bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2812: Development and characterization of the ultra immunodeficient B6;129-Rag2
tm1Fwa
IL2rg
tm1Rsky/DwlHsd (R2G2) mouse model
Authors: Wildt Sheryl J. , McClellan Jamie , Horn Mandy 
Published: July 2017

Abstract
The “R2G2” (B6;129-Rag2tm1FwaIL2rgtm1Rsky/DwlHsd) knockout mouse is the latest advancement to provide an alternative option in the highly immunodeficient mouse model category for the oncology, immunology and other biomedical research communities. This model was generated by backcrossing an IL2rg (common gamma) knockout model to a RAG2 (recombinase activating gene) knockout model. The resulting mouse lacks various cytokines including IL-2, IL-4, IL-7, IL-9 and IL-15. In addition, this model lacks B cells, T cells, NK cells and has a deficit in lymphocyte development. The R2G2 model is not only ultra immunodeficient, but provides a model that is less leaky and more tolerant to gamma radiation than traditional SCID models. This model is particularly useful for both tumor transplantation and humanization studies. Herein we describe the development and characterization of the R2G2 model, which includes breeding history, growth curve, CBC/Chemistry, flow cytometry and both huHSC and huPMBC humanization studies.
Citation Format: Sheryl J. Wildt, Jamie McClellan, Mandy Horn. Development and characterization of the ultra immunodeficient B6;129-Rag2tm1FwaIL2rgtm1Rsky/DwlHsd (R2G2) mouse model [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 2812. doi:10.1158/1538-7445.AM2017-2812
Abstract 2825: Gene expression profile in genetically engineered mouse model of lung cancer correlates with that in human lung adenocarcinoma
Authors: Lakshmanan Imayavaramban , Rachagani Satyanarayana , Ponnusamy Moorthy , Chugh Seema , Dutta Samikshan , Muniyan Sakthivel , Batra Surinder , Kishore Apar 
Published: July 2017

Abstract
Introduction: Despite recent advances in the understanding of the biology of lung cancer, there are no agents that can target Kras, the most common mutation seen in lung adenocarcinoma. Development of genetically engineered mouse (GEM) models with krasG12Dand p53R172H+ will help us to understand the biology of kras mutated lung cancer and develop specific targeted therapeutic agents.
Material and Methods: We have developed two GEM models of lung adenocarcinoma harboring the KrasG12D mutation [KrasG12D;AdCre (KA) and KrasG12D; p53R172H;AdCre (KPA)] by conditional activation in the lung. We performed RNA-seq analysis from KA and KPA tumor tissues and compared them to normal lungs from littermate controls. The results were compared with publicly available human data (TCGA, cBioportal). In addition, we have developed two novel syngeneic cell lines from KA and KPA tumors, which will be used to test the efficacy of candidate drugs.
Results: Hyaluronan binding protein (Habp2) was top most upregulated gene [LogFC 12.7 (KA) 10.4 (KPA)] in both KA and KPA tumor tissues compared to normal. The TCGA and cBioportal data suggest Habp2 is overexpressed in lung adenocarcinoma as opposed to other histologic subtypes. We then analyzed Habp2 associated gene signature and observed that fibrinogen alpha chain (FGA), fibrinogen gamma chain (FGG), hyaluronan synthase 1 (HES1), serpin peptidase inhibitor, clade E1(Serpine1) were also upregulated in both models. On comparison of KA and KPA tumors, we observed that St6galnac1(ST6 N Acetylgalactosaminide Alpha-2,6 Sialyltransferase 1) was upregulated only in the KPA model, suggesting that p53R175H mutation leads to St6galnac1 overexpression.
Conclusion: Hyaluronan binding protein (Habp2) was top most upregulated gene in the KA and KPA models, while St6galnac1expression appeared to be associated with p53R175H mutation. Gene expression data from our GEM models of lung cancer agree with the TCGA and cBioportal analyses. Thus these GEM models seem to replicate human lung cancer and can be used to test drugs for in vivo therapeutic efficacy, prior to use in humans.
Citation Format: Imayavaramban Lakshmanan, Satyanarayana Rachagani, Moorthy Ponnusamy, Seema Chugh, Samikshan Dutta, Sakthivel Muniyan, Surinder Batra, Apar Kishore. Gene expression profile in genetically engineered mouse model of lung cancer correlates with that in human lung adenocarcinoma [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 2825. doi:10.1158/1538-7445.AM2017-2825
Abstract 2837: Differential expression of Protocadherin-7 (PCDH7) in prostate cancer (PCa) cells: a direct association between PCDH7 and castrate resistant PCa
Authors: Shishodia Gauri , Koul Sweaty , Dong Qin , Koul Hari K. 
Published: July 2017

Abstract
Introduction: PCa is the most commonly diagnosed disease in American men and the second leading cause of death among them. Most of PCa deaths are a result of distant metastasis and due to emergence of castrate resistant PCa. Protocadherin-7 (PCDH7), a Cadherin superfamily transmembrane protein that is known to function in cell-cell recognition and adhesion, is reported to be overexpressed in breast cancer and non-small cell lung cancer (NSCLC). PCDH7 has been shown to mediate brain metastasis of breast cancer. Overexpression of PCDH7 was reported to be associated with poor clinical outcome of NSCLC. However, there is no report on involvement of PCDH7 in PCa tumorigenesis and metastasis. In the present study we evaluated expression of PCDH7 in androgen dependent and androgen independent PCa cells and in TCGA and Trento/Cornell/Broad 2016 clinical data sets.
Materials and Methods: PCa cells- LNCaP, C4-2b, DU145, PC3, 22Rv1 and RWPE1 were used in this study. Protein expression was checked by Western Blotting. mRNA levels were checked by quantitative real time PCR.
Results: Our data reveal high PCDH7 protein expression in PC3 cells and low levels of PCDH7 in LNCaP and RWPE1 cells. qRT-PCR confirmed an increased transcript level of PCDH7 in PC3 and low levels in LNCaP cells. We also observed elevated transcript levels for PCDH7 in castrate resistant and Enzalutamide refractory PCa (22Rv1) cells. These data suggest a direct relationship between castrate resistance and PCDH7 expression. Our results also show an inverse relationship between PCDH7 and E-Cadherin and a direct relationship between PCDH7 and EMT markers, indicating expression of PCDH7 is associated with tumor progression. Interestingly, there was no correlation between PCDH7 with tumor grade or metastasis from TCGA data, but analysis of NEPC (Trento/Cornell/Broad 2016) data set revealed amplification of PCDH7 in 9% of NEPC tumors. Collectively, these data suggest PCDH7 expression may be associated with advanced PCa in general and NEPC phenotype PCa in particular.
Conclusion: Our results suggest direct association of PCDH7 expression and castrate resistance in PCa cell lines. Role of PCDH7 in castrate resistant PCa needs further evaluation.
Citation Format: Gauri Shishodia, Sweaty Koul, Qin Dong, Hari K. Koul. Differential expression of Protocadherin-7 (PCDH7) in prostate cancer (PCa) cells: a direct association between PCDH7 and castrate resistant PCa [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 2837. doi:10.1158/1538-7445.AM2017-2837
Abstract 284: The trending of lymph node dissection for esophageal squamous cell carcinoma over 40 years in China
Authors: Chen Pei Nan , Zhou Fu You , Chen Hong Mei , Feng Xiao Shan , Sun Lei , Yuan Ling , He Ping , Pan Ying , Jiang Tao , Wu Min Jie , Gao Wen Jun , Wei Jin Chang , Wang Li Dong 
Published: July 2017

Abstract
The accumulated evidences have indicated the importance of lymph node dissection (LND) in improving survival for esophageal squamous cell carcinoma (ESCC). However, it is largely unclear in terms of standard lymph node dissection, e.g., how many is suitable and which node station is more important, etc. The present study was undertaken to summarize the trending of lymph node dissection for ESCC over 40 years at a single institute in northern China. A total of 27,260 ESCC patients were enrolled in this study from 1974 to 2016, including 16,565 males with a mean age of 59.72±7.82 and 10695 females with a mean age of 60.3±8.51. All the patients were from the ESCC database in Henan Key Laboratory for Esophageal Cancer Research of the First Affiliated Hospital, Zhengzhou University (1973-2016). All the patients had pathological LND records, including the number dissected. The patients were classified into four period groups based on the diagnosed time, group I (1974 to 1986, 367/1.3%), group II (1987 to 1996, 3182/11.7%), group III (1997 to 2006, 10, 494/38.5%) and group IV (2007 to 2016, 13,217/48.5%). The SPSS21.0 software was used to evaluate the trending changes of LND at different periods. The results showed that the total number of LND/the mean number by each patient from group I to group IV was 3,000/8.43, 22,001/7.07, 87,740/8.36, and 159,340/12.06, respectively (p&lt;0.0001). Further analysis indicated that the total number of LND/the mean number by each patient from group I to group IV in males was 1,634/7.93, 13,428/6.99, 53,143/8.53 and 100,073/12.19, respectively and 1,366/8.48, 8,573/6.80, 34,597/8.11, 59,267/11.83, respectively in females. The present results indicate an apparent increasing in number of LND from 1987 to 2016 for esophageal cancer surgical treatment in China. Further analysis is needed to correlate the LND and metastasis and survival. [National High-Tech Research and Development Program of China (SQ2015AA0202183), Major Science and Technology Projects of Henan Province (161100311300).]
Note: This abstract was not presented at the meeting.
Citation Format: Pei Nan Chen, Fu You Zhou, Hong Mei Chen, Xiao Shan Feng, Lei Sun, Ling Yuan, Ping He, Ying Pan, Tao Jiang, Min Jie Wu, Wen Jun Gao, Jin Chang Wei, Li Dong Wang. The trending of lymph node dissection for esophageal squamous cell carcinoma over 40 years in China [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 284. doi:10.1158/1538-7445.AM2017-284
Abstract 2840: Integrative approach to biomarker discovery by performing comparative analysis of two cancers, hepatocellular carcinoma and endometrioid endometrial carcinoma, using genetics and transcriptomics from RNA sequencing data
Authors: Billaud Jean-Noel , Tugendreich Stuart , Toburen Debra 
Published: July 2017

Abstract
Hepatocellular Carcinoma (HCC) and Endometrioid Endometrial Carcinoma (EEC) are two lethal diseases of public health importance worldwide. Using QIAGEN’s RNA sequencing solution, we were able to highlight key molecular and biological processes that indicate similarities in the tumor progression toward metastasis between one EEC patient and the three HCC patients. We have identified ITGB1-001 isoform as a potential common biomarker between these two complex cancers. We have also shown these two cancers share activated pathways such as actin cytoskeleton signaling, and RAF1 as an upstream regulator indicating similar transcriptional program between these patients. Furthermore, we have identified as a potential therapeutic target the master regulator CTGF that connects a network of 286 downstream targets to invasion of tumor cells. We have filtered a set of unique variants in the EEC patient that affect a network of upstream regulators common with HCC. This approach may be useful in the context of precision or personalized medicine. Examining the gene expression in tumors from groups of patients with each disease revealed that at a molecular level, early stages of EEC resemble established HBV-positive, HCV-negative, liver cirrhosis positive HCC.
Citation Format: Jean-Noel Billaud, Stuart Tugendreich, Debra Toburen. Integrative approach to biomarker discovery by performing comparative analysis of two cancers, hepatocellular carcinoma and endometrioid endometrial carcinoma, using genetics and transcriptomics from RNA sequencing data [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 2840. doi:10.1158/1538-7445.AM2017-2840
Abstract 2846: Identify urinary biomarkers for colorectal carcinoma liver metastasis
Authors: Cai Meng , Sun Yulin , Gao Jiajia , Zhao Lina , Liu Fang , Sun Wei , Zhou Zhixiang , Zhao Xiaohang 
Published: July 2017

Abstract
Colorectal cancer (CRC) is the third leading prevalent cause of death from cancer in adults, and more than one third of CRC patients are accompanied by liver metastasis. The disease begins as a benign adenomatous polyp, and it subsequently develops into an advanced adenoma and gradually progresses to an invasive cancer. The driving factors behind CRC comprise a series of successive accumulated gene mutations that follow the order “APC-KRAS-TP53-DCC”. Moreover, urine is an important display window for tumor-derived exosomes. Here, to explore the roles of TP53 in CRC and identify novel urinary biomarkers for colorectal cancer metastatic to the liver, a comprehensive proteomic analysis of exosomal proteins from HCT116 TP53-wild type (WT), TP53-knockout (KO) and constructed TP53 (R273H)-mutant (MT) cells, as well as urine samples from CRC patients with and without liver metastasis was performed using the isobaric tag for relative and absolute quantitation (iTRAQ)-2D-LC-MS/MS strategy. The exosomes from the MT and KO cells exhibited significantly reduced sizes compared with the WT cells. A total of 3437 protein groups with ≥2 matched peptides were identified. Specifically, hepatocyte growth factor-regulated tyrosine kinase substrate (HGS) was consistently down-regulated in the exosomes from the MT and KO cells. Functional studies demonstrated that low HGS levels were responsible for the decreased exosome size. TP53 regulated HGS expression and thus HGS-dependent exosome formation. Furthermore, the HGS expression was gradually increased concomitant with CRC carcinogenesis and was an independent poor prognostic factor. In addition, HGS was one of the differentially expressed urine proteins between CRC liver metastasis and healthy individuals. In conclusion, HGS mediates TP53-regulated exosome formation. HGS may serve as a novel histological and urinary prognostic biomarker and a candidate target for therapeutic interventions in CRC.
Citation Format: Meng Cai, Yulin Sun, Jiajia Gao, Lina Zhao, Fang Liu, Wei Sun, Zhixiang Zhou, Xiaohang Zhao. Identify urinary biomarkers for colorectal carcinoma liver metastasis [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 2846. doi:10.1158/1538-7445.AM2017-2846
Abstract 2856: Measuring tumor metabolism in cancer spheroids and biopsies
Authors: Tee Sui Seng 
Published: July 2017

Abstract
Introductory Sentence
Real-time metabolic flux can be measured non-invasively using hyperpolarized magnetic resonance spectroscopy in cancer spheroids as well as tumor biopsies.
Experimental Procedures
LnCAP cells were resuspended in a 1:1 mixture of Matrigel:alginate (1x105 cells/ml) and grown in a porous hollow fiber (A/G Technology Corporation, NY). [1-13C] pyruvate was polarized in a SpinLab (General Electric, NY) before dissolving with appropriate buffers. NMR studies were performed on a 1 Tesla Magritek Spectrometer (Magritek, CA). HP spectra were acquired (10o degree flip angle with repetition time of 4s for 25 scans in total). Cell tracking used the manual tracking function in ImageJ. Xenograft biopsies were obtained from LnCAP tumors using a 2mm punch.
Data Summary
LnCAP cells seeded sparsely enable cancer spheroid formation remain viable as assessed by Live/DEAD fluorescent staining. Histological sectioning revealed spheroids of approximately 200 µm in diameter. Direct deposition of these threads into a 5mm NMR tube allows measurement of metabolic flux using hyperpolarized [1-13C] pyruvate resulting in the formation of [1-13C] lactate. To modulate metabolism, we used an allosteric AKT inhibitor, MK2206. This drug resulted in relocalization of AKT from the plasma membrane as well as a reduction in cell motility from 0.72 ± 0.04 to 0.46 ± 0.03 μm/s (n=5, p&lt;0.05). Administration of hyperpolarized pyruvate resulted in approximately 30% of lactate production 24 hr after treatment. Histological staining of spheroids after treatment revealed sustained decrease of AKT phosphorylation after treatment. These measurements are in good accordance with measurements of lactate secretion in the same cells grown under standard conditions, with MK2206 resulting in loss of AKT Ser473 phosphorylation as early as 2 hr post-treatment, followed by a decrease in lactate secretion in the media from 5.16 ± 0.2 to 1.35 ± 0.05 mM/106 cells (n=3, p&gt;0.05) 24 hr after treatment.
To ensure that these methods are applicable clinical settings, LnCAP xenograft biopsies (~60mg) were deposited directly into an NMR tube to measure hyperpolarized [1-13C] pyruvate metabolism. Line-width of the pyruvate peak was measured to be 1.72 ± 0.19 Hz (n=3) in the first spectra, demonstrating good homogeneity of the magnetic field and conversion to lactate was observed. Future experiments will focus on measuring the metabolism of patient-derived xenografts and effects of treatment response.
Conclusions
Metabolic measurements using hyperpolarized pyruvate can be performed on cancer spheroids as well as biopsies, allowing quantification of metabolism to complement on-going clinical trials utilizing hyperpolarized MR imaging.
Citation Format: Sui Seng Tee. Measuring tumor metabolism in cancer spheroids and biopsies [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 2856. doi:10.1158/1538-7445.AM2017-2856
Abstract 2863: Magnetic resonance imaging based analysis of tumor growth and vascular parameters in animal model of GBM following IV formulated of HET0016 treatments
Authors: Arbab Ali S. , Jain Meenu , Achyut Bhagelu , Angara Kartik , Rashid Mohammad H. , Iskander Asm , Borin Thaiz F. , Zhi Wenbo , Ara Roxan , Lebedyeva Irina , Bagher-Ebadian Hassan 
Published: July 2017

Abstract
Glioblastoma (GBM) is a hypervascular primary brain tumor with poor prognosis. HET0016 a selective CYP450 inhibitor has been shown to inhibit angiogenesis and tumor growth. Therefore, to explore novel treatments, we have generated an improved intravenous (IV) formulation of HET0016 with HPßCD and tested in animal models of human and syngeneic GBM. Tumor growth and vascular parameters (tumor blood volume, permeability and, extravascular and extracellular space volume) were determined by in vivo dynamic contrast enhanced (DCE) magnetic resonance imaging (MRI). The pharmacokinetics of HPßCD-HET0016 were evaluated in plasma and tumor tissues using IV and IP routes of administration. IV treatment with HPßCD-HET0016 decreased tumor growth, tumor blood volume, permeability and, extravascular and extracellular space volume, when compared with the vehicle group (p&lt;0.05). Similar growth inhibition was also observed in syngeneic GL261 GBM (p&lt;0.05). Survival studies using patient derived xenografts of GBM (PDX), showed prolonged survival to 25-27 weeks in animals treated combinedly with focal radiation, IV HET0016 and TMZ (p&lt;0.05). Administration of a single dose resulted in 7-fold higher levels of HET0016 in the IV group in plasma and 3.6-fold higher levels in tumor tissue at 60 min compared to that of IP route. We observed reduced expression of markers of cell proliferation (Ki-67), decreased neovascularization (laminin and αSMA) and migration (MHC-1) in the treated group (p&lt;0.05). Decreased tumor growth was associated with reduced expression of pro-angiogenic markers (IL-8, MCP-1, VEGF, HIF-1α, and VE-Cadherin), inflammation (p-NFκB), intermediates of MAPK pathway (p-AKT, p-ERK and p-STAT1, EGFR), arachidonic acid metabolism (COX-1, CYP4A11) and increased expression of anti-angiogenic markers (Ang2, Angiostatin and Tie-2). Our results indicate that the improved IV formulation of HPßCD-HET0016 is effective in inhibiting tumor growth through decreasing proliferation, migration, and neovascularization. Furthermore, HET0016 significantly enhanced sensitivity of TMZ and prolonged survival in PDX GBM.
Citation Format: Ali S. Arbab, Meenu Jain, Bhagelu Achyut, Kartik Angara, Mohammad H. Rashid, Asm Iskander, Thaiz F. Borin, Wenbo Zhi, Roxan Ara, Irina Lebedyeva, Hassan Bagher-Ebadian. Magnetic resonance imaging based analysis of tumor growth and vascular parameters in animal model of GBM following IV formulated of HET0016 treatments [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 2863. doi:10.1158/1538-7445.AM2017-2863
Abstract 2871: Non-invasive monitoring of the efficacy of anticancer therapeutic agent in lung orthotopic xenograft models of NSCLC using Bio-Luminescence Imaging (BLI)
Authors: Dey Sanchareeka , Kalainayakan Sarada Preeta , Ghosh Poorva , Zhang Li 
Published: July 2017

Abstract
Non-Small Cell Lung Cancer (NSCLC) patients have a poor rate of survival owing to diagnosis at a later stage. This necessitates development of novel therapeutic strategies that limit rapid progression of NSCLC and imaging techniques that monitor such changes in vivo. There has been a significant growth of bioluminescence imaging applications in small laboratory animal models in recent years, owing to its high sensitivity, efficiency, and non-invasive nature.
Our lab has previously demonstrated that a therapeutic agent that disrupts mitochondrial respiration effectively hampers proliferation of NSCLC cell lines in vitro. With an effort to investigate the potential of this therapeutic agent in clinical settings, we used a lung orthotopic xenograft mouse model along with bioluminescence imaging (BLI) to continuously monitor the efficacy of the drug in vivo. Briefly, we implanted NSCLC cell line transduced with lentiviral particles carrying luciferase sequence, in the left lung of 6-8 weeks old female NOD/SCID mice to generate lung orthotopic xenografts. The therapeutic agent was administered intravenously over several weeks. Tumor growth was then compared between the untreated versus the treated mice, non-invasively through bioluminescence imaging (Perkin Elmer’s IVIS Lumina III Imager). On sacrificing the mice, the lungs were harvested, formalin fixed and paraffin embedded for Immunohistochemistry.
Our BLI data show that in the mice treated with the therapeutic agent, tumors are localized to the left lung (site of implantation) as opposed to the control mice where the tumors metastasized to the right lung. The BLI data indicates significant decrease in radiance (total flux in photons per second) in mice subjected to treatment when compared to control mice.
We show that the therapeutic agent significantly inhibits progression and metastasis of human NSCLC cell line orthotopically injected in the lungs of NOD/SCID mice. The results suggest that it might be potent anti-cancer drug as it is effective in a model that recapitulates the natural environment of lung tumorigenesis. Immunohistochemical studies are underway to discern the mechanistic details.
Citation Format: Sanchareeka Dey, Sarada Preeta Kalainayakan, Poorva Ghosh, Li Zhang. Non-invasive monitoring of the efficacy of anticancer therapeutic agent in lung orthotopic xenograft models of NSCLC using Bio-Luminescence Imaging (BLI) [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 2871. doi:10.1158/1538-7445.AM2017-2871