bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 810: Integrative genomic and transcriptomic analysis in idenfitication of biomarkers of chemoresistance in serous epithelial ovarian cancer.
Authors: Koti Madhuri , Gooding Robert J. , Nuin Paulo , Haslehurst Alexandria , Crane Colleen , Weberpals Johanne , Childs Timothy , Bryson Peter , Dharsee Moyez , Evans Kenneth , Feilotter Harriet E. , Park Paul C. , Squire Jeremy A. 
Published: August 2014

Abstract
Resistance to platinum-based chemotherapy remains a major impediment in the treatment of serous epithelial ovarian cancer. The objective of this study was to use gene expression and copy number profiling to delineate major deregulated pathways and biomarker networks associated with the development of intrinsic chemotherapy resistance with exposure to standard first-line therapy for ovarian cancer. The study cohort comprised 28 high grade serous ovarian cancer patients divided into two groups based on their varying sensitivity to first-line chemotherapy using progression free survival (PFS) as a surrogate of response. Twelve patient tumors demonstrating relative resistance to platinum based chemotherapy corresponding to shorter PFS (less than 6 months) were compared to 16 tumors from platinum-sensitive patients (PFS more than 18months). Molecular profiling was performed using Affymetrix high-resolution microarray platforms to permit global comparisons of gene expression levels and copy number profiles between tumors from the resistant group with the sensitive group. Microarray data analysis revealed a set of 227 discriminating genes of which expression levels may be influencing differential chemotherapy response between the two groups. Pathway analysis of these genes showed the,PI3K,NFkB and IGF1 networks as some of the significant networks distinguishing the chemotherapy resistant with the sensitive group. Copy number analysis performed using Nexus copy number version 6.1 revealed differences in the chromosomal regions, 4q31.22, 5q13.2, 9p24.3, 2p23.2, 16q21, 6q14.1, 7p22.3, 12p13 and Xq.
Integrative copy number and gene expression profiling will delineate the drivers of chemotherapy resistance in patients undergoing standard platinum-based treatment of ovarian cancer. Future studies to validate these markers are necessary to apply this knowledge to biomarker-based clinical trials.
Citation Format: Madhuri Koti, Robert J. Gooding, Paulo Nuin, Alexandria Haslehurst, Colleen Crane, Johanne Weberpals, Timothy Childs, Peter Bryson, Moyez Dharsee, Kenneth Evans, Harriet E. Feilotter, Paul C. Park, Jeremy A. Squire. Integrative genomic and transcriptomic analysis in idenfitication of biomarkers of chemoresistance in serous epithelial ovarian 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 810. doi:10.1158/1538-7445.AM2013-810
Abstract 833: S100A4 interacts with p53 in the nucleus promoting its degradation.
Authors: Orre Lukas , Panizza Elena , Kaminskyy Vitaliy , Gräslund Torbjörn , Zhivotovsky Boris , Lehtiö Janne 
Published: August 2014

Abstract
Background.
S100A4 is a calcium binding protein which has no known enzymatic activity, but it exerts its function by binding and regulating other molecules, among which have been described Myosin and p53. S100A4 has been shown to be upregulated in several types of cancers, correlating with poor prognosis and metastasis.
In a previous study (Orre et al., 2007), S100A4 has been shown to be involved the cellular response to ionizing irradiation in a p53 dependent manner; our aim here was therefore to investigate the cellular interaction partners of S100A4 in response to p53 and then, based on this data, to further elucidate the cellular function of S100A4.
Observations.
Nutlin-3A is a compound that specifically stabilizes p53 through inhibiting the interaction between p53 and mdm2. We could show an interaction between S100A4 and p53 via immunoprecipitation in the NSCLC cell line A549 (which has a high expression of S100A4 and a wild-type p53), and that this interaction is increased after Nutlin-3A treatment. The interaction has been independently confirmed via Proximity Ligation Assay, showing as well that the protein complexes are localized in the nucleus.
Since this interaction increased after inhibition of the mdm2-p53 interaction, we hypothesized that S100A4 could be involved in regulation of p53 degradation; therefore we generated two cell lines from A549, infected with S100A4 shRNA (shS100A4) or an Empty Vector shRNA (shEV) as a control. Knockdown of S100A4 resulted in stabilization of p53 and transactivation of p53 transcriptional targets; it also resulted in higher sensitivity to cisplatin-mediated apoptotic cell death, measured as a drop in mitochondrial membrane potential, caspase-3 activation and AV/PI assay.
We confirmed this finding by an independent method using transient S100A4 down regulation via siRNA; this resulted in an increase in p53 level and of p21 and MDM2 level in A549 adenocarcinoma cells. S100A4 siRNA resulted also in p53-dependent growth arrest, that was reversed after co-transfecting p53 siRNA.
Conclusions.
Our data show that S100A4 interacts with p53 increasing its degradation, resulting in higher cell viability and lower apoptosis after cisplatin treatment. A possible correlation in patients between S100A4 overexpression and cisplatin resistance could be used to drive treatment selection.
Citation Format: Lukas Orre, Elena Panizza, Vitaliy Kaminskyy, Torbjörn Gräslund, Boris Zhivotovsky, Janne Lehtiö. S100A4 interacts with p53 in the nucleus promoting its degradation. [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 833. doi:10.1158/1538-7445.AM2013-833
Abstract 84: The role of redox state in human breast cancer progression.
Authors: Jorgenson Tonia C. , Zhong Weixiong , Oberley Terry D. 
Published: August 2014

Abstract
We are investigating the role of reduction-oxidation (redox) state in human breast cancer progression. Physiologic levels of oxidants and antioxidants within subcellular compartments regulate and coordinate normal cell functions. Cells in a state of redox imbalance undergo adaptation and/or altered behavior. We propose to investigate the thioredoxin 1 (TRX1) redox couple in human breast cancer progression. This molecule is known to interact with several molecules involved in breast carcinogenesis, including redox-sensitive transcription factors and estrogen receptor (ER) alpha. We hypothesize human breast cancer tissues are in a state of redox imbalance favoring a more reducing environment, and post-translational redox modifications involving TRX1, thioredoxin reductase 1 (TRXR1), and thioredoxin interacting protein (TXNIP) are involved. Preliminary data demonstrated redox imbalance in comparisons of breast cancers to surrounding tissues. TRX1 protein levels were 1.5-fold increased, while TRXR1 and TXNIP were 10-fold and 2.4-fold decreased, respectively. The redox state of TRX1 demonstrated a 4.7-fold increase in the reduced form versus the oxidized, and TRX1 activity was 2.1-fold increased. Our future plans involve analyzing redox-regulated protein subcellular distribution patterns of TRX1, TRXR1, TXNIP, and ER alpha utilizing immunohistochemistry in human breast cancer tissue microarrays varying in histological grade; determine protein levels of TRX1, TRXR1, and TXNIP, redox state of TRX1, and activities of TRX1 and TRXR1 in human breast cancer cell lines relative to normal primary epithelial cells in cell culture; and investigating the effects of modulating the extra- and intracellular redox state on cell invasion in hormone dependent/independent breast cancer cell lines.
Citation Format: Tonia C. Jorgenson, Weixiong Zhong, Terry D. Oberley. The role of redox state in human 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 84. doi:10.1158/1538-7445.AM2013-84
Abstract 844: Peroxisome proliferator-activated receptor γ agonists abrogate tumor invasion and promote TRAIL-induced apoptosis in malignant glioma.
Authors: Choi Kyungsun , Chong Kyuha , Lee Jungwhoi , Choi Hojun , Choi Chulhee 
Published: August 2014

Abstract
Glioblastoma multiforme is the most common brain tumors and have a worse prognosis, so it is needed to develop effective treatments. Peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists, including 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) and synthetic ligands, troglitazone and rosiglitazone, are known to sensitize tumor cells to apoptosis via various molecular mechanisms. In this study, we investigated the therapeutic potentials of combined treatment with PPAR-γ agonists and TRAIL in TRAIL-resistant astrocytoma cells. TRAIL alone and each PPAR-γ agonist exhibited no cytotoxic effects; while the pre-incubation with PPAR-γ agonists enhanced dramatically TRAIL-induced cell death, which was abrogated by a broad spectrum caspase inhibitor, z-VAD-fmk. And also, the combined treatment with PPAR-γ agonists and TRAIL increased the enzymatic activity of caspase-3. These results indicate that PPAR-γ agonists might promote TRAIL-mediated apoptosis by modulating the caspase activity. In addition, the expression of anti-apoptotic proteins including FLIP, Bcl-2, Bcl-xL and XIAP was suppressed by the combined treatment. Besides the cytotoxic effect, treatment with PPAR-γ agonists significantly inhibited glioma invasion in vitro and in vivo. These results collectively suggest that PPAR-γ agonists may provide a promising strategy to treat malignant glioma.
Citation Format: Kyungsun Choi, Kyuha Chong, Jungwhoi Lee, Hojun Choi, Chulhee Choi. Peroxisome proliferator-activated receptor γ agonists abrogate tumor invasion and promote TRAIL-induced apoptosis in malignant glioma. [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 844. doi:10.1158/1538-7445.AM2013-844
Abstract 850: Sirt1-mediated suppression of cell death in breast cancer.
Authors: Mortenson Jeffrey B. , Weerasekara Vajira K. , Andersen Josh 
Published: August 2014

Abstract
Several lines of evidence suggest that protein lysine acetylation pathways are deregulated in cancer (1). Moreover, deacetylase inhibitors are emerging as important anti-tumor therapeutics, suggesting that the forced reprogramming of protein-lysine acetylation is toxic to tumor cells. In this study we show that Sirt1, an NAD+-dependent Sirtuin deacetylase that promotes cancer cell survival, is aberrantly mislocalized to the cytoplasm of breast tumor cells. Moreover, the depletion of cytosolic Sirt1 by siRNA sensitizes breast tumor cells to paclitaxel-induced death. Previously, we developed a biotin-switch proteomics approach to identify cytosolic Sirt1 substrates (2). This approach yielded a variety of substrates with roles in metabolism, survival, and oxidative stress signaling. Our current work focuses on three of the proteins identified as Sirt1 substrates: SOD1, DJ-1, and 14-3-3z. SOD1 and DJ-1 both suppress oxidative stress-induced death, and high levels of 14-3-3z expression suppress chemotherapy-induced apoptosis and correlate with negative patient outcomes in breast cancer. Our preliminary results suggest that acetylation of DJ-1 and SOD1 suppress their anti-oxidant functions, while acetylation of 14-3-3z disrupts its binding to pro-survival proteins. Taken together, our data support a model in which cytosolic Sirt1 activates multiple pathways that work together to promote tumor cell survival.
Citation Format: Jeffrey B. Mortenson, Vajira K. Weerasekara, Josh Andersen. Sirt1-mediated suppression of cell death in 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 850. doi:10.1158/1538-7445.AM2013-850
Abstract 859: miR-638, a novel tumor suppressor for ER-negative breast cancer.
Authors: Peng Jin , Fu Yebo , Brem Rachel F. , Teal Christine B. , Fu Sidney W. 
Published: August 2014

Abstract
MicroRNAs (miRNAs) are endogenous non-coding RNAs of 19∼25 nt in length, which regulate many protein-coding genes. miRNA dysregulation is observed in a variety of cancers, including breast cancer. miRNAs have emerged as an important set of biomarkers. miRNA profiling studies have led to the identification of miRNAs that are aberrantly expressed in human breast cancer, with miR-10b, miR-125b and miR-145 being down-regulated and miR-21, and 155 being up-regulated. In our previous miRNA expression profiling studies using microdissected FFPE tissues, we identified 8 clusters of miRNAs, which discrete the normal and breast lesions such as ADH, DCIS and IDC. miR-638 is one of the differentially expressed miRNAs during breast cancer progression. We first sought to determine the expression of miR-638 in different breast cancer cell lines such as MCF-7, Hs578T, T47D and MDA-MB-231 using qRT-PCR, which shows a very low expression compared to normal tissues. This led us to hypothesize that miR-638 may function as a tumor suppressor during breast cancer development. To determine the role of miR-638 in both ER+ and ER- breast cancer cells, we transfected miR-638 mimic oligos and scrambled oligo mocks into MCF-7 (ER+), T47D (ER+), MDA-MB-231 (ER-) and Hs578T (ER-) cells. After 48 hours, we found that the proliferation rate was significantly down-regulated in ER- cells but not in ER+ cells by MTT assay. Our preliminary matrigel analysis shows that miR-638 overexpressing MDA-MB-231 cells had 3∼4 fold invasiveness decrease compared to the control. Further, our TargetScan analysis revealed that BRCA1 is one of the direct targets of miR-638 among the 30 conservative target genes. We found that overexpression of miR-638 resulted in an upregulation of BRCA1 mRNA expressions in ER- cell lines, MDA-MB-231 and Hs578T but not in ER+ cell lines, T47D and MCF-7. Taken together, these findings showed that miR-638 may function as a tumor suppressor in ER- breast cancer, possibly in part by upregulating BRCA1 tumor suppressor gene. Further functional analysis is underway to decipher the exact role of miR-638 in ER- breast cancer, which could become a therapeutic target.
Citation Format: Jin Peng, Yebo Fu, Rachel F. Brem, Christine B. Teal, Sidney W. Fu. miR-638, a novel tumor suppressor for ER-negative 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 859. doi:10.1158/1538-7445.AM2013-859
Abstract 866: Cetuximab treatment reduces VEGF expression and targeting of radiolabeled bevacizumab in breast cancer xenografts.
Authors: Heskamp Sandra , Boerman Otto C. , Molkenboer-Kuenen Janneke D.M. , Oyen Wim J.G. , van der Graaf Winette T.A. , van Laarhoven Hanneke W.M. 
Published: August 2014

Abstract
Introduction: Bevacizumab (anti-VEGF) and cetuximab (anti- EGFR) are approved for the treatment of cancer. However, in advanced colorectal cancer, the combination of bevacizumab and cetuximab did not improve survival (Tol et al. NEJM 2009). Up to now, the reason for the lack of activity of the combination therapy remains unclear. Previously, we have shown that bevacizumab reduces the vascular density of xenografts and consequently limits the delivery of cetuximab to tumors. Thereby, it can potentially limit the therapeutic efficacy of cetuximab. Alternatively, cetuximab treatment could alter VEGF expression, limiting tumor targeting by bevacizumab. The aim of this study was to determine the effect of cetuximab treatment on VEGF expression and targeting of bevacizumab to the tumor.
Material and methods: Mice with subcutaneously implanted SUM149 xenografts, which express EGFR and VEGF, were treated intraperitoneally with 1 mg/kg cetuximab (twice a week). Before start of treatment and after 7, 14, and 21 days, the uptake of radiolabeled bevacizumab in the tumor was measured by immunoSPECT/CT. Three days prior to scanning, mice received 15 MBq of 111In-bevacizumab. After scanning, tumors were dissected for ex vivo biodistribution and immunohistochemical analysis of VEGF and CD34 expression.
Results: After cetuximab treatment, tumor targeting of bevacizumab was significantly reduced on immunoSPECT/CT compared to untreated tumors. Tumor uptake measured ex vivo was 28.9 ± 4.0 %ID/g for untreated tumors, compared to 18.2 ± 2.8 %ID/g for tumors treated 21 days with cetuximab (p = 0.009). Immunohistochemical analysis showed that the vascular density was unaltered while VEGF expression decreased during cetuximab treatment.
Conclusion: Cetuximab treatment reduced VEGF expression and targeting of radiolabeled bevacizumab to the tumor. This could at least partly explain why the combination of bevacizumab and cetuximab does not result in improved therapeutic efficacy.
Citation Format: Sandra Heskamp, Otto C. Boerman, Janneke D.M. Molkenboer-Kuenen, Wim J.G. Oyen, Winette T.A. van der Graaf, Hanneke W.M. van Laarhoven. Cetuximab treatment reduces VEGF expression and targeting of radiolabeled bevacizumab in breast cancer xenografts. [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 866. doi:10.1158/1538-7445.AM2013-866
Abstract 872: Novel potent and orally active STAT3 inhibitors for cancer therapies.
Authors: Yang Zhengduo , Chen Haijun , Chu Lili , Zhang Yusong , Ding Chunyong , Liu Huiling , Zhou Jia , Shen Qiang 
Published: August 2014

Abstract
Signal transducers and activators of transcription (STATs) are proteins which have dual roles as cytoplasmic signaling proteins and transcription factors that activate sets of genes including those contribute to tumorigenesis. Among the STATs family members, STAT3 has been shown to play an important role in breast carcinogenesis and is often overexpressed in primary breast tumors. Increased STAT3 transcriptional activity is reported to correlate with ER-negative phenotype in breast cancer cell lines and in primary human invasive ductal breast carcinomas. Therefore, STAT3 is a promising target for breast cancer therapies. Current strategies of inhibiting STAT3 activity did not sufficiently block STAT3 activation in cancer cells due to their limited potency, poor solubility or bioavailability. Despite several STAT3 inhibitors have been advanced into early clinical trials, there is an urgent need to develop orally active, potent STAT3 inhibitors as cancer therapeutics. We have designed, synthesized and screened a series of novel STAT3 inhibitors utilizing fragment-based drug design strategy. A number of small molecules with novel scaffolds have been discovered with low-micromolar to nanomolar potency in inhibiting the proliferation of various human breast cancer and pancreatic cancer cells. The identified compounds HJC0152, HJC0123, HJC0125, and HJC0416 significantly suppress STAT3 promoter activity and STAT3 phosphorylation (pY705), reduce total STAT3 protein expression, induce cell growth arrest, and early apoptosis in ER-negative breast cancer cell line MDA-MB-231. These novel compounds have demonstrated a better efficacy in suppressing the growth of MDA-MB-231 breast xenograft tumors via intraperitoneal and oral administrative routes, with remarkably improved aqueous solubility and less toxicity than the lead compounds. In conclusion, we have developed a new class of orally active STAT3 inhibitors with superior drug-like properties, for further evaluation in cancer therapeutic and preventive settings. This work was supported by The University of Texas MD Anderson Cancer Center DFI Funding Program.
Citation Format: Zhengduo Yang, Haijun Chen, Lili Chu, Yusong Zhang, Chunyong Ding, Huiling Liu, Jia Zhou, Qiang Shen. Novel potent and orally active STAT3 inhibitors for cancer therapies. [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 872. doi:10.1158/1538-7445.AM2013-872
Abstract 885: Human organic cation transporter 1 (hOCT1) as a mediator of bendamustine cytotoxic action.
Authors: Arimany-Nardi Cristina , Montraveta Arnau , Lee-Vergés Eriong , Koepsell Hermann , Colomer Dolors , Pastor-Anglada Marçal 
Published: August 2014

Abstract
Bendamustine hydrochloride is a cytotoxic agent that encompasses structural features of alkylating and nucleoside-derived drugs. This drug is currently used in the treatment of several haemotological malignancies; among them Chronic Lymphocytic Leukemia (CLL). CLL is the most common leukemia in Western countries and is characterized by the accumulation of monoclonal CD5+ B cells in the blood, bone marrow, lymph nodes, spleen and other organs. The pathways facilitating the uptake of bendamustine hydrochloride into target cells still remain poorly understood. Here we have addressed this issue by monitoring the interaction of the drug with selected plasma membrane transporter candidates, which might be relevant to bendamustine pharmacokinetics and pharmacodynamics. We have used a panel of HEK293 cells stably expressing selected drug transporter proteins to prove that bendamustine is able to interact with human Organic Cation Transporter 1 (hOCT1) with a Ki of 140+/-10 μM, as deduced from cis-inhibition studies using tritiated 1-methyl-4-phenylpyridinium (MPP+) as hOCT model substrate. Genetic variants known to modify substrate/transporter interactions, some of them with high allelic frequency in humans, were also tested and, in particular, hOCT1M420Del showed a significant decrease in its affinity for the drug (Ki value 234+/-24 μM, p&lt;0.05 vs the wild type transporter). The whole panel of hOCT1 and hOCT1 allelic variants were also tested for bendamustine-induced cytotoxicity and data consistent with bendamustine being a hOCT1 substrate were obtained. This was based upon the finding that hOCT1 expression triggered increased sensitivity to the drug and variants known to decrease drug-transporter affinity interactions were also shown to induce resistance. hOCT1 is expressed in CLL cells and genotyping of a cohort of 125 CLL patients is now allowing the analysis of the relationships between particular genetic variants and ex vivo bendamustine-induced cytotoxicity, thus opening the possibility that hOCT1 genotyping might be a useful tool in optimizing bendamustine-based therapies.
Citation Format: Cristina Arimany-Nardi, Arnau Montraveta, Eriong Lee-Vergés, Hermann Koepsell, Dolors Colomer, Marçal Pastor-Anglada. Human organic cation transporter 1 (hOCT1) as a mediator of bendamustine cytotoxic action. [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 885. doi:10.1158/1538-7445.AM2013-885