bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2014: Gene expression profiling identifies characteristic oncogenetic pathways in age-related Epstein-Barr virus (EBV)-positive B-cell lymphoproliferative disorders.
Authors: Kato Harumi , Yamamoto Kazuhito , Karube Kennosuke , Takizawa Jun , Tsuzuki Shinobu , Yatabe Yasushi , Kanda Teru , Katayama Miyuki , Ozawa Yukiyasu , Ishitsuka Kenji , Okamoto Masataka , Kinoshita Tomohiro , Oshima Koichi , Nakamura Shigeo , Morishima Yasuo , Seto Masao 
Published: August 2014

Abstract
Age-related EBV-associated B-cell lymphoproliferative disorder (AR-EBVLPD) is newly classified as a subtype of diffuse large cell lymphoma (DLBCL) according to the WHO classification. AR-EBVLPD cases have poor prognosis compared to that of EBV-negative DLBCL patients. Until now, its molecular pathogenesis remains largely unknown. We investigated gene expression profiling to identify molecular genetic characterization of AR-EBVLPD. Total RNA was extracted from fresh-frozen tumor samples of five AR-EBVLPD and eight EBV-negative DLBCL cases. Expression profiling was studied using the Agilent 44K human oligonucleotide microarray. Genes highly expressed in AR-EBVLPD included inflammatory and immune-related genes. Gene set enrichment analysis and gene ontology analysis showed that gene sets of the JAK-STAT and NF-kB pathways were enriched in AR-EBVLPD cases. In vitro analysis showed that high activation of JAK-STAT and NF-kB pathways was induced by EBV infection into DLBCL cell lines. The immunoprecipitation assay confirmed that the NF-kB pathway was activated in EBV-infected cell lines compared to EBV-naïve cell lines. The protein expression level of phosphorylated STAT3 increased in an EBV-infected cell line according to western blot analysis. A total of 61 patients (25 AR-EBVLPD and 36 EBV-negative DLBCL) were analyzed immunohistochemically for pSTAT3. Protein expression of phospho-STAT3 was frequently observed in lymphoma cells of AR-EBVLPD clinical samples using immunohistochemistry [AR-EBVLPD: (80.0%, n=20/25) vs. EBV-negative DLBCL: (38.9%, n=22/36), p=0.001]. These results suggested that STAT3 and NF-kB activation was characteristic of AR-EBVLPD, which may reflect the nature of EBV-positive tumor cells. Targeting these pathways as therapies might improve clinical outcomes of AR-EBVLPD.
Citation Format: Harumi Kato, Kazuhito Yamamoto, Kennosuke Karube, Jun Takizawa, Shinobu Tsuzuki, Yasushi Yatabe, Teru Kanda, Miyuki Katayama, Yukiyasu Ozawa, Kenji Ishitsuka, Masataka Okamoto, Tomohiro Kinoshita, Koichi Oshima, Shigeo Nakamura, Yasuo Morishima, Masao Seto. Gene expression profiling identifies characteristic oncogenetic pathways in age-related Epstein-Barr virus (EBV)-positive B-cell lymphoproliferative disorders. [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 2014. doi:10.1158/1538-7445.AM2013-2014
Abstract 2015: BRCA1 expression and genomic aberrations in triple negative breast tumors.
Authors: Tapia Teresa , Aravena Andrés , Alvarez Carolina , Cornejo Valeria , Fernandez Wanda , Camus Mauricio , Maass Alejandro , Carvallo Pilar 
Published: August 2014

Abstract
Among breast cancer tumors, a group named as triple-negative breast cancer (TNBC) which do not express hormone receptors and HER2 (ER-, PR-, HER2-) do not have specific therapy. Therefore, knowing the genes involved in this type of tumor is highly relevant for treatment. Intense research in these tumors has been performed in order to identify new targets. We studied 48 TNBC tumors from Chilean patients by different approaches. In these tumors, we determined the expression, by immunohistochemistry, the different cytokeratins (CK5, CK14, and CK8/18) and EGFR. In addition, we analyzed BRCA1 expression and localization by immunohistochemistry. Using array-CGH, we characterized the genomic aberrations, in order to identify common alterations between tumors. A 62.5% (30/48) of the tumors were classified as basal-like. Expression and localization of BRCA1 analysis revealed that a 22.9% (11/48) of tumors presented normal expression of nuclear BRCA1, a 29.2% (14/48) has low or absent nuclear expression and a 47.9% (23/48) has altered BRCA1 localization, in addition to low expression in some cases. This suggests that the loss of expression of BRCA1 or its altered localization may be relevant for tumor progression. Analysis of genomic alterations by array-CGH revealed regions of gain (4p16.3-p16.2, 7p22.3-p22.2, 11p15.5, 19p13.3) and deleted regions (1q21.1, 6p11.2; 11q22.3) shared by more than 30% of these tumors. By grouping these tumors we identified three main groups, one of which correlates with the low expression / miss-localization of BRCA1. An analysis of the genes contained in these regions can determine the signaling pathways relevant to the progression of breast cancer. In this regard, by clustering, we identified a group of TNBC tumors (17/48) with amplification of AKT1, which may be relevant as a therapeutic target. FONDECYT 1080595, CONICYT 24091058.
Citation Format: Teresa Tapia, Andrés Aravena, Carolina Alvarez, Valeria Cornejo, Wanda Fernandez, Mauricio Camus, Alejandro Maass, Pilar Carvallo. BRCA1 expression and genomic aberrations in triple negative breast tumors. [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 2015. doi:10.1158/1538-7445.AM2013-2015
Abstract 202: Tocopherols inhibit the dietary carcinogen PhIP-induced prostate carcinogenesis in a CYP1A-humanized mouse model.
Authors: Li Guangxun , Wang Hong , Liu Anna B. , Chen Jayson X. , Lee Mao-Jung , Yang Chung S. 
Published: August 2014

Abstract
γ-TmT, a tocopherol mixture that is rich in γ-tocopherol (γ-T), containing 56.8% γ-T, 24.3% δ-T, 13.0% α-T and 1.5% β-T, has been shown to inhibit colon, lung, mammary and prostate tumorigenesis in our previous studies, whereas α-T was ineffective. The present work investigated the inhibition of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced prostate carcinogenesis in CYP1A-humanized (hCYP1A) mice by γ-TmT. Male hCYP1A mice, maintained on the AIN93M diet or the same diet supplemented with 0.3% γ-TmT, were treated with a dose of PhIP (200 mg/kg, i.g.). At week 40 after PhIP treatment, all mice developed high-grade prostate intraepithelial neoplasia (hgPIN) in the dorso-lateral glands. The hgPIN was associated with elevated levels of 8-oxo-deoxyguanosine (8-oxo-dG), DNMT1, COX-2 and p-AKT, as well as with loss of expression of the tumor suppressor PTEN, E-cadherin, GSTP1 and Nrf2 in the dorso-lateral glands. In the γ-TmT group, the number of glands with hgPIN (per 100 glands) was significantly lower than the control group (14.6 ± 4.87 vs. 34.81 ± 3.87, p &lt; 0.01). The γ-TmT treatment also prevented the elevation of 8-oxo-dG, COX-2 and p-AKT and the loss of PTEN and Nrf2. The γ-TmT treatment significantly increased the plasma levels of γ-T and δ-T (to 1.7 and 0.8 μM, respectively) as well as their side-chain degradation metabolites, carboxyethyl hydroxychromans and carboxymethylbutyl hydroxychromans (to 2.6-4.0 μM, higher than their parent tocopherols). In a short-term experiment, PhIP-treatment elevated levels of 8-oxo-dG, γH2AX and DNMT1, and caused gene expression changes in several p53-associated genes, including p53bp1, p21WAF1/CIP1, cyclin D1, Bax, Igf1 and cyclinG1 at 1 and/or 3 days after PhIP treatment. Dietary γ-TmT treatment partially prevented the elevation of 8-oxo-dG, γH2AX and DNMT1. This action may contribute to the prostate cancer preventive effect of tocopherols. The presently observed inhibitory activities of γ-TmT against prostate carcinogenesis are hypothesized to be due to the decrease of oxidative stress and inhibition of AKT phosphorylation by γ- and δ-tocopherols, and this hypothesis remains to be tested further (supported by NIH grants CA159361 & CA133021).
Citation Format: Guangxun Li, Hong Wang, Anna B. Liu, Jayson X. Chen, Mao-Jung Lee, Chung S. Yang. Tocopherols inhibit the dietary carcinogen PhIP-induced prostate carcinogenesis in a CYP1A-humanized mouse model. [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 202. doi:10.1158/1538-7445.AM2013-202
Abstract 2028: Co-targeting histone deacetylases and oncogenic BRAF synergistically kills human melanoma cell by caspase-independent cell death.
Authors: Guo Su Tang , Lai Fritz , Jiang Chen Chen , Wang Chun Yan , Farrelly Margaret , Tseng Hsin-Yi , Chi Meng Na , Jin Lei , Hersey Peter , Zhang Xu Dong 
Published: August 2014

Abstract
Inherent and acquired resistance of melanomas carrying active mutations in BRAF to mutant BRAF inhibitors (BRAFi) remains a major obstacle for curative treatment of the disease. Since both BRAFi and histone deacetylase inhibitors (HDACi) kill sensitive melanoma cells by activating the BH3-only protein Bim, we examined whether they cooperate in killing of BRAF(V600E) melanoma cells. We show here that co-treatment with the HDACi SAHA and the BRAFi PLX4720 synergistically kills BRAF(V600E) melanoma cells in vitro, and that the combination of SAHA and the clinically available BRAFi vemurafenib cooperatively inhibits melanoma growth in vivo. Although SAHA plus PLX4720 activated the caspase cascade, the latter did not appear to be indispensable for induction of cell death. Likewise, PLX4720 alone kills sensitive melanoma cells in a caspase-independent manner. Similar to caspases, Bim seemed dispensable for synergistic killing by SAHA and PLX4720. The mechanism by which co-treatment with HDACi and BRAFi kills BRAFV600E melanoma cells remains to be elucidated, but we have found that this is not mediated by receptor-interacting protein 1 (RIP1), which is essential for induction of programmed necrosis. Regardless, our results suggest that combinations of HDACi and BRAFi may have therapeutic advantages, in that the conventional caspase-dependent, mitochondrial-mediated apoptotic machinery is often suppressed in melanoma cells.
Citation Format: Su Tang Guo, Fritz Lai, Chen Chen Jiang, Chun Yan Wang, Margaret Farrelly, Hsin-Yi Tseng, Meng Na Chi, Lei Jin, Peter Hersey, Xu Dong Zhang. Co-targeting histone deacetylases and oncogenic BRAF synergistically kills human melanoma cell by caspase-independent cell death. [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 2028. doi:10.1158/1538-7445.AM2013-2028
Abstract 2038: Unraveling the mechanism of action: drugs that activate the tumor suppressor 2A .
Authors: Dun Matthew D. , Smith Amanda M. , Kahl Richard G. S. , Smith Nathan D. , Khanna Anchit , Don Anthony S. , Toop Hanish F. , Morris Jonathan C. , Verrills Nicole M. 
Published: August 2014

Abstract
The tumor suppressor 2A (PP2A) is a multi-enzyme complex that targets a variety of oncogenic signaling cascades such as Raf, MEK and AKT. Numerous reports have now emerged indicating that the inhibition of PP2A leads to the development of tumors including breast, gastric and lung and a range of hematological malignancies such as chronic and acute myeloid leukemia (CML and AML, respectively). We and others have shown that inhibition of PP2A is crucial for the oncogenic effects of leukemia associated receptor tyrosine kinases such as BCR/Abl, c-KIT and FLT3. Importantly when PP2A is reactivated using pharmacological agents (FTY720 and AAL(S)), growth and survival of these cells is inhibited. This approach targets molecules downstream of these oncogenic kinases and thus PP2A reactivation is designed to avoid resistance associated with kinase inhibitor therapy. As the mechanism of action of these PP2A activators is unknown, it is essential that we now determine the molecular targets of these compounds to generate more effective drugs. Using a chemical proteomics approach incorporating click chemistry linking the drugs to beads, unbiased pull down assays were performed in myeloid leukaemia cells and protein isolates were identified by mass spectrometry. Using this approach we have identified a novel cellular target, which is known to be overexpressed in a range of cancers, including leukemias. We have also shown that this protein associates with PP2A complexes in these cells, and thus may act as an endogenous inhibitor of PP2A activity. We have also performed phospho-proteomics and co-immunoprecipitation studies to identify protein changes in myeloid leukemia cells in response to PP2A activators. In addition to identifying known PP2A targets, such as Akt and ERK, we have also identified a number of novel protein changes, including altered expression of the SET oncoprotein. SET is a known inhibitor of PP2A, suggesting that FTY720 may act via inhibition of SET. Other PP2A regulatory proteins such as CIP2A, PME-1 and PP2A-B56alpha are also affected by FTY720/AAL(S) treatment. Our research findings are thus providing the vital clues necessary for determining the mechanism of action of clinically relevant PP2A activators, thereby moving us towards the provision of novel anti-cancer treatment regimes.
Citation Format: Matthew D. Dun, Amanda M. Smith, Richard G. S. Kahl, Nathan D. Smith, Anchit Khanna, Anthony S. Don, Hanish F. Toop, Jonathan C. Morris, Nicole M. Verrills. Unraveling the mechanism of action: drugs that activate the tumor suppressor 2A . [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 2038. doi:10.1158/1538-7445.AM2013-2038
Abstract 204: Breast cancer stem and non-stem-like cells express varying levels of selectin ligand activities.
Authors: Shirure Venktesh S. , Xiong Chengkai , Benencia Fabian , Burdick Monica M. 
Published: August 2014

Abstract
Cancer stem cells are a subset of tumor cells proposed to possess traits enabling metastatic invasion. Independently, selectins and their ligands are believed to play major roles in mediating the adhesion of circulating tumor cells to vascular endothelium during hematogenous metastasis. We thus hypothesized that the expression level of selectin ligands on breast cancer cells is related to breast cancer stem cell (BSC) or non-BSC phenotypes. Five breast carcinoma cell lines analyzed by flow cytometry were categorized as BSCs by the surface expression profile CD44+/CD24-/low, or non-BSCs marked by alternative expression of these proteins. All cell lines positively expressed E-, P-, and L-selectin ligand activity by flow cytometric analysis as well as under physiological flow conditions. Consistent with their E-selectin ligand activities, all cell lines expressed putative glycans for E-selectin binding, including sLeX, sLeA, and/or VIM-2 glycans, found by flow cytometric analysis. Yet the level of selectin ligand activity and glycan expression in BSCs was conspicuously lower than in non-BSCs. The abundant production of selectin-reactive glycans in non-BSCs was associated with α-(1,3)- and α-(1,4)-fucosyltransferases, as indicated by qRT-PCR analysis. Importantly, BSCs as well as non-BSCs expressed molecules, such as CD44, that are capable of carrying carbohydrates necessary for E-selectin ligand function. Furthermore, BSCs were mesenchymal-like and non-BSCs were epithelial-like cells, as found by immunostaining of breast cancer cells for E-cadherin and N-cadherin in fluorescence microscopy. Significantly, treatment of a non-BSC cell line with TGF-β induced epithelial-to-mesenchymal transition (EMT) marked by changes in cell morphology, increases in expression levels of N-cadherin, and increases in E-cadherin suppressor genes. These EMT cells showed reduced levels of E-selectin ligand activity under physiological flow conditions, indicating loss of selectin ligand activity upon acquisition of mesenchymal properties. In summary, the selectin ligand activity of BSCs is lower than that of non-BSCs, and the level of selectin ligand activity of breast cancer cells is potentially controlled by BSC and EMT states.
Citation Format: Venktesh S. Shirure, Chengkai Xiong, Fabian Benencia, Monica M. Burdick. Breast cancer stem and non-stem-like cells express varying levels of selectin ligand activities. [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 204. doi:10.1158/1538-7445.AM2013-204
Abstract 2041: Inhibition of autophagy in melanoma: using cell lines to model chloroquine sensitivity.
Authors: White Kirsten A. , Torres Salina M. , Gurule Natalia J. , Berwick Marianne , Hu Chien-An A. 
Published: August 2014

Abstract
Metastatic melanoma offers an ongoing clinical challenge. According to the American Cancer Society, the 5-year survival rate in 2012 for stage IV melanoma is only about 15% even with therapies. To improve outcomes, it is important to investigate new pathways involved in the regulation of metastasis as possible targets for prevention or treatment, such as autophagy. Autophagy (self-eating pathway) destroys a cell's damaged proteins and organelles through lysosomal degradation and has been shown to play roles in a wide variety of normal physiological processes including energy metabolism, nutrient or stress responses, growth regulation, and aging. The role of dysregulated autophagy in melanoma has not been well characterized. Preliminary research found cutaneous malignant melanoma cells display high levels of autophagy suggesting that this cellular process may provide an active metabolic state for invasive and metastatic melanoma. Chloroquine (CLQ), a classic antimalarial agent, is a potent inhibitor of autophagy and has been used safely in human patients for decades. This study is designed to dissect the role of autophagy in melanoma using melanoma cell lines (e.g. SK-Mel 19, 103, and 147), and primary melanocytes as controls to determine whether these cell types respond to CLQ as measured by cell viability . Similar to pancreatic and prostate cancer cell lines, our preliminary results indicate that metastatic melanoma cells require autophagy for growth and show high sensitivity to CLQ at doses as low as 20uM which resulted in greater than 60% decreases in cell viability. These findings suggest that metastatic melanoma cell lines rely on lysosomal degradation to a greater extent than what has been reported for other cell types. In addition, both N-ras mutation and androgen deprivation mitigate the effects of CLQ on melanoma cells. Ongoing experiments will confirm the expression of autophagy related genes, as well as imaging to determine the rate of autophagy in these cell lines. Finally, we will introduce stripped hormonal factors including vitamin D and estrogen, to evaluate whether this addition will progressively restore the original chloroquine sensitive phenotype. Findings from this work have the potential to be immediately translatable to patients as CLQ is already approved for therapeutic use in other human diseases.
Citation Format: Kirsten A. White, Salina M. Torres, Natalia J. Gurule, Marianne Berwick, Chien-An A. Hu. Inhibition of autophagy in melanoma: using cell lines to model chloroquine sensitivity. [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 2041. doi:10.1158/1538-7445.AM2013-2041
Abstract 2042: TOB1 promotes cell survival in estrogen-independent estrogen receptor-positive breast cancer.
Authors: Zhang Yong-Wei , Nasto Rochelle , Clarke Robert , Weiner Louis M. 
Published: August 2014

Abstract
Antiestrogens are the most widely administered endocrine agents for the treatment of estrogen receptor (ER)-expressing breast cancers, such as tamoxifen, fulvestrant and aromatase inhibitor. However, most initially responsive breast tumors acquire resistance and become estrogen-independent. To find potential therapeutic target(s) against drug resistance, we performed siRNA library screening studies to identify cell survival determinants in estrogen independent cell lines from 631 ER network related genes. LCC1 and LCC9 cells, derivatives of MCF-7, are estrogen-independent. LCC1 cells are sensitive to fulvestrant and tamoxifen. LCC9 cells are resistant to fulvestrant and cross-resistant to tamoxifen. A number of genes selectively support the survival of estrogen-independent tumor cells, including TOB1 (Transducer of ErbB2). TOB1 gene knockdown significantly inhibited (&gt;50%) estrogen-independent cell growth in LCC1 and LCC9 cells, but had much less effect on the survival of MCF-7 cells (10%). These cell lines have similar levels of Tob1 protein. TOB1 knockdown did not cause apoptosis or autophagy. DNA replication was reduced and G1 to S phase transition was blocked by TOB1 knockdown in the estrogen-independent cell lines. Next, we studied cell-signaling pathways that regulate cell cycle transition. Cyclin D1 was upregulated and activated by TOB1 knockdown in estrogen-independent cells, but not in MCF-7 cells. Therefore, cyclin D1 might be involved in G1/S transition blockage induced by Tob1 inhibition. TOB1 knockdown also activated cell cycle checkpoint kinase 2 (Chk2) and induced DNA damage. Our data demonstrated that Tob1 promotes cell survival after ER+ breast cancer cells acquire estrogen-independence, which might be mediated by cyclin D1.
Citation Format: Yong-Wei Zhang, Rochelle Nasto, Robert Clarke, Louis M. Weiner. TOB1 promotes cell survival in estrogen-independent estrogen receptor-positive breast cancer. [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 2042. doi:10.1158/1538-7445.AM2013-2042