bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1006: Novel adjuvants in triple negative breast cancer chemotherapy
Authors: Rampoldi Antonio , Harbuzariu Adriana , Harmon Tia L. , Gonzalez-Perez Ruben R. 
Published: July 2016

Abstract
Background: Obese patients develop more frequently triple negative breast cancer (TNBC) that has not target therapy and are commonly treated with chemotherapeutics. Leptin, whose levels are elevated in obesity, can induce TNBC proliferation, angiogenesis and resistance to chemotherapeutics. An antagonist for leptin receptor OB-R, leptin peptide receptor antagonist 2 (LPrA2), has been shown to block leptin signaling and decrease tumor progression. LPrA2 also countervails leptin induced resistance to chemotherapeutic agents. We used pegylation or iron oxide nanoparticle (IONPs) as adjuvants to increase LPrA2 solubility, stability and effectiveness.
Hypothesis: Conjugated LPrA2 will decrease TNBC cells proliferation, expression of leptin target molecules and tumorigenesis.
Methods: Human TNBC and murine breast adenocarcinoma derived cell line E0771 (progesterone and HER2 receptor negative) were used. The E0771 cell line was generated from an estrogen receptor positive (ER+) mammary adenocarcinoma isolated from a C57BL/6J mouse. E0771 was made insensitive to estrogen by treatment with drug Tamoxifen (TAM) mimicking TNBC. To specifically assess the role of RBP-Jk (CBS/CSL, an essential transcription factor for Notch signaling) the CRISPR/Cas9 system was used to disrupt RBP-JK gene expression in both wild-type and TAM treated E0771 cells. Cells were treated with chemotherapeutics (Paclitaxel, Doxorubicine, Ciclophosphamide) in presence of leptin and LPrA2-conjugates. The expression of leptin-targeted molecules, Breast Cancer Stem Cells (BCSC) and EMT markers were analyzed after cell treatment.
Results: Chemotherapeutics effects on proliferation, survival and molecular markers were modified by the addition of LPrA2-conjugates. Notch molecules (receptors and ligands) were downregulated by LPrA2 treatment.
Conclusion: The current data indicate that Leptin inhibition could be used as an adjuvant for chemotherapeutic treatments in TNBC patients. LPrA2-conjugates could increase the efficacy of chemotherapy.
Acknowledgements: This work was partially supported by the National Institute of Health and National Cancer Institute Grant U54 CA118638, NIH/SBIR 1R41CA183399-01A1, and DOD Idea Award BC W81XWH-13-1-0382 to RRGP; and facilities, and support services at Morehouse School of Medicine (NIH RR03034 and 1C06 RR18386) and NIH/NCRR grant 1G12RR026250-03.
Citation Format: Antonio Rampoldi, Adriana Harbuzariu, Tia L. Harmon, Ruben R. Gonzalez-Perez. Novel adjuvants in triple negative breast cancer chemotherapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1006.
Abstract 1013: Quantification of NADPH balance in cancer
Authors: Liu Ling , Chen Li , Ducker Greg , Park Junyoung , Shah Supriya , Wellen Kathryn E. , Rabinowitz Joshua D. 
Published: July 2016

Abstract
NADPH is a key cofactor involved in antioxidant defense and reductive biosynthesis. The quantitative contribution of different NADPH pathways, either in normal tissues or in tumors, remains unclear. Here we enable tracing of NADPH production using deuterium-labeled nutrients and mass spectrometry, providing methods that for the first time can track each of the major cytosolic pathways: malic enzyme, isocitrate dehydrogenase, folate metabolism, and the pentose phosphate pathway. This is achieved via a battery of different 2H-tracers. A linear algebra method for deducing the fractional contribution of each pathway, even when a specific tracer for that pathway is not available, will be described. Utility of these methods will be illustrated through examples drawn from both normal cellular physiology and cancer. Specifically, we find that most NADPH in differentiating adipocytes is made by malic enzyme. Examining cancer cells, we find that the pentose phosphate pathway is typically the largest cytosolic NADPH source, but that the collective contribution of alternative pathways is often larger than the pentose phosphate pathway. The specific other pathways involved differ strongly depending on the cancer cell type. We also provide examples where NADPH production routes in both normal and cancer cells vary with nutrient availability, including hypoxia. Given the heightened redox stress of cancer cells, understanding NADPH production routes is likely to illuminate new avenues for therapeutic intervention.
Citation Format: Ling Liu, Li Chen, Greg Ducker, Junyoung Park, Supriya Shah, Kathryn E. Wellen, Joshua D. Rabinowitz. Quantification of NADPH balance in cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1013.
Abstract 102: Pan-cancer analysis of sex differences in somatic mutation profiles
Authors: Li Constance H. , Haider Syed , Boutros Paul C. 
Published: July 2016

Abstract
Sex influences the clinical and pathological characteristics of a number of cancers including those of the lung, colon and kidney. Men and women differ in incidence rate, response to treatment and survival - even after controlling for confounding factors such as smoking status, age and weight. Some gene-specific sex differences have been identified in these cancers, but there has not been a rigorous, genome-wide analysis of the mutational differences in tumors between men and women. We fill this gap, providing a comprehensive assessment of sex-associated differences in cancer genomics.
We leverage resources from the International Cancer Genome Consortium-The Cancer Genome Atlas pan-cancer project, which includes genomic, transcriptomic and epigenomic profiles of 25,000 tumours and whole genome sequences of 5,000 tumours. Using this data, we analyzed mutational differences between the sexes in 15 tumor types.
We use both univariate (t-test, proportions test) and multivariate (multinomial logistic regression) statistical techniques, along with bioinformatics and pathway analyses. We found distinct sex-associated genomic differences in the copy number aberration (CNA) profiles of six tumor types and in pan-cancer analysis. We observe higher genome instability in male-derived tumors and sex-biased mutations in specific genes and across genomic intervals. Using multivariate modeling to control for confounding variables reinforces the significance of sex in these genomic regions and also reveals additional sex-biased CNAs. Ongoing work with mRNA abundance data suggests an association between sex-differences in CNAs and mRNA abundance both in cis and in trans. Further investigation into affected genes and pathways may reveal fundamental differences in how tumors develop in men and women and provide explanations for reported clinical and pathological sex differences.
Citation Format: Constance H. Li, Syed Haider, Paul C. Boutros. Pan-cancer analysis of sex differences in somatic mutation profiles. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 102.
Abstract 1023: Functional genomics reveals dependency on 6-phosphogluconate dehydrogenase in OXPHOS-deficient tumors
Authors: Sun Yuting , Bandi Madhavi , Lofton Timothy , Smith Melinda , Bristow Christopher , Rogers Norma , Edward Chang , Geck Do Mary , Jiang Yongying , Morlacchi Pietro , Muller Florian , Mseeh Faika , Czako Barbara , Palmer Wylie , Toniatti Carlo , Jones Philip , Draetta Giulio , Heffernan Timothy , Marszalek Joseph 
Published: July 2016

Abstract
Cancer cells display metabolic properties distinct from normal cells and are therefore believed to be dependent on key metabolic enzymes. The effectiveness of targeting metabolism for cancer therapy has been largely restricted due to metabolic adaptability. We postulate that tumors with metabolic vulnerabilities will be limited in such adaptation, thus providing a unique opportunity for therapeutic intervention. Hereditary leiomyomatosis renal cell carcinoma (HLRCC) is a metabolically vulnerable cancer, due to mutations in a key TCA cycle enzyme - fumarate hydratase (FH), thus rendering them deficient in oxidative phosphorylation (OXPHOS). We performed a loss-of-function genetic screen in a FH-null HLRCC model (UOK262 cells) and identified 6-phosphogluconate dehydrogenase (6PGD) - a rate-limiting enzyme in the non-oxidative arm of pentose phosphate pathway - as a critical regulator of cell growth. Inhibition of 6PGD using either dox-inducible shRNA or a small molecule inhibitor dramatically blocks the growth of UOK262 cells, and in contrast, has no effect on 6PGD-deficient NB1 cells. The growth inhibition from knockdown is fully rescued by expressing shRNA-resistant 6PGD. Conversely, ectopic expression of 6PGD in NB1 cells results in a gain of function phenotype. Importantly, in vivo, 6PGD knockdown causes robust regression of established UOK262 xenografts. Mechanistically, 6PGD inhibition causes the accumulation of 6-phosphogluconate, blocks glycolysis, and induces ROS production. Furthermore, in tumors with intact TCA cycle, 6PGD inhibition shows synergism with OXPHOS Complex I inhibitor IACS-10759. Together, our data suggest that 6PGD is a bona fide oncology target and provide a strong rationale for developing small molecule inhibitors that could be used to treat OXPHOS-deficient tumors as single agent, or combined with inhibitors of OXPHOS.
Citation Format: Yuting Sun, Madhavi Bandi, Timothy Lofton, Melinda Smith, Christopher Bristow, Norma Rogers, Chang Edward, Mary Geck Do, Yongying Jiang, Pietro Morlacchi, Florian Muller, Faika Mseeh, Barbara Czako, Wylie Palmer, Carlo Toniatti, Philip Jones, Giulio Draetta, Timothy Heffernan, Joseph Marszalek. Functional genomics reveals dependency on 6-phosphogluconate dehydrogenase in OXPHOS-deficient tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1023.
Abstract 1025: A prolyl-hydroxylase inhibitor, ethyl-3,4-dihydroxybenzoate, induces cell autophagy and apoptosis in esophageal squamous cell carcinoma cells
Authors: Li Wei , Hou Guixue , Zhou Dianrong , Lou Xiaomin , Xu Yang , Liu Siqi , Zhao Xiaohang 
Published: July 2016

Abstract
The protocatechuic acid ethyl ester ethyl-3,4-dihydroxybenzoate (EDHB) is an antioxidant found in the testa of peanut seeds. The cytotoxic effect of EDHB on esophageal squamous cell carcinoma (ESCC) cells was investigated and 46 up- and down-regulated genes involved in several signaling pathways associated with cell cycle regulation and cellular metabolism were identified. Our studies have shown that EDHB can effectively induce autophagy and apoptosis of esophageal cancer cells by BNIP3 and NDRG1 respectively, and AKR1C family were one of the differentially expressed genes after cells treated with EDHB. We also found that the esophageal cancer cells with higher (KYSE 180) and lower (KYSE 510) AKR1C expressing levels were selected, and the cell proliferation was found inhibited more effectively in KYSE 180 than KYSE 510 cells after treated with EDHB. Furthermore, at the same condition, the effective subunits of AKR1C superfamily, AKR1C1/C2, were identified quantitatively by multiple reaction monitoring (MRM) assays. And the involvement of AKR1C1/C2 in the metabolism of the EDHB in ESCC cells and induced cell death. When autophagy was inhibited using 3-methyladenine (3-MA), KYSE 180 cells exhibited higher sensitivity to EDHB and it may act as metabolic substrate of AKR1C1/C2. These results indicate that esophageal cancer patients with high expression of AKR1C1/C2 are more sensitive to EDHB and facilitate its induced autophagy and apoptosis that providing potential guidance for the chemoprevention of ESCC.
Citation Format: Wei Li, Guixue Hou, Dianrong Zhou, Xiaomin Lou, Yang Xu, Siqi Liu, Xiaohang Zhao. A prolyl-hydroxylase inhibitor, ethyl-3,4-dihydroxybenzoate, induces cell autophagy and apoptosis in esophageal squamous cell carcinoma cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1025.
Abstract 103: Gene expression based subtypes of colorectal cancer
Authors: Berg Kaja G. , Eilertsen Ina A. , Alagaratnam Sharmini , Danielsen Stine A. , Nesbakken Arild , Sveen Anita , Lothe Ragnhild A. 
Published: July 2016

Abstract
Colorectal cancer is a heterogeneous disease and improved molecular stratification of patients is warranted for precise treatment. Several gene expression classification systems are reported in the literature, albeit many have shown low reproducibility in external validation. A robust random forest classification system based on gene expression profiles was recently proposed, suggesting the existence of four biologically different subtypes with associations to prognosis (CMS1, CMS2, CMS3 and CMS4) (Guinney,J., et al., Nat Med, 2015). By applying the CMS classifier to high-quality gene expression profiles from a consecutive series of &gt;400 stage I-IV primary colorectal cancers we are able to reproduce results from Guinney et al in an independent cohort. Analyses of mutational hotspots in BRAF / KRAS and the complete coding sequence of TP53 confirms enrichment of BRAF mutations in CMS1 (p&lt;0.001), TP53 mutations in CMS2 and KRAS mutations in CMS4 (p&lt;0.001). We further validate high levels of somatic copy number aberrations (SCNAs) in CMS2 and CMS4 compared to CMS1 and CMS3 (pair-wise comparisons, fraction of genome affected by SCNAs: CMS1 vs CMS2: p&lt;0.001; CMS1 vs CMS4: p&lt;0.01; CMS2 vs CMS3: p&lt;0.001; CMS3 vs CMS4: p&lt;0.01). Additionally we explore within-subtype variations with respect to SCNAs in the CMS2 and CMS4 subtypes. Altogether our results validate the CMS system as a robust classification system for colorectal cancer.
Citation Format: Kaja G. Berg, Ina A. Eilertsen, Sharmini Alagaratnam, Stine A. Danielsen, Arild Nesbakken, Anita Sveen, Ragnhild A. Lothe. Gene expression based subtypes of colorectal cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 103.
Abstract 1032: Characterizing the metabolic dependencies of rhabdomyosarcoma and Ewing's sarcoma cells
Authors: Issaq Sameer , Helman Lee 
Published: July 2016

Abstract
Sarcomas represent a diverse group of malignancies with unique molecular and pathological characteristics. In order to improve sarcoma treatment, a better understanding of the alterations associated with specific sarcoma subtypes is critically important. Renewed interest in the altered metabolic properties of cancer cells has led to an exploration of targeting metabolic dependencies as a novel therapeutic strategy. In this study, we have characterized the dependency of rhabdomyosarcoma (RMS) and Ewing's sarcoma (EWS) cells on key metabolic substrates by examining cell proliferation and bioenergetic properties under varying concentrations of glucose and glutamine. We utilized two alveolar RMS cell lines, one embryonal RMS cell line, and five EWS cell lines. While all cell lines tested were completely growth-inhibited by lack of glucose, individual RMS and EWS cell lines were differentially sensitive to removal of glutamine. Furthermore, glutamine deprivation significantly reduced mitochondrial bioenergetic function, as demonstrated by Seahorse metabolic flux analysis. The observed effects of glutamine deprivation on proliferation and mitochondrial bioenergetics were rescued by the re-introduction of glutamine into the culture media. Our findings suggest that metabolic dependencies of RMS and EWS cells should be further investigated in order to identify metabolic vulnerabilities that could be targeted for potential therapeutic benefit.
Citation Format: Sameer Issaq, Lee Helman. Characterizing the metabolic dependencies of rhabdomyosarcoma and Ewing's sarcoma cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1032.
Abstract 1040: Differential levels of glycogen in breast cancer cell lines: A potential new target
Authors: Yates Joel A. , Altemus Megan , Wu Zhifen , Wynn Michelle L. , Merajver Sofia D. 
Published: July 2016

Abstract
Cancer cells have been known to alter their metabolic processes in order to survive and proliferate. Normally in muscle and liver, excess glucose is stored within the cells as glycogen. Elevated levels of glycogen have also been found in various cancers, including breast cancers. Recent studies have implicated glycogen metabolism as important in promoting survival of cancer cells, suggesting targeting of glycogen metabolism as a possible treatment to inhibit cancer cell growth. In general, modulation of cancer metabolism is believed to be an attractive adjunct strategy to conventional or targeted therapies. Here we set out to investigate glycogen levels as well as levels of proteins involved in glycogen synthesis and degradation vary across different breast cancer cell lines.
A glucose metabolism qPCR array found differential levels of the alpha subunit of phosphorylase kinase 1, a key enzyme involved in glycogen degradation among three different breast cancer cell lines. Expression levels of glycogen synthesis and degradation enzymes were assessed using qPCR and immunoblot in various breast cancer cell lines. Glycogen levels in these breast cancer cell lines were quantified using an amyloglucosidase reaction coupled with other enzymatic reactions to produce a fluorescent product. It was found that MDA-MB-231, SUM149, and MCF7 cell lines had increased levels of glycogen, between 6.5 and 23.5 μg glycogen per mg protein, whereas SUM190 and normal-like breast epithelial cell line MCF10A had undetectable levels of glycogen. These findings demonstrate that glycogen metabolism can vary widely amongst cancer types, indicating that therapies targeted to disrupt glycogen degradation may produce differential results and that further study of the role of glycogen metabolism in cancer is warranted.
Citation Format: Joel A. Yates, Megan Altemus, Zhifen Wu, Michelle L. Wynn, Sofia D. Merajver. Differential levels of glycogen in breast cancer cell lines: A potential new target. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1040.
Abstract 1046: Statin inhibits malignant mesothelioma cell growth by inactivating YAP1
Authors: Tanaka Kosuke , Kato Taketo , Matsushita Akihiro , Furuta Hiromi , Murakami Yuko , Osada Hirotaka , Sekido Yoshitaka 
Published: July 2016

Abstract
The prognosis of patients with malignant mesothelioma (MM) remains very poor because of highly invasive tumor characteristics and therapeutic resistance of this tumor. Recent studies have shown that MM frequently shows Hippo signaling pathway inactivation, which leads to activation of YAP1 transcriptional co-activator. Although substantial data from clinical trials and epidemiological studies showed promising results for the use of statins in many cancers, few studies have argued about the underlying tumor-suppressive mechanisms of statins. Here, we show that statins act as an inhibitor of YAP1-dependent MM cell growth via mevalonate pathway. In cell culture, statins attenuate migration and invasion of H290 malignant mesothelioma cells with homozygous deletion of NF2, which encodes Merlin, an upstream regulator of Hippo pathway. In contrast, geranylgeranyl diphosphate (GGPP), a down-stream activator of mevalonate pathway, completely rescues H290 cell growth inhibition by statins. We also found that statins accelerate YAP phosphorylation/inactivation, which results in the downregulation of Hippo-pathway targeting gene transcriptions including CTGF, CYR-61 and ANKRD1. Moreover, among 11 MM cell lines, we demonstrated that five out of the six cell lines, which showed significant cell growth inhibition with statins, harbor NF2 and/or LATS2 mutations. Finally, we found that phospho-YAP/YAP ratio was increased in statin-sensitive cells, but not in statin-resistant cells. Together, our findings suggest that mevalonate pathway plays crucial roles in YAP-dependent MM cells by Hippo pathway inactivation, and therefore represents a potential therapeutic target for MM.
Citation Format: Kosuke Tanaka, Taketo Kato, Akihiro Matsushita, Hiromi Furuta, Yuko Murakami, Hirotaka Osada, Yoshitaka Sekido. Statin inhibits malignant mesothelioma cell growth by inactivating YAP1. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1046.
Abstract 1047: Effect of 1,25-Dihydroxyvitamin D in regulating glutamic-oxaloacetic transaminase 1 (GOT1) and redox balance during breast cancer progression
Authors: Zhou Xuanzhu , Wilmanski Tomasz , Teegarden Dorothy 
Published: July 2016

Abstract
Breast cancer is the second most common cancer among women in the US. The active form of vitamin D, 1α,25 dihydroxyvitamin D (1,25(OH)2D), is proposed to inhibit cellular processes that may prevent breast cancer. Possible pro-oxidative effects of 1,25(OH)2D in breast cancer cells which may selectively promote cell death have been proposed. Glutamic-oxaloacetic transaminase 1 (GOT1) is an essential transaminase in glutamine metabolism. GOT1 converts aspartate into oxaloacetate in the cytoplasm, which is then subsequently converted to malate and pyruvate. NADPH is produced during the last step of this process and increased NADPH/NADP+ ratio has the potential to maintain cellular redox balance. Therefore, it is of interest to study 1,25(OH)2D regulation of GOT1 during cancer progression to understand the role of vitamin D in regulating oxidative stress as a mechanism to prevent breast cancer. We employed untransformed MCF10A human breast epithelial cells (MCF10A), as well as Harvey ras-oncogene or ErbB2 (HER-2/neu) oncogene transformed cells (MCF10A-ras and MCF10A-ErbB2) as cell models for early cancer progression. Results showed that 1,25(OH)2D significantly decreased GOT1 mRNA expression at 48 hours in MCF10A-ras cells and MCF10A-ErbB2 cells by 35 ± 8.8% and 49 ± 10%, respectively, and GOT1 protein expression at 72 hours by 51 ± 4.9% and 51 ± 16%, respectively. The susceptibility of MCF10A-ras cells to hydrogen peroxide induced cell death was significantly increased by 1,25(OH)2D, as determined by measuring viable cell number using MTT assay. We further showed that 96-hour 1,25(OH)2D treatment significantly reduced cellular NADPH/NADP+ ratio by 30 ± 2.8% and GSH/GSSG ratio by 34 ± 2.7% in MCF10A-ras cells. Collectively, these results support that 1,25(OH)2D inhibits GOT1 expression and has pro-oxidative effects in oncogene transformed MCF10A cell lines, which may contribute to its role in preventing breast cancer development.
Citation Format: Xuanzhu Zhou, Tomasz Wilmanski, Dorothy Teegarden. Effect of 1,25-Dihydroxyvitamin D in regulating glutamic-oxaloacetic transaminase 1 (GOT1) and redox balance during breast cancer progression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1047.