bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2895: Phylogenetic models of tumor progression from fluorescence in situ hybridization (FISH) data on many single cells of a solid tumor.
Authors: Chowdhury Salim A. , Schäffer Alejandro A. , Shackney Stanley E. , Wangsa Darawalee , Heselmeyer-Haddad Kerstin , Ried Thomas , Schwartz Russell 
Published: August 2014

Abstract
Purpose: Characterizing the common pathways through which tumors progress is critical to understanding the molecular basis of cancer and developing effective treatments. Algorithms for phylogenetics, i.e., evolutionary tree building, can be used to infer progression pathways of single tumors when there is widespread intra-tumor heterogeneity from cell to cell. We describe computational methods to compute likely evolutionary histories from single-cell copy number data and apply the methods to single-cell gene copy number data derived from paired primary and metastatic samples of cervical cancers.
Materials and methods: The inputs to our methods are lists of cell types for each patient sample, where a cell type is an array of copy numbers of gene probes measured by FISH. In the cervical cancer data set, copy numbers of four genes (LAMP3, PROX1, PRKAA1 and CCND1) were measured on up to 250 cells each of paired primary and metastatic samples from 16 patients. An example of a cell type is (4, 1, 3, 2). Our algorithms derive maximum parsimony phylogenetic trees explaining how all observed cell types might have evolved from a common diploid ancestor (2,2,2,2), seeking to explain the observed cells with as few copy number changes as possible across the tree. Due to the computational difficulty, we apply a heuristic algorithm to infer an approximately optimal tree by identifying likely unobserved ancestral cell states through a variant of the median joining method and then find the most parsimonious tree connecting these states. Our software also includes a method of computing consensus trees that facilitate the comparison of the tree models for each primary/metastasis sample pair.
Results and Conclusion: Our methods allow us to build models of evolution of single tumors at the cellular level that provide insights into possible progression pathways and varying selective pressures in primary and metastatic sites. Analysis of tree geometry shows significant variability in evolutionary patterns between primary and metastatic sites consistent with more specific selective pressures in the metastases. Analysis of specific patterns of gene gain or loss in each environment shows a complicated portrait of tumor evolution with substantial variability from patient to patient.
Citation Format: Salim A. Chowdhury, Alejandro A. Schäffer, Stanley E. Shackney, Darawalee Wangsa, Kerstin Heselmeyer-Haddad, Thomas Ried, Russell Schwartz. Phylogenetic models of tumor progression from fluorescence in situ hybridization (FISH) data on many single cells of a solid tumor. [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 2895. doi:10.1158/1538-7445.AM2013-2895
Abstract 2923: Glucose-regulated protein 78(GRP78) mediated the therapeutic efficacy of epirubicin via the downregulation of intracellular oxidative stress in colon cancer cells.
Authors: Chang Yu-Jia , Chen Ching-Hsein , Wei Po-Li 
Published: August 2014

Abstract
Background: The 78-kDa glucose-regulated protein (GRP78) is induced in the cancer microenvironment and can be considered as a novel predictor of responsiveness to chemotherapy in many cancers. However, there is little information regarding whether the expression level of GRP78 affects epirubicin treatment in colon cancer.
Methods: The expression levels of GRP78 were determined in HT-29 and DLD-1 colon cancer cells. GRP78 expression was suppressed in DLD-1 cells using a short interfering RNA (siRNA) technique. The anti-cancer effects of epirubicin were examined using a MTT assay, TUNEL assay, and cell cycle analysis. The status of intracellular reactive oxygen species (ROS) was determined.
Results: In this study, we found thateEpirubicin resistance reduced in cells with suppressed GRP78, in contrast to the parental cells, as determined by survival assays. Cell cycle analysis and TUNEL assays revealed that the apoptotic cell population was increased in the GRP78 knockdown cells treated with epirubicin compared to the scrambled control cells. We found that intracellular reactive oxygen species were higher in GRP78 knockdown DLD-1 colon cancer cells compared with scrambled control cells. Treatment with epirubicin in GRP78-knockdown DLD-1 cells enhanced apoptosis and was associated with decreased production of intracellular ROS.
Conclusions: In summary, our results indicate that GRP78 expression levels were highly correlated with the therapeutic efficacy to epirubicin which was associated with decreased production of intracellular ROS.
Citation Format: Yu-Jia Chang, Ching-Hsein Chen, Po-Li Wei. Glucose-regulated protein 78(GRP78) mediated the therapeutic efficacy of epirubicin via the downregulation of intracellular oxidative stress in colon cancer cells. [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 2923. doi:10.1158/1538-7445.AM2013-2923
Abstract 2927: Breast tumor kinase (Brk/PTK6) mediates hypoxia/HIF-1α-associated breast cancer progression.
Authors: Anderson Tarah Regan , Hubbard Gregory , Daniel Andrea R. , Peacock Danielle , Wenger Roland H. , Schörg Alexandra , Hoogewijs David , Vande Woude George , Seagroves Tiffany N. , Lange Carol A. 
Published: August 2014

Abstract
Triple negative (basal type) breast cancers are more aggressive and difficult to treat relative to HER2/ER/PR positive (luminal type) breast cancers; these tumors frequently express abundant Met receptors and contain high constitutive levels of hypoxia inducible factor alpha (HIF-1α), a principal mediator of cellular stress that predicts cancer relapse and increased risk of metastasis. Breast tumor kinase (Brk/PTK6; Sik in mice) is a soluble tyrosine kinase that is not found in normal breast tissue, but is aberrantly expressed in up to 86% of all breast cancers. We recently showed that Brk is a critical downstream effector of Met signaling and required for HGF-induced cell migration. Herein, we show that Brk and HIF-1α are co-expressed in human triple negative cell lines and tumors. Brk mRNA and protein levels are strongly upregulated during conditions that induce cellular stress in vitro, including low glucose, H2O2, and hypoxia. Chromatin-immunoprecipitation (ChIP) assays revealed that Brk is a direct early transcriptional target of HIF-1α; HIF knockdown demonstrated that Brk expression is dependent upon both HIF-1α and HIF-2α. Notably, Brk expression rescued the growth of MDA-MB-231 xenografts knocked-down for both HIF1α and HIF2α in vivo. Finally, we crossed WAP-Brk (FVB) transgenic mice into the MMTV-METmut model (FVB mice engineered to express MMTV-driven constitutively active mutant Met receptors); the addition of the human wt Brk transgene decreased survival in this model. Notably, mouse mammary tumors that arose in MMTV-METmut mice expressed abundant Sik, the mouse homolog of Brk; high Sik expression conferred markedly decreased latency to tumor formation independently of the presence of the Brk transgene. These results identify HIF-1α as a novel regulator of Brk mRNA expression and suggest that Brk is a key mediator of HIF-1α-induced breast cancer progression. Targeting Brk expression or activity (downstream of the HGF/Met receptor signaling pathway) may provide an effective means to block the progression of deadly triple-negative breast cancers.
Citation Format: Tarah Regan Anderson, Gregory Hubbard, Andrea R. Daniel, Danielle Peacock, Roland H. Wenger, Alexandra Schörg, David Hoogewijs, George Vande Woude, Tiffany N. Seagroves, Carol A. Lange. Breast tumor kinase (Brk/PTK6) mediates hypoxia/HIF-1α-associated breast cancer progression. [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 2927. doi:10.1158/1538-7445.AM2013-2927
Abstract 2931: Synergy between secreted factors promotes a hyper-secretory phenotype which may fuel ovarian cancer progression.
Authors: Davalos Albert R. , Schaum Nicholas , Campisi Judith 
Published: August 2014

Abstract
The challenge in ovarian cancer research is twofold: 1) identification of early biomarkers of the disease and 2) uncovering targetable molecules to treat malignancy while minimizing toxicity. Mutations in the BRCA1/BRCA2 gene locus account for approximately 15% of patients with ovarian cancer, but several other risk factors are known, including increasing age and obesity. We recently uncovered that a nuclear protein (HMGB1) becomes secreted when cells undergo cellular senescence and we detect increased levels in plasma from elderly compared to young individuals. Significantly, we detect abundant extranuclear HMGB1 staining in tissue from patients with serous ovarian carcinoma, suggesting the presence of senescence cells in the tumor.
We find elevated levels of circulating HMGB1 in patients diagnosed with serous carcinoma. Tissue microarray data analysis correlates with reduced survival in ovarian cancer patients staining with higher levels of HMGB1.
Like aging, obesity is a risk factor for ovarian cancer but how remains poorly understood. We found that plasma from mice on high fat diets contained higher levels of HMGB1 compared to mice on normal diets. To extend this observation, we found that culturing ovarian cancer derived cells with saturated fatty acids promoted significantly increased secretion of HMGB1, IL-6 and MMP-3. Moreover, senescent cells which exhibit a secretory phenotype became “hyper-secretory” when cultured with saturated fatty acids. Recent data revealed that the redox state of HMGB1 establishes the protein's function. Secreted HMGB1 synergizes with other secreted factors to stimulate secretion of inflammatory molecules. Indeed we found cells cultured with fatty acid released cf DNA (cell free DNA) which can complex with secreted HMGB1 to promote cytokine secretion. Immunocytochemsitry revealed that tissue from serous ovarian cancer patients exhibited strong FABP-4 expression, a marker for adipoctyes but also shown to be secreted in obese individuals. Taken together these results lead to the possibility that multiple cells types synergize to create a permissive microenvironment to foster ovarian cancer development and progression.
Citation Format: Albert R. Davalos, Nicholas Schaum, Judith Campisi. Synergy between secreted factors promotes a hyper-secretory phenotype which may fuel ovarian cancer progression. [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 2931. doi:10.1158/1538-7445.AM2013-2931
Abstract 2946: AY4, an agonistic anti-death receptor 4 monoclonal antibody, induces death receptor 4-mediated apoptotic cell death in anaplastic thyroid cancer cells via downregulation of Bcl-xL with reactive oxygen species generation.
Authors: Lee Bok-Soon , Cha Hyun-Young , Shin Yoo Seob , Kang Sung Un , Hwang Hye Sook , Kang Sam , Chang Jae Won , Kim Yong- Sung , Kim Chul-Ho 
Published: August 2014

Abstract
Background: Anaplastic thyroid carcinoma (ATC) is an aggressive human tumor with a median survival of 6 months. We previously developed an agonistic anti-death receptor 4 monoclonal antibody, AY4, and demonstrated the anti-tumor effects of AY4 in head and neck cancer cells. Presently, we show that ATC cells are sensitive to AY4 and that the sensitivity correlates with reduced expression level of Bcl-xL and reactive oxygen species (ROS) generation.
Methods: The effects of AY4 in Thyroid cell lines (C-643, U-HTH7, HTH83 and SW1736) was studied on apoptosis using MTT assy, Annexin V assay and Western blot analysis and was examed on the production of reactive oxygen species with DCFDA staining. HTH83 and C-643 cells were transfected with Bcl-xL siRNA using Lipofectamine 2000.
Results: AY4 induced cell death of C-643, U-HTH 7, HTH83, and SW1736 cells. To elucidate the role of ROS generation in AY4-induced apoptosis of ATC cells, U-HTH 7 and SW1736 cells were pretreated with an anti-oxidant (N-acetyl-cysteine, NAC) followed by AY4 treatment. The cell death was blocked by NAC. AY4-induced cell death was accompanied by the down-regulation of the anti-apoptotic protein, Bcl-xL. To examine the link between the apoptotic response and Bcl-xL protein expression, U-HTH 7 cells were transfected with Bcl-xL plasmid. The consequence of the over-expression of Bcl-xL appeared to decrease AY4-mediated cell death by blocking ROS generation in U-HTH 7 cells. In contrast, Bcl-xL knock-down using small interfering RNA of Bcl-xL enhanced AY4 sensitivity in HTH83 and C-643 cells, and rendered the cells sensitive to AY4-induced cell death..
Conclusion: The results support the conclusion that the expression level of Bcl-xL is important in the AY4-induced apoptosis of ATC cells through ROS generation. AY4 may be a promising tool for ATC therapy.
Keywords: Death receptor 4, agonistic antibody, apoptosis, ROS, anaplastic thyroid carcinoma (ATC)
Citation Format: Bok-Soon Lee, Hyun-Young Cha, Yoo Seob Shin, Sung Un Kang, Hye Sook Hwang, Sam Kang, Jae Won Chang, Yong- Sung Kim, Chul-Ho Kim. AY4, an agonistic anti-death receptor 4 monoclonal antibody, induces death receptor 4-mediated apoptotic cell death in anaplastic thyroid cancer cells via downregulation of Bcl-xL with reactive oxygen species generation. [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 2946. doi:10.1158/1538-7445.AM2013-2946
Abstract 2969: A Novel pathway for regulation of ANXA2 expression in lung cancer cell metastasis by SETDB1/SMAD3 repressor complex.
Authors: Tzeng Tsai-Yu , Hsu Ming-Ta 
Published: August 2014

Abstract
Aberrant histone methylation contributes to tumor development and progression by histone methyltransferase. SETDB1 is an H3K9 methyltransferase that contributes to the epigenetic silencing of target genes in cancer cells, but the role of SETDB1 in the progression of tumorigenesis remains largely unknown. We show here that H3K9Me2 and SETDB1 are down-regulated in metastatic lung cancer cell lines. Immunohistochemistry examination of the lung carcinoma tissue microarray revealed that expression of SETDB1 is significant decreased in metastasis status. Ectopic expression of SETDB1 in highly invasive lung cancer cells suppressed cancer cell migration, invasion and filopodia formation. In contrast, knockdown of endogenous SETDB1 in non-invasive lung cancer cells by RNA interference increases cell migration and invasion in vitro. Mechanistic investigations suggested that SETDB1 is specifically down-regulated by miR-29b in metastatic lung cancer cells. Ectopic miR-29b expression in non-invasive lung cancer cells increases cell invasion ability. Furthermore, we also establish a causal role for the SETDB1/SMAD3 complex in driving metastasis and identify ANXA2 as a critical target in this process among numerous target genes. These findings suggest a novel pathway regulated by SETDB1/SMAD3 complex in lung cancer metastasis.
Citation Format: Tsai-Yu Tzeng, Ming-Ta Hsu. A Novel pathway for regulation of ANXA2 expression in lung cancer cell metastasis by SETDB1/SMAD3 repressor complex. [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 2969. doi:10.1158/1538-7445.AM2013-2969
Abstract 297: Loss of giant obscurins expression in breast epithelium disrupts epithelial junctions and promotes cell motility and invasion.
Authors: Shriver Marey , Stroka Kimberly , Konstantopoulos Konstantinos , Kontrogianni-Konstantopoulos Aikaterini 
Published: August 2014

Abstract
Obscurin A (∼720kDa) and B (∼870kDa) are giant multidomain proteins, encoded by the single OBSCN gene, originally shown to play important roles in the structural organization and contractile activity of striated muscles. Early studies have indicated that the OBSCN gene is highly mutated in different types of cancers. In light of this observation, our laboratory set forth to examine the expression profile and roles of giant obscurins in normal and cancer breast tissue. Obscurins are readily expressed in breast epithelial cells, but their expression is dramatically diminished in breast cancer cells. Down-regulation of obscurin A and B using small hairpin RNAs (shRNAs) in non-tumorigenic MCF10A breast epithelial cells resulted in decreased protein expression of β-catenin and E-cadherin, which are major components of adherens junctions and have been heavily implicated in the formation and metastasis of breast tumors. Specifically, β-catenin exhibited a preferential nuclear accumulation accompanied by a concomitant loss from cell-cell junctions. Additionally, loss of obscurins led to alterations in the expression levels and localization of multiple proteins associated with epithelial to mesenchymal transition (EMT). Obscurin-deficient MCF10A cells showed significantly increased motility in 2-Dimensional (2-D) substrata and confined spaces, and invasion through a matrigel coated chamber. Consistent with this, actin filaments re-distributed to extending filopodia-like protrusions where they exhibited increased dynamics. Taken together, our findings indicate that loss of giant obscurins from breast epithelium results in disruption of cell contacts and acquisition of a mesenchymal phenotype that leads to enhanced migration and invasiveness.
Citation Format: Marey Shriver, Kimberly Stroka, Konstantinos Konstantopoulos, Aikaterini Kontrogianni-Konstantopoulos. Loss of giant obscurins expression in breast epithelium disrupts epithelial junctions and promotes cell motility and invasion. [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 297. doi:10.1158/1538-7445.AM2013-297
Abstract 2977: Malignant transformation associated with repetitive Ras/Rac1 activation, increased production of superoxide anion, and global DNA methylation alterations.
Authors: Molognoni Fernanda , Melo Fabiana M. , Tainah Camila , Jasiulionis Miriam G. 
Published: August 2014

Abstract
Driver mutations in N-Ras and BRAF, and more recently in Rac1, were described in melanomas. Using a malignant transformation model of murine melanocytes developed in our laboratory, in which melanoma cell lines were obtained after submitting the melanocyte lineage melan-a to sequential cycles of anchorage blockade, we identified dysfunction in both N-Ras and Rac1 during stressful condition. Our group has already showed increased global DNA methylation as well increased DNA methyltransferase 1 (Dnmt1) protein level few hours after anchorage blockade. This increase seems to be related with elevated amounts of superoxide anion. Previous works have showed that both Ras may regulate superoxide level as Ras activation may affect DNA methylation. Therefore, we aimed to study the relation among Ras/MEK/ERK signaling pathway, oxidative stress and DNA methylation during melan-a anchorage blockade. We showed that Ras, Rac1 and ERK are activated few hours after melan-a anchorage blockade and inhibiting this activation abrogates superoxide increase. Furthermore, global DNA methylation levels decrease during anchorage blockade after treating cells with superoxide scavenger or Ras inhibitor (FTI). Dnmt1 protein level is also decreased after treating melan-a cells during anchorage blockade with FTI or ERK inhibitor (U0126). Ras/MEK/ERK pathway seems to be regulated by and regulates superoxide production during melan-a anchorage restriction. In this way, superoxide anion depletion impairs Ras and ERK activation and FTI or U0126 treatment decreases superoxide during adhesion impediment. This aberrant signaling seems to have a significant impact in melanoma genesis since the malignant transformation was drastically compromised when melan-a melanocytes were pre-treated with superoxide scavenger before each anchorage impediment cycle. Elucidating the relation among oxidative stress, epigenetic changes and melanocyte malignant transformation may provide novel avenues to develop alternative therapeutic approaches.
Citation Format: Fernanda Molognoni, Fabiana M. Melo, Camila Tainah, Miriam G. Jasiulionis. Malignant transformation associated with repetitive Ras/Rac1 activation, increased production of superoxide anion, and global DNA methylation alterations. [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 2977. doi:10.1158/1538-7445.AM2013-2977