Cox coefficient values of 65 genes in the training set (n = 139) and its robustness was validated in test sets (n = 292). The risk score was a highly significant predictor of overall survival (OS) in the first test cohort (P = 5.6 × 10−5, n = 100) and the second test cohort (P = 5.0 × 10−5, n = 192). In multivariate analysis, the risk score was a significant risk factor among clinical variables examined together (hazard ratio [HR], 1.36; 95% confidence interval [CI], 1.13-1.64; P = 0.001 for OS). Conclusion: The risk score classifier we have developed can identify two clinically distinct HCC subtypes at early and late stages of the disease in a simple and highly reproducible manner across multiple datasets. (HEPATOLOGY 2011)

Liquid–liquid phase equilibria (LLE) for the ternary system containing water + tri-octylamine (TOA) or tri-butylphosphate (TBP) + 1-decane were reported in a previous paper. These ternary combinations can be used as selective solvents and diluents in the molybdenum (Mo) extraction process. In the interest of industrial applicability, the LLE for the system containing aqueous sulfuric acid solution (pH 1.0) + TOA or TBP + 1-decane has been discussed at the temperature of 298.15 K and a normal atmospheric pressure. The solubility of TOA and TBP in water was a little decreased with the addition of sulfuric acid. Nonrandom two-liquid (NRTL) and universal quasichemical (UNIQUAC) models were used for the description of the determined LLE data. In addition, the density (ρ) and the refractive index (nD) for the systems TOA + 1-decane and TBP + 1-decane at 298.15 K were determined. These data were used to calculate the binary excess molar volume (VE) and the deviations of the refractive indices (ΔR) over the entire composition range. The ternary VE and ΔR prediction for the TOA + TBP + 1-decane system was determined from the binary data with the Radojkovic equation.

Purpose: This study was aimed at developing and validating a quantitative multigene assay for predicting tumor recurrence after gastric cancer surgery. Experimental Design: Gene expression data were generated from tumor tissues of patients who underwent surgery for gastric cancer (n = 267, training cohort). Genes whose expression was significantly associated with activation of YAP1 (a frequently activated oncogene in gastrointestinal cancer), 5-year recurrence-free survival, and 5-year overall survival were first identified as candidates for prognostic genes (156 genes, P < 0.001). We developed the recurrence risk score (RRS) by using quantitative RT-PCR to identify genes whose expression levels were significantly associated with YAP1 activation and patient survival in the training cohort. Results: We based the RRS assay on 6 genes, IGFBP4, SFRP4, SPOCK1, SULF1, THBS, and GADD45B, whose expression levels were significantly associated with YAP1 activation and prognosis in the training cohort. The RRS assay was further validated in an independent cohort of 317 patients. In multivariate analysis, the RRS was an independent predictor of recurrence [HR, 1.6; 95% confidence interval (CI), 1.02–2.4; P = 0.03]. In patients with stage II disease, the RRS had an HR of 2.9 (95% CI, 1.1–7.9; P = 0.03) and was the only significant independent predictor of recurrence. Conclusions: The RRS assay was a valid predictor of recurrence in the two cohorts of patients with gastric cancer. Independent prospective studies to assess the clinical utility of this assay are warranted. Clin Cancer Res; 22(24); 6228–35. ©2016 AACR.

We have demonstrated fixed-current operation of a vertical-cavity surface-emitting laser (VCSEL) transmitter operating at 1.25 Gb/s over a wide temperature range by using an elevated-oxide-layer structure. Four different types of oxide VCSELs have been prepared for the transmitter modules; conventional-oxide and elevated-oxide-layer VCSELs with the oxide-aperture diameter of 6.6 and 10 μm, and their temperature dependence of the threshold current and turn-off transient responses have been measured. Approximately 10%-reduced both fall time and timing jitter mainly originating from the alleviated turn-off-induced abnormalities in the elevated-oxide-layer VCSEL transmitters contributed to achieve the fixed-current operation in the temperature range from 20 °C to 80 °C. Although the operating current of the elevated-oxide-layer VCSEL transmitter should be increased as the threshold current increases, a simple driving circuit owing to the fixed-current operating transmitter over a wide temperature range will bring a drastic energy saving in the optical data transmission system that incorporates VCSEL as a light source.

We carried out to investigate the refining effect of molybdenum by Ar-H vacuum arc melting(VAM) process for recycling Mo scrap. The purity of the Mo metals refined by VAM was evaluated using glow discharge mass spectromety(GDMS). From the result of GDMS, most impurities in the Mo metals except for W were removed by Ar-H VAM down to a few mass ppm levels. The purity of the refined molybdenum scrap was improved up to 4N5(99.995%) from 3N(99.95%) of the initial Mo scrap. The amount of gaseous impurities such as C, N, and O in Mo scrap were decreased from 1290 ppm to 132 ppm. As a result, it is considered that a possibility of refining and cost-effective method for recycling Mo scrap by Ar-H vacuum arc melting process was confirmed in this study.

Aims Despite continual efforts to develop prognostic and predictive models of colorectal cancer by using clinicopathological and genetic parameters, a clinical test that can discriminate between patients with good or poor outcome after treatment has not been established. Thus, the authors aim to uncover subtypes of colorectal cancer that have distinct biological characteristics associated with prognosis and identify potential biomarkers that best reflect the biological and clinical characteristics of subtypes. Methods Unsupervised hierarchical clustering analysis was applied to gene expression data from 177 patients with colorectal cancer to determine a prognostic gene expression signature. Validation of the signature was sought in two independent patient groups. The association between the signature and prognosis of patients was assessed by Kaplan–Meier plots, log-rank tests and the Cox model. Results The authors identified a gene signature that was associated with overall survival and disease-free survival in 177 patients and validated in two independent cohorts of 213 patients. In multivariate analysis, the signature was an independent risk factor (HR 3.08; 95% CI 1.33 to 7.14; p=0.008 for overall survival). Subset analysis of patients with AJCC (American Joint Committee on Cancer) stage III cancer revealed that the signature can also identify the patients who have better outcome with adjuvant chemotherapy (CTX). Adjuvant chemotherapy significantly affected disease-free survival in patients in subtype B (3-year rate, 71.2% (CTX) vs 41.9% (no CTX); p=0.004). However, such benefit of adjuvant chemotherapy was not significant for patients in subtype A. Conclusion The gene signature is an independent predictor of response to chemotherapy and clinical outcome in patients with colorectal cancer.

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.

We have decomposed light-emitting diode (LED) current into component currents by identifying the ideality factor of each component and by fitting the measured and simulated current-voltage ( I-V ), I(dV/dI)-I and the shape of the relative luminescence efficiency-current characteristics. Nearly unity ideality factor of the radiative recombination current is found from luminescence-voltage (L- V) characteristics in AlGaInP red and GaInN green and blue LEDs. The current-component analysis enables an estimation of the internal quantum efficiency (IQE) as a function of current. Compared with red LEDs, blue LEDs suffer from lower radiative recombination efficiency and much larger efficiency droop to result in lower IQE.

Molybdenum is chemically combined with other elements and usually extracted from acid leaching a residual solution of molybdenite. Understanding the behavior of the solvents is important for the optimization of the separation procedures. Therefore, binary and ternary liquid−liquid equilibria (LLE) were measured for a mixture of chloroform, acetylacetone, and water at (293.15 to 333.15) K and atmospheric pressure (101.3 ± 0.7 kPa). The solid−liquid equilibrium (SLE) between chloroform and acetylacetone was also determined by visual techniques. This system has a single eutectic point. The experimental LLE and SLE data were well-correlated by the nonrandom two-liquid (NRTL) and universal quasichemical activity coefficient (UNIQUAC) models. In addition, the excess molar volume (VE) and refractivity (nD) for the binary chloroform + acetylacetone mixture were measured at 298.15 K over the entire composition range. The experimental data were satisfactorily fit using the Redlich−Kister polynomial.

Leaching of nickel garnierite ore with sulfuric acid resulted in a mixed sulfate solution of Co(II) and Ni(II) with high magnesium content. In order to find an optimum condition to separate cobalt, solvent extraction experiments have been performed from the synthetic leaching sulfate solution with the following composition: Co(II) ¼ 0:08 g/L, Ni(II) ¼ 4:4 g/L, Mg(II) ¼ 32:2 g/L. The effects of extraction variables on the separation of Co(II) from nickel and magnesium were investigated by using D2EHPA, PC88A, Cyanex272, and Alamine336. Saponifiaction degree of cationic extractants, extractant concentration, and volume ratio were changed. In our experimental range, extraction of nickel was negligible. Among the cationic extractants tested in this study, the highest separation factor between Co(II) and Mg(II) was obtained with saponified Cyanex272. Alamine336 in the presence of MgCl2 extracted only Co(II), while the extraction percentage of Mg(II) was nearly zero. [doi:10.2320/matertrans.M2011027]

A new process for producing ferromolybdenum powder master alloy without generating secondary pollutants by a two-step hydrogen reduction process involving MoO3 and mill scale has been developed. In this process, mill scale which is an iron byproduct generated from the steel rolling process is used as an iron source. Experimentally, ferromolybdenum powder master alloy was produced by a two-step hydrogen reduction process: The first hydrogen reduction stage was carried at a horizontal furnace for 60 min at 848 K under a hydrogen gas at a partial pressure of 101.3 kPa, and the second hydrogen reduction stage was done at the same furnace for 40 min at 1123 K under the same hydrogen partial pressure. In the process, the reduction reactions of MoO3 to MoO2 and mill scale to Fe proceed simultaneously in the first reduction step, and then the reduction reaction of MoO2 to Mo does in the second reduction step. The reaction rate of the second step in the two-step hydrogen reduction process of MoO3-Fe2O3 mixture was also measured under isothermal condition in hydrogen atmosphere using TGA equipment. As an example, at 1173 K under a hydrogen partial pressure of 101.3 kPa, almost 100% of MoO2 was reduced to Mo in 5 min. The nucleation and growth model were found to be applicable to the reaction rate. The reaction was first order with respect to hydrogen partial pressure and had an activation energy of 83.8 kJ/mol (20.1 kcal/mol). [doi:10.2320/matertrans.M2011037]

Natural resources of platinum group metals (PGMs) are limited and their demand is increasing because of their extensive uses in industrial applications. The low rate of production of PGMs due to low concentration in the related natural ores and high cost of production have made the recovery of PGMs from previously discarded catalytic converters a viable proposition. The ceramic-honeycomb-type automobile catalytic converter contains appreciable amount of PGMs. These valuable substances, which are embedded in the catalyst layer and covered on the surface of the supporting matrix, were selectively recovered by attrition scrubbing. The attrition scrubbing was effective for the selective recovery of catalyst layer. The process was convinced as the comminution and separation process by physical impact and shearing action between particles in the scrubbing vessel. The catalyst layer was dislodged from the surface of the supporting matrix into fine particles by attrition scrubbing. The recovery of Al 2 O 3 and total PGMs in the fraction less than 300 μm increased with the residence time whereas their contents in the recovered materials slightly decreased. The interparticle scrubbing became favorable when the initial input size increased. However, the solid/liquid ratio in the mixing vessel was slightly affected by the low density of converter particles.

Phase equilibriums were studied with related extractive solvents of Molybdenum (Mo). Tri-butylphosphate, tri-octylamine and heavy alcohols are used in the extraction of Mo from the acidic media of Mo roasted ore, as a selective solvent or modifier. Solid–liquid equilibrium (SLE) between these solvents and modifiers were determined by visual technique. The combination of solvent and modifier were binary systems of tri-butylphosphate + 1-octanol, tri-butylphosphate + 1-decanol and 1-octanol + 1-decanol. They have a single eutectic point. Non-random two liquid (NRTL) and universal quasi chemical (UNIQUAC) models were used for the description of the determined SLE data. The extraction process of Mo usually progressed with solvents in the kerosene diluents. In order to analyze solvent capability, liquid–liquid equilibrium (LLE) for the ternary systems 1-decane + tri-butylphosphate + water and 1-decane + tri-octylamine + water were determined because 1-decane is usually considered as a model compound of kerosene. The measured ternary LLE data were correlated well with NRTL and UNIQUAC model.

Human squamous cell cancers are the most common epithelially derived malignancies. One example is esophageal squamous cell carcinoma (ESCC), which is associated with a high mortality rate that is related to a propensity for invasion and metastasis. Here, we report that periostin, a highly expressed cell adhesion molecule, is a key component of a novel tumor-invasive signature obtained from an organotypic culture model of engineered ESCC. This tumor-invasive signature classifies with human ESCC microarrays, underscoring its utility in human cancer. Genetic modulation of periostin promotes tumor cell migration and invasion as revealed in gain-of-loss and loss-of-function experiments. Inhibition of epidermal growth factor receptor signaling and restoration of wild-type p53 function were each found to attenuate periostin, suggesting the interdependence of two common genetic alterations with periostin function. Collectively, our studies reveal periostin as an important mediator of ESCC tumor invasion and they indicate that organotypic (three-dimensional) culture can offer an important tool to discover novel biological effectors in cancer. Cancer Res; 70(13); 5281–92. ©2010 AACR.

Aberrations in oncogenes and tumor suppressors frequently affect the activity of critical signal transduction pathways. To analyze systematically the relationship between the activation status of protein networks and other characteristics of cancer cells, we did reverse phase protein array (RPPA) profiling of the NCI60 cell lines for total protein expression and activation-specific markers of critical signaling pathways. To extend the scope of the study, we merged those data with previously published RPPA results for the NCI60. Integrative analysis of the expanded RPPA data set revealed five major clusters of cell lines and five principal proteomic signatures. Comparison of mutations in the NCI60 cell lines with patterns of protein expression showed significant associations for PTEN, PIK3CA, BRAF, and APC mutations with proteomic clusters. PIK3CA and PTEN mutation enrichment were not cell lineage-specific but were associated with dominant yet distinct groups of proteins. The five RPPA-defined clusters were strongly associated with sensitivity to standard anticancer agents. RPPA analysis identified 27 protein features significantly associated with sensitivity to paclitaxel. The functional status of those proteins was interrogated in a paclitaxel whole genome small interfering RNA (siRNA) library synthetic lethality screen and confirmed the predicted associations with drug sensitivity. These studies expand our understanding of the activation status of protein networks in the NCI60 cancer cell lines, demonstrate the importance of the direct study of protein expression and activation, and provide a basis for further studies integrating the information with other molecular and pharmacological characteristics of cancer. Mol Cancer Ther; 9(2); 257–67

Sonochemical synthesis of zeolite A has been conducted by ultrasonic irradiation of mixtures of metakaolinite and NaOH solution. The hydrothermal synthesis at conventional synthesis conditions was undertaken to determine the sonochemical reliability. The enhancement of nucleation and crystallization rate of zeolite A was achieved by ultrasound. In the ultrasonic field, zeolite A once formed in the suspension has been converted into hydroxysodalite and losod as sonicating proceeded. Comparing the results with those of conventional methods, this heterogeneous reaction was particularly accelerated by ultrasound, leading to improved reactivity of solid reactant through intensive mixing. The use of ultrasound enables us to prepare well-dispersed fine zeolite A particles with mean particle size of around 1 mm. The cation exchange capacity values of the products increased as the synthesis reaction for zeolite A proceeded. The high solid concentration in the suspension, however, hindered the ultrasound from intense agitating, resulting in the decrease of zeolite A yield. [doi:10.2320/matertrans.M2010191]

Molybdenite concentrate is the major mineral for the molybdenum industry. The industrial processing of molybdenite concentrate is first to convert to technical grade molybdenum trioxide by its oxidative roasting, followed by its purification by distillation or its ammonia leaching. In the present research, detailed experimental results for the oxidative roasting of low grade Mongolian molybdenite concentrate are presented. The experiments were carried out in the temperature range of 778 to 838 K under air atmosphere by using a thermogravimetric analysis technique. The particle size of the molybdenite concentrate was varied between 53 and 103 mm. As an example of the oxidative roasting of low grade Mongolian molybdenite concentrate, more than 95% of 53 mm particle size molybdenite was converted to molybdenum trioxide in 40 min at 823 K. The Jander equation was found to be useful in describing the rates of the oxidative roasting, which had an activation energy of 215.0 to 259.3 kJ/mol (51.4 to 62.0 kcal/mol) for various sizes, such as 53 mm ,6 7mm and 103 mm. [doi:10.2320/matertrans.M2009197]

The effect of forward and reverse electrostatic discharge (ESD) on the electro-optical characteristics of oxide vertical-cavity surface-emitting lasers is investigated using a human body model for the purpose of understanding degradation behavior. Forward ESD-induced degradation is complicated, showing three degradation phases depending on ESD voltage, while reverse ESD-induced degradation is relatively simple, exhibiting two phases of degradation divided by a sudden distinctive change in electro-optical characteristics. We demonstrate that the increase in the threshold current is mainly due to the increase in leakage current, nonradiative recombination current, and optical loss. The decrease in the slope efficiency is mainly due to the increase in optical loss.