bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 796: Reproductive hormones modulate cardioprotection from doxorubicin-induced cardiomyopathy in female spontaneously hypertensive rats
Authors: Pokrzywinski Kaytee , Rosen Elliot T. , Bonanno Julia L. , Aryal Baikuntha , Biel Thomas , Moshkelani Delaram , Mog Steven , Rao Ashutosh 
Published: July 2017

Abstract
Doxorubicin (Dox) causes cardiomyopathy, partially driven by the excess generation of mitochondrial reactive oxygen species (ROS). The incidence of Dox-induced cardiac stress is greater in prepubescent and postmenopausal females compared to reproductively mature women, suggesting that reproductive hormones may mediate cardioprotection. We investigated the role of exogenous hormone replacement therapy (HRT) and naturally cycling reproductive hormones in providing cardioprotection from Dox chemotherapy. Mammary adenocarcinoma SST-2 cells were implanted in spontaneously hypertensive rats (SHRs) that were either ovariectomized and received HRT, or left reproductively normal and maintained natural hormone cycling. HRT animals received time-release pellets containing 17-β-estradiol (E2), progesterone (P4), Tamoxifen (Tam) or combinations thereof, and were subsequently treated with Dox. Naturally cycling animals were treated with Dox, the iron chelator Dexrazoxane (Drz), or Dox+Drz. Tumor size was used to evaluate anticancer activity. Vaginal cytologies and circulating E2 and P4 levels were obtained. Serum cardiac troponin I (cTnI), histopathology and echocardiograms were used to assess cardiac health. Dox treated animals supplemented with E2 and P4 (alone) showed cardioprotection relative to the Dox treated animals. Dox+/-Drz exhibited sustained anti-tumor activity independent of endocrine status. After 13 days with Dox, all naturally cycling animals arrested in diestrus (lowest hormone levels). These results demonstrate that E2 and P4 have a role in providing cardioprotection from Dox therapy in SHRs, and that estrous cycle stage may provide a safety treatment window, potentially reducing the risk of cardiomyopathy in reproductively normal females. We are also currently analyzing RNA sequencing data obtained from heart tissues to achieve a better understanding of the molecular mechanisms of cardioprotection.
Citation Format: Kaytee Pokrzywinski, Elliot T. Rosen, Julia L. Bonanno, Baikuntha Aryal, Thomas Biel, Delaram Moshkelani, Steven Mog, Ashutosh Rao. Reproductive hormones modulate cardioprotection from doxorubicin-induced cardiomyopathy in female spontaneously hypertensive rats [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 796. doi:10.1158/1538-7445.AM2017-796
Abstract 809: A novel woodchuck model of hepatic artery infusion (HAI) with FACT complex targeted drug CBL0137
Authors: Kim Minhyung , Curtin Leslie I. , Powers Colin A. , Sexton Sandra , Gurova Katerina V. , Gudkov Andrei V. , Iyer Renuka V. 
Published: July 2017

Abstract
Background: The liver has unique anatomy in that most blood flow to normal hepatocytes is derived from the portal venous system, while liver tumors obtain their nutrient blood supply exclusively from the hepatic artery. Hepatic artery infusion (HAI) concentrates chemotherapy agents delivering them directly to the tumor bed with the first-pass effect. Although, HAI chemotherapy as a regional therapy has been used clinically for decades in the treatment of both primary and metastatic cancers of the liver, significant toxicity remains a concern, and clinical results have been mixed. The purpose of this study was to establish preclinical HAI model in a woodchuck and administer the FACT (facilitates chromatin transcription) complex targeted drug CBL0137.
Material and methods: Woodchuck hepatitis virus infected Eastern Woodchucks (Marmota monax) were used for the study. Hepatocellular carcinoma (HCC) developed spontaneously about 18 months after birth. The size of HCC was monitored with ultrasound every 2 weeks, and 4 woodchucks bearing over 2 cm tumors were used for the experimental group. Prophylactic cholecystectomy was performed first, and then a 2Fr. (ID=0.012”, OD=0.025”) vascular access port (VAP) was implanted in the gastroduodenal artery (GDA) after collateral vessel ligations. HAI was performed at room temperature via a VAP using 15mg/kg of CBL0137 at a volume of 3 mL/kg for 30 minutes, and tumor responses were investigated with MRI on day 0 (the surgery day of HAI port) and day 7 after HAI.
Results: Anatomy variations existed in the size and location of the supraduodenal artery or pancreatico-duodenal artery. 4/4 success rate of a port implantation was achieved without mortality, but 1/4 animals suffered post-operative bleeding at the port head site, attributed to coagulopathy secondary to hepatic dysfunction. And, 4/4 animals were partially anorexic for up to 7 days post-surgery. Decreased tumor volume and Ktrans (a measure of capillary permeability) were detected 7 days after single HAI with CBL0137.
Conclusion: Although the anticancer effect of CBL0137 on HCC was not clear because of a lack of the control group, we successfully implanted a VAP into the GDA of 4 woodchucks bearing unresectable HCC for HAI. The described woodchuck model may serve as a platform for identifying novel drugs and optimal conditions for the treatment of primary and metastatic liver tumors.
Citation Format: Minhyung Kim, Leslie I. Curtin, Colin A. Powers, Sandra Sexton, Katerina V. Gurova, Andrei V. Gudkov, Renuka V. Iyer. A novel woodchuck model of hepatic artery infusion (HAI) with FACT complex targeted drug CBL0137 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 809. doi:10.1158/1538-7445.AM2017-809
Abstract 810: Establishing patient derived preclinical in vitro and in vivo models of pediatric brain cancers
Authors: Yadavilli Sridevi , Kambhampati Madhuri , Gittens Jamila , Panditharatna Eshini , Stampar Mojca , Kilburn Lindsay B. , Magge Suresh , Packer Roger J. , Nazarian Javad 
Published: July 2017

Abstract
The recent surge in understanding genomic aberrations of some of the deadliest childhood brain cancers has highlighted the need for robust preclinical models. Such models will allow for robust drug screening and preclinical evaluation of efficacy, toxicity, and tumor penetrance in vivo. Given the rarity and importance of patient derived specimens, handling and processing methods are perhaps the most critical steps for successful establishment of viable and reproducible in vitro and in vivo models. Since specimen source varies (biopsy, autopsy, or cryo-preserved), processing methods should be refined to allow for optimal extraction of maximum numbers of viable cells from each specimen type. We have developed standardized procedures for handling and processing of tissue samples obtained from biopsy, autopsy, or cryo-preserved specimens as well as necropsy tissue obtained from existing xenograft models. Two processing methods for generating viable cell suspensions are described. The first method, which uses collagenase-DNAse mediated digestion of the tissue is efficient with bulky samples and can be used with tissues obtained at autopsy. The second method uses a commercially available enzymatic dissociation kit optimal for small volume samples such as biopsy, cryo-preserved and mouse necropsy specimens. We show that obtaining viable cell suspension from precious tumor tissue by these methods results in successful generation of pre-clinical in vitro and in vivo models of DIPG, pilocytic astrocytoma and medulloblastoma that represent the exact genetic makeup of the original patient tumor. We further demonstrate intracranial injections of these cells into P2 mice for generating orthotopic xenograft models of brainstem or cortical tumors. Our methods and results allow for rapid establishment of preclinical models using rare and valuable childhood brain tumor specimens. These pre-clinical models serve as valuable tools for understanding the molecular mechanisms of the disease, identifying targetable molecules, and screening of novel therapeutics.
Citation Format: Sridevi Yadavilli, Madhuri Kambhampati, Jamila Gittens, Eshini Panditharatna, Mojca Stampar, Lindsay B. Kilburn, Suresh Magge, Roger J. Packer, Javad Nazarian. Establishing patient derived preclinical in vitro and in vivo models of pediatric brain cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 810. doi:10.1158/1538-7445.AM2017-810
Abstract 811: Histological heterogeneity contributes to sunitinib resistance in clear cell renal cell carcinoma
Authors: Lichner Zsuzsanna , Saleeb Rola , Butz Henriett , Nofech-Mozes Roy , Riad Sara , Farag Mina , Kapus Andras , Yousef George 
Published: July 2017

Abstract
Introduction: The receptor tyrosine kinase (RTK) inhibitor sunitinib is the first line treatment for advanced clear cell renal cell carcinoma (ccRCC). Sunitinib inhibits angiogenesis via blocking signaling through VEGFR. About 80% of patients develop resistance after a drug-sensitive period. Molecular changes early in treatment may impact drug resistance, but are poorly understood.
Experimental Procedures: ACHN, 786-O and Renca cell lines were treated with 1 µM sunitinib. NSG mice were s.c. xenografted with the model cell lines and were treated with sunitinib at 40 mg/kg/day dose. mRNA expression was screened using Illumina HT-12 bead chip array and miRNA expression was assessed by Nanostring nCounter assay. R statistical packages were used for data processing. Reactome and miRPath softwares were used for downstream analysis.
Results: Sunitinib treatment of ccRCC xenografts led to several early changes in tumor histology, such as the emergence of live tumor areas within the necrotic spaces. These areas showed membranous staining for E-cadherin, and β-catenin, while the rest of the tumor and vehicle-treated tumors were negative. In vitro model cell lines developed cancer spheroids when treated with sunitinib. Cancer spheroids were highly tumorigenic and metastatic, and expressed several established cancer stem cell markers. ccRCC cancer spheres, but not the 2D adherent cells, showed membranous staining for E-cadherin and β-catenin; similarly to the live tumor areas observed in
in vivo sunitinib treatment. In vitro inhibition of E-cadherin by EGTA or by siRNA, interfered with viability of sunitinib treated ccRCC cell lines.
Conclusions: Sunitinib treatment causes early phenotypic changes of the tumor in vivo and in vitro. The formation of highly metastatic and tumorigenic cancer spheres in model cell lines is the most prominent effect in vitro. We provide preliminary evidence that sunitinib induced in vitro cancer spheres and the live tumor areas that survive within necrotic patches of the sunitinib-treated xenografts, are related. Finally, membranous expression of E-cadherin enhances the survival of ccRCC cell lines under sunitinib treatment.
Citation Format: Zsuzsanna Lichner, Rola Saleeb, Henriett Butz, Roy Nofech-Mozes, Sara Riad, Mina Farag, Andras Kapus, George Yousef. Histological heterogeneity contributes to sunitinib resistance in clear cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 811. doi:10.1158/1538-7445.AM2017-811
Abstract 833: Alginate hydrogels for three-dimensional culture and real-time monitoring of cancer cell metabolism and radiation response
Authors: Kesarwala Aparna H. , Carter Jenna L. , Read Graham H. , Miura Natsuko , Yamamoto Kazutoshi , Mitchell James B. , Krishna Murali C. 
Published: July 2017

Abstract
The purpose of this study was to characterize a three-dimensional calcium alginate culture system for real-time monitoring of cancer cell metabolism and radiation response. HCT116 colorectal cancer cells were encapsulated in 2.5% calcium alginate using a custom electrostatic rig adapted from a previously published system. Bead diameter was a function of voltage and alginate concentration: 4 x 107 cells/mL encapsulated at 4 and 8 kV resulted in mean diameters of 880 and 584 µm, respectively. The distribution of bead radii for all voltages showed positive excess kurtosis (4 kV = 1.6, 8 kV = 3.0) and 72.9% of 4 kV and 77.2% of 8 kV bead diameters fell within one standard deviation of the mean. Encapsulated cell viability was assessed by staining with Trypan Blue and clonogenic survival assays (CSAs). The baseline viability of cells immediately after encapsulation was 93.2%, which decreased 2 days after a single 10 Gy dose (90.7%, p&lt;0.05). After two weeks of continuous culturing, 84.1% of non-irradiated and 73.8% of irradiated encapsulated cells remained viable (p&lt;0.003). Pimonidazole staining demonstrated the presence of hypoxic cores proportional to bead size. CSAs of 8 kV beads showed a dose modifying factor (DMF) of 1.06 relative to cells grown in a monolayer, while larger 4 kV beads showed a DMF of 1.58. Mean oxygen consumption rate rose with increasing number of 8 kV beads/well: 1 bead, 35.5; 2 beads, 97.4; 3 beads, 175.5; 4 beads, 209.9; 2.0 x 104 monolayer cells, 92.6 (all pmol/min, ~8.2 x103 cells/bead, p&lt;0.005). Hyperpolarized 13C-NMR spectroscopy of 400 uL of 8 kV beads containing 1.2 x 108 cells/mL showed a detectable conversion of [1-13C]-pyruvate to [1-13C]-lactate; 1 hour after a single 10 Gy dose, the lactate:pyruvate ratio decreased by 25%. Unpaired 2-tailed Student’s t-tests were used to determine significance between and one-way ANOVA was used to determine significance among groups with α set at p≤0.05. These data demonstrate the versatility of alginate hydrogels for real-time metabolic and radiation response studies which are non-invasive, higher throughput, and lower cost compared to in vivo systems. Future directions include additional metabolic flux analysis and hyperpolarized 13C-NMR spectroscopy to further investigate the cancer cell metabolic response to drug and/or radiation therapy.
Citation Format: Aparna H. Kesarwala, Jenna L. Carter, Graham H. Read, Natsuko Miura, Kazutoshi Yamamoto, James B. Mitchell, Murali C. Krishna. Alginate hydrogels for three-dimensional culture and real-time monitoring of cancer cell metabolism and radiation response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 833. doi:10.1158/1538-7445.AM2017-833
Abstract 859: Epigenetic regulation of epithelial-mesenchymal transition in esophageal squamous cell carcinoma
Authors: Chen Chen , Zhao Ming , Huang Xiaojie , Wang Xiang , Liu Wenliang , Chen Mingjiu , Yin Bangliang , Li Zhi , Yuan Yunchang , Lu Qianjin , Yu Fenglei 
Published: July 2017

Abstract
Epithelial-mesenchymal transition (EMT) is a developmental program, which is associated with tumor progression and metastasis. Here we investigated the DNA methylation and histone modifications in the regulation of EMT in esophageal squamous cell carcinoma (ESCC). The RNA-Seq analysis identified a total of 6150 differentially expressed genes (3423 up-regulated and 2727 down-regulated). The GO terms showed that these genes belonged to several molecular functions and biological pathways. The abnormal expression of key EMT genes, some of Sox family genes and EZH2 significantly related to patient survival. The MeDIP-Seq analysis identified differentially methylated regions (DMRs) on the whole genome level with focal hypermethylation and widespread global DNA hypomethylation. The gene ontology analysis showed that the DMRs related genes belonged to several different ontological domains, such as EMT progression, cell cycle, adhesion, proliferation, and apoptosis. The results of the bisulfite-sequencing confirmed the EMT gene DMRs identified by MeDIP-Seq. However, further analyses showed that the EMT gene DMRs only related to gene expression, but not the patient survival. ChIP-Seq was then performed to observe the relationship between histone methylation and gene expression. A total of 295 genes were found to correlate with H3K27 tri-methylation (H3K27me3) , and a certain number of key EMT genes, such as ZEB1/2,AREG, GATA4,and CDH8 were identified. Further study showed that Ezh2-mediated H3K27me3 regulate the expression of key EMT genes. Ablation of Ezh2 expression prevents EMT, whereas forced expression of Ezh2 restores EMT. Sox4 gene could directly regulate Ezh2 expression, tri-methylated H3K27me3 for EMT gene repression. Taken together, our results suggest that both of the DNA methylation and H3K27me3 modification involved in the regulation of EMT in ESCC. Sox4-Ezh2-mediated H3K27me3 marks associate with key EMT gene regulation, representing an important epigenetic EMT signature.
Note: This abstract was not presented at the meeting.
Citation Format: Chen Chen, Ming Zhao, Xiaojie Huang, Xiang Wang, Wenliang Liu, Mingjiu Chen, Bangliang Yin, Zhi Li, Yunchang Yuan, Qianjin Lu, Fenglei Yu. Epigenetic regulation of epithelial-mesenchymal transition in esophageal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 859. doi:10.1158/1538-7445.AM2017-859
Abstract 861: Olfactomedin 4 downregulation is associated with enhancing epithelial-mesenchymal transition in human benign prostate cells and prostate cancer cells
Authors: Li Hongzhen , Liu Wenli , Zhu Jianqiong , Chin Kay , Rodriguez-Canales Jaime , Rodgers Griffin P. 
Published: July 2017

Abstract
We have previously reported that lost or reduced olfactomedin 4 (OLFM4) expression is caused by deletions within the OLFM4 gene in 10-25% of all human prostate-cancer samples, and that its expression is lost in more than 58% of advanced prostate-cancer samples. Therefore, we sought to study the role of epigenetic factors in the regulation of OLFM4 gene expression in normal prostate, as well as prostate-cancer, cell lines. Pyrosequencing of genomic DNA extracted from normal prostate or prostate-cancer tissue cells demonstrated that three of the eight CpG sites in the OLFM4 gene promoter were significantly hypermethylated in prostate cancer compared with normal tissue. Exposure to the methylation inhibitor 5-azadeoxycytidine (5-Aza 5 μM) significantly increased OLFM4 expression in RWPE1 benign prostate cells. Knockdown of OLFM4 expression in RWPE benign prostate cells reduced autophagy and enhanced the epithelial-mesenchymal transition (EMT). Restoration of OLFM4 expression in metastatic prostate-cancer cells lacking OLFM4 inhibited cell growth in both in vitro culture models and an in vivo xenograft tumor model, and also inhibited EMT marker gene expression in these cells. 5-Aza induced OLFM4 expression in PC-3 prostate cancer cells and OLFM4 shRNA transfected PC-3 cells affects 5-Aza mediated cell proliferation compared to control-shRNA transfected PC-3 cells. Taken together, our results suggest that OLFM4 inhibits the EMT program in both normal prostate and prostate-cancer cells, and may play a critical role in regulating the EMT program during the progression of cancer. They also suggest that modulation of OLFM4 expression might be a novel molecular target for advancing prostate-cancer therapies.
Citation Format: Hongzhen Li, Wenli Liu, Jianqiong Zhu, Kay Chin, Jaime Rodriguez-Canales, Griffin P. Rodgers. Olfactomedin 4 downregulation is associated with enhancing epithelial-mesenchymal transition in human benign prostate cells and prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 861. doi:10.1158/1538-7445.AM2017-861
Abstract 863: Neuronal splicing regulatory factors are upregulated in models of epithelial-mesenchymal transition
Authors: Khodor Yevgenia L. , Froese Julia , Gertler Frank , Weinberg Robert A. , Burge Christopher B. 
Published: July 2017

Abstract
Epithelial-mesenchymal transition (EMT) is an essential developmental program through which epithelial cells lose their polarity and junctions with neighboring cells and acquire migratory and invasive properties. Cancer cells hijack at least a portion of the EMT program to increase their invasive properties, acquire resistance to senescence, and metastasize. Major changes in cell signaling, transcriptional and post-transcriptional regulation occur during EMT. To study post-transcriptional changes we characterized gene expression and splicing across EMT in 3 cell culture models of EMT: the luminal epithelial MCF7ras breast cancer cell line with EMT induced by SLUG+SOX9 and in basal human mammary epithelial (HMLEras) cells, with EMT induced by either SNAIL or ZEB1. RNA-seq was performed at 2-day intervals across these transitions. We observed broad overlaps between these systems, with 821 genes that changed significantly in all three. In all three time courses, genes associated with cell cycle and growth decreased in expression, while genes associated with signaling, cell motion, adhesion, extracellular matrix organization, and differentiation increased. Intriguingly, genes associated with neurogenesis and angiogenesis were also induced in the MCF7 and HMLER-Snail time courses. Those include known axon guidance and angiogenic factors in the Robo and Slit families. We also found many alternative splicing events shared in all 3 systems, including 272 skipped exons. Sequence analysis of regions around these exons revealed binding motifs for canonical splicing regulators, including ESRP1 and ESRP2 and the RBFOX protein family, which are known to play a role in EMT. While most genes encoding RNA binding proteins decreased in expression in EMT, a small subset consistently increased in expression, including some that matched our motif analysis. Specifically, several splicing factors associated with nervous system development were upregulated, including factors of the QKI and NOVA families. We have validated the increased expression of QKI and NOVA1 proteins during EMT in vitro, and of QKI and NOVA2 in tumor sections. Further, we found that perturbation of QKI expression affects the motility of mesenchymal cancer cells in culture. Together, our results point to the existence of a program of alternative splicing shared between neuronal and mesenchymal cells.
Citation Format: Yevgenia L. Khodor, Julia Froese, Frank Gertler, Robert A. Weinberg, Christopher B. Burge. Neuronal splicing regulatory factors are upregulated in models of epithelial-mesenchymal transition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 863. doi:10.1158/1538-7445.AM2017-863