bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4660: HPRT as a biomarker for tumor classification and its variability of expression in breast cancer
Authors: Townsend Michelle H. , Felsted Abigail M. , Clarke Jacob , Robison Richard A. , O'Neill Kim L. 
Published: July 2017

Abstract
The purpose of this study is to investigate the differential expression of HRPT between various
breast cancer tissues in comparison to healthy breast tissue in order to evaluate its potential use
as a diagnostic tool. Breast cancer is the most common malignancy diagnosed in women and
remains incurable in the metastatic setting requiring accurate and reliable tools for early
diagnosis. We analyzed HPRT, a purine salvage pathway enzyme responsible for synthesizing
90% of the available GMP and IMP in cellular maintenance. Due to its critical role in
maintaining necessary nucleotides for cell proliferation, we hypothesized an increase in the
expression of HPRT in cancer. Tissues from 48 patients with breast carcinoma were stained
using standard immunohistochemistry (IHC) techniques. We examined infiltrating ductal
carcinoma, margin of carcinoma, hyperplasia, atypical hyperplasia, adenosis, collagen fibers
tissues, and normal breast tissue in order to determine expression between various breast cancers.
Briefly, tissues were treated with a polyclonal anti-HPRT antibody along with a GADPH
positive control and a universal negative control. Tissues were incubated with an HRP-polymer
conjugated antibody, and DAP substrate which reacts to antibody-antigen binding sites and
results in a color change. Adenosis and hyperplasia are benign breast conditions and are early
signs of breast carcinoma development. Hyperplasia tissues, which are in a state of rapid
proliferation, showed significant upregulation of HPRT and adenosis tissues showed
approximately 42% upregulation. This HPRT upregulation in pre-stage 1 tissues indicates that it
may be used as a biomarker to detect early stages of breast cancer. Expression of HPRT was also
found to be upregulated in 65% of infiltrating duct carcinoma showing high expression in active
malignant areas. In marginal tissue located on the perimeter of primary tumors only 31% of
tissues show upregulation of the protein. Because the levels of HPRT in marginal tissue is
significantly lower than those found in primary tumors, HPRT may serve as a useful diagnostic
tool when evaluating successful tumor removal. These data suggests HPRT as a useful diagnostic
tool when identifying tissue with a high proliferation rate indicative of potential cancer
development. Additionally, HPRT may also be used as a tool for pathologists to evaluate the
success of tumor removal.
Citation Format: Michelle H. Townsend, Abigail M. Felsted, Jacob Clarke, Richard A. Robison, Kim L. O'Neill. HPRT as a biomarker for tumor classification and its variability of expression in breast cancer [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 4660. doi:10.1158/1538-7445.AM2017-4660
Abstract 471: HER2 regulates PARP-1 expression by suppressing the let-7a microRNA in HER2+ breast cancer
Authors: Yang Eddy Shih-Hsin , Wielgos Monicka , Rajbhandari Rajani , Wei Shi , Nozell Susan 
Published: July 2017

Abstract
Background:
HER2+ breast cancers are sensitive to PARP inhibition and express elevated levels of the PARP-1 protein. However, the mode of regulation of PARP-1 expression by HER2 is not well understood. MicroRNAs are small non-coding RNAs that function in RNA silencing and post-transcriptional regulation of gene expression. In this study, we investigate whether PARP1 expression in human breast cancer cells is regulated by HER2 regulation of microRNAs.
Methods:
Human HER2+ breast cancer cell lines BT-474 and SKBR3 were used in this study. MDA-MB-231 (non-HER2 expressing breast cancer cells) stably transfected with a HER2 wild-type plasmid (231 HER2) or the vector control (231 NEO) were also utilized. To identify candidate microRNAs regulated by HER2 overexpression, we performed the nCounter miRNA Expression Assay. MicroRNA and mRNA expression were validated via qRT-PCR analysis in breast cancer cell lines or patient primary tumors. Cells were also transfected with a HER2 siRNA, a let-7a mimic, and an inhibitor of let-7a as well as their respective controls. Western blot analysis and firefly luciferase assays were used to determine whether the 3’UTR of PARP1 was being directly targeted by the let-7a microRNA.
Results:
HER2 did not regulate PARP-1 at the mRNA level but increased PARP-1 protein in HER2+ breast cancer cells. Specifically, ectopic HER2 overexpression correlated with increased PARP-1 protein levels in the 231 HER2 cell line. Conversely, silencing HER2
reduced PARP-1 protein levels in the BT-474 and SKBR3 cell lines. NanoString nCounter analysis revealed that the HER2+ breast cancer cell lines expressed low levels of the let-7a microRNA. Further, let-7a expression was upregulated after HER2 knockdown in the two native HER2+ breast cancer cell lines. The let-7a mimic also reduced both PARP1 protein expression and luciferase activity in the 231 HER2 and BT-474 cell lines, whereas the let-7a inhibitor reversed these effects in the 231 NEO cell line. Importantly, human HER2+ breast tumors expressed higher levels of PARP-1 and lower levels of let-7a; whereas, the HER2- breast tumors expressed lower levels of PARP-1 and higher levels of let-7a. Further, overexpression of the let-7a mimic reduced cell proliferation in HER2+ breast cancer cells.
Conclusions:
These results suggest that let-7a regulates PARP-1 expression in HER2+ breast tumors. Let-7a may also be a potential therapeutic target and predictive biomarker of PARPi sensitivity in HER2+ breast cancer patients.
Citation Format: Eddy Shih-Hsin Yang, Monicka Wielgos, Rajani Rajbhandari, Shi Wei, Susan Nozell. HER2 regulates PARP-1 expression by suppressing the let-7a microRNA in HER2+ breast cancer [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 471. doi:10.1158/1538-7445.AM2017-471
Abstract 4715: Protective anti-tumor immune responses in breast cancer depend on tumor mutation rate
Authors: Miller Lance D. , Routh Eric D. , Chou Jeff W. , Thomas Alexandra 
Published: July 2017

Abstract
The relationship between tumor antigenicity and anti-tumor immune responses in breast cancer are poorly understood. Metrics that can accurately predict tumor immunogenic potential could guide therapeutic decisions for breast cancer patients. We examined the relationship between tumor immune subclasses and patient overall survival in the context of the rate of nonsynonymous mutations in breast cancers. These analyses were conducted using RNAseq and exome sequencing data from the Cancer Genome Atlas (TCGA) breast cancer cohort (n=1,098 patients). A previously described tumor-immune classification system, based on the relative abundance of infiltrating effector immune cells, was employed for assigning patients to favorable, weak or poor immunogenic dispositions (FID, WID or PID, respectively). In breast tumors exhibiting low mutation rates (LMR), no significant survival differences were observed among patients comprising the immune subclasses. By contrast, in the context of tumors with high mutation rates (HMR), the immune subclasses exhibited highly significant survival differences (p&lt;0.001). Patients with FID tumors achieved 100% survival at 10 years as compared to those with PID tumors who displayed a 10-year survival rate of 44%. These survival differences were independent of molecular subtype composition, with the majority of the excellent-outcome FID subclass comprising predominantly of Basal-like, HER2-enriched and Luminal B breast tumors. In the smaller subset of HMR Luminal A breast tumors, the immune subclasses also exhibited significantly different survival outcomes (p=0.01), with patients of the poor-outcome Luminal A PID subclass experiencing a 10-year survival rate of 22%. By Cox proportional hazards regression analysis, the immune subclasses contributed significant additive prognostic information in the presence of AJCC stage (p=0.003). A mutation rate of 1.63 mutations per megabase of sequenced DNA was found to be an optimal threshold for distinguishing immune-relevant low and high mutational load. These findings fit a model where mutational burden, reflective of tumor antigenicity, is a major determinant of clinically-relevant breast tumor immunogenicity. This relationship between immunogenic tumor subclasses, overall survival and mutational burden may offer opportunities for therapeutic stratification of breast cancer patients.
Citation Format: Lance D. Miller, Eric D. Routh, Jeff W. Chou, Alexandra Thomas. Protective anti-tumor immune responses in breast cancer depend on tumor mutation rate [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 4715. doi:10.1158/1538-7445.AM2017-4715
Abstract 4721: Novel lincRNA SLINKY is a prognostic biomarker in kidney cancer
Authors: Gong Xue , Siprashvili Zurab , Eminaga Okyaz , Shen Zhewei , Sato Yusuke , Kume Haruki , Homma Yukio , Ogawa Seishi , Khavari Paul A. , Pollack Jonathan R. , Brooks James D. 
Published: July 2017

Abstract
Clear cell renal cell carcinomas (ccRCC) show a broad range of clinical behavior, and prognostic biomarkers are needed to stratify patients for appropriate management. We sought to determine whether long intergenic non-coding RNAs (lincRNAs) might predict patient survival. Candidate prognostic lincRNAs were identified by mining The Cancer Genome Atlas (TCGA) transcriptome (RNA-seq) data on 466 ccRCC cases (randomized into discovery and validation sets) annotated for ~21,000 lncRNAs. A previously uncharacterized lincRNA, SLINKY (Survival-predictive LINcRNA in KidneY cancer), was the top-ranked prognostic lincRNA, and validated in an independent University of Tokyo cohort (P=0.004). In multivariable analysis, SLINKY expression predicted overall survival independent of tumor stage and grade [TCGA HR=3.4 (CI, 2.1-5.4), P &lt; 0.001; Tokyo HR=9.2 (CI, 2.2-43), P = 0.003], and by decision tree, ROC and decision curve analysis, added independent prognostic value. In ccRCC cell lines, SLINKY knockdown reduced cancer cell proliferation (with cell-cycle G1 arrest) and induced transcriptome changes enriched for cell proliferation and survival processes. Notably, the genes affected by SLINKY knockdown in cell lines were themselves prognostic and correlated with SLINKY expression in the ccRCC patient samples. From a screen for binding partners, we identified direct binding of SLINKY to Heterogeneous Nuclear Ribonucleoprotein K (HNRNPK), whose knockdown recapitulated SLINKY knockdown phenotypes. Thus, SLINKY is a robust prognostic biomarker in ccRCC, where it functions possibly together with HNRNPK in cancer cell proliferation.
Citation Format: Xue Gong, Zurab Siprashvili, Okyaz Eminaga, Zhewei Shen, Yusuke Sato, Haruki Kume, Yukio Homma, Seishi Ogawa, Paul A. Khavari, Jonathan R. Pollack, James D. Brooks. Novel lincRNA SLINKY is a prognostic biomarker in kidney cancer [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 4721. doi:10.1158/1538-7445.AM2017-4721
Abstract 4729: Association of mitochondrial DNA copy number variation in peripheral blood leucocytes with risk and prognosis of gallbladder cancer
Authors: Chandra Abhijit , Kazmi Hasan R. , Satyam Leena K. , Kumar Saket 
Published: July 2017

Abstract
Gallbladder Cancer (GBC) is the most common malignancy of the biliary tract with very high incidence in Northern India, especially around Gangetic belt. Late diagnosis and poor prognosis are the important features of this disease. For improving treatment strategies and outcomes, novel non invasive prognostic biomarkers are needed. Variations in peripheral blood mitochondrial DNA (mtDNA) copy number in various cancers are widely studied but information in relation to gallbladder malignancy is unknown. In this pilot study, we investigated leucocytes mtDNA copy number variation in relation to risk and prognosis of GBC.
A total of 300 histologically confirmed or fine needle aspiration cytology proven GBC patients were recruited along with equal number of age and sex matched controls. The mtDNA copy number was measured by real-time polymerase chain reaction through absolute quantification using SYBR green chemistry. We also explore prognostic utility of mtDNA content in relation to overall survival of GBC patients. Statistical analysis was done by Student’s test and survival data was compared using Kaplan Meier method. Two tailed p value less than 0.05 was considered to be significant.
We observed high mtDNA content in cases as compared with controls (mean±standard deviation, 1.21±0.88 vs. 1.02±0.76). Higher mtDNA copy number was significantly associated with increased gallbladder cancer risk (p=0.005). In this study, we compared overall survival (OS) for gallbladder cancer patients in relation to mtDNA copy number median value (median, 1.12). Kaplan Meir survival curve predicts decrease in OS (p=0.03, Hazard ratio=2.54; 95% CI = 1.79-5.86) for GBC patients in relation to high mtDNA content (&gt;median) as compared with low mtDNA copy number (&lt;median).
This study supports an association between increased mtDNA copy number with susceptibility to gallbladder cancer in this endemic belt. Future studies are warranted to confirm these findings and to elucidate the biological role of mtDNA copy number in relation to gallbladder cancer.
Citation Format: Abhijit Chandra, Hasan R. Kazmi, Leena K. Satyam, Saket Kumar. Association of mitochondrial DNA copy number variation in peripheral blood leucocytes with risk and prognosis of gallbladder cancer [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 4729. doi:10.1158/1538-7445.AM2017-4729
Abstract 4754: Fractionated whole brain radiation-induced behavioral changes in athymic nude mice is associated with sustained neuroinflammation and microglial M1-phenotype
Authors: Kanji Suman , Johnson Benjamin , Witcher Kristina , Gulati Pooja Gulati , Chen Shannon , Godbout Jonathan , Nelson Randy J. , Haque Saikh , Chakravarti Arnab 
Published: July 2017

Abstract
The objective of this study is to study the late-chronic effects of fractionated whole brain irradiation (fWBI) on cognitive impairment and associated cellular and molecular neuro-inflammatory mechanisms using clinically relevant and reliable mouse models. Microglia are recognized as the primary innate immune component of neuroinflammation. However, microglial contributions to radiation-induced cognitive impairment are poorly understood. Here, an athymic nude (Nu/Nu) mouse model was employed to address this issue. Mice were divided into two groups: radiation treatment (XRT) and no-treatment control (CTL). The whole brain of each XRT mouse received 30 Gy (3 Gy/fraction) of radiation over two weeks. XRT and CTL mice were assessed for cognitive and behavioral changes at 1, 4, and 6 months posttreatment using the novel object recognition test (for long-term, non-spatial memory), the free running Y-Maze (for short-term, spatial memory) and Barnes Maze (for spatial learning and memory). A significant decline in novel object recognition in the XRT group (P&lt;0.05) was seen at the 4 month time point and continued to persist at 6 months (P&lt;0.05). No significant changes in the Barnes maze or Y-maze were seen at these time points. Expression of neuroinflammatory mediator genes, from both whole brain and isolated microglia, were measured by RT-PCR. We found that markers of the M1-phenotype, which include TNF-α, and MHC II, were significantly upregulated (P&lt;0.05) and markers of the general M2 Phenotype, which include IL-4ra, IL-10ra, and TGF-β, were downregulated (P&lt;0.05) at 1 and 6 month time points. These results indicate that sustained neuroinflammation and microglial M1-polarization are associated with long-term cognitive impairment induced by fWBI. Radiotherapy is the most prevalent treatment for primary and metastatic brain tumors. Whereas previous studies that identified important mechanisms underlying XRT-induced cognitive decline had used treatment regimens that were not clinically relevant ones, we have employed a clinically relevant fractionation scheme to address the cellular and molecular deregulations in association with cognitive impairment.
Citation Format: Suman Kanji, Benjamin Johnson, Kristina Witcher, Pooja Gulati Gulati, Shannon Chen, Jonathan Godbout, Randy J. Nelson, Saikh Haque, Arnab Chakravarti. Fractionated whole brain radiation-induced behavioral changes in athymic nude mice is associated with sustained neuroinflammation and microglial M1-phenotype [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 4754. doi:10.1158/1538-7445.AM2017-4754
Abstract 477: Down-regulated miR-23a contributes to invasion and metastasis of cutaneous melanoma by promoting autophagy
Authors: Guo Weinan , Wang Huina , Yang Yuqi , Guo Sen , Zhang Weigang , Zhao Tao , Liu Lin , Jian Zhe , Liu Ling , Wang Gang , Gao Tianwen , Shi Qiong , Li Chunying 
Published: July 2017

Abstract
Background: The occurrence of invasion and metastasis is the major cause of mortality in melanoma. Recent studies suggest that dysregulated miRNAs play critical roles in this procedure, but the underlying mechanism remains elusive. Here, we show that down-regulated miR-23a can promote invasion-metastasis cascade through autophagy in melanoma.Methods: The role of miR-23a in prognosis was assessed in a cohort of melanoma patients (n = 192) with Kaplan-Meier analysis. The effects of miR-23a overexpression were investigated using assays of invasion, migration and in a xenograft model (n = 10 mice per group). Autophagy-related target of miR-23a was confirmed by bioinformatics analysis, luciferase assays and immunoblotting. Molecular studies were performed to determine the downstream cellular and molecular mechanisms. All statistical tests were two-sided.Results: Serum miR-23a level was significantly down-regulated in melanoma patients (P&lt; .001) and was highly correlated with poor clinical outcomes (P = .027, log-rank test). In addition, miR-23a level was remarkably decreased in metastatic melanoma tissues and cell lines (P&lt;.05, P&lt;.01). Moreover, miR-23a overexpression prevented the invasion and migration in vitro and lung and liver metastasis in vivo (both P&lt; .05), by targeting ATG12 and inhibiting autophagy. Mechanically, miR-23a-ATG12 axis attenuated invasion and migration through autophagy-mediated AMPK-RhoA pathway. Finally, the down-regulation of miR-23a in metastatic melanoma was caused by RUNX2 in a transcriptional repression-manner. Conclusion: MiR-23a can act as a crucial epigenetic repressor of melanoma invasion and metastasis in an autophagy-dependent way, which indicates that miR-23a-mediated autophagy inhibition can be exploited to restrain invasion-metastasis cascade in melanoma treatment.
Note: This abstract was not presented at the meeting.
Citation Format: Weinan Guo, Huina Wang, Yuqi Yang, Sen Guo, Weigang Zhang, Tao Zhao, Lin Liu, Zhe Jian, Ling Liu, Gang Wang, Tianwen Gao, Qiong Shi, Chunying Li. Down-regulated miR-23a contributes to invasion and metastasis of cutaneous melanoma by promoting autophagy [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 477. doi:10.1158/1538-7445.AM2017-477
Abstract 4772: Stearoyl-CoA Desaturase (SCD1) regulates liver tumor initiating cells through modulating ER stress
Authors: Ma Kin Fai , Lau Eunice Yuen Ting , Ng Irene Oi Lin , Lee Kin Wah 
Published: July 2017

Abstract
Sorafenib is the FDA approved drug for patients with advanced hepatocellular carcinoma (HCC), but the survival benefit is only modest, partly due to drug resistance. Increasing evidence shows that tumor-initiating cells (T-ICs) are intrinsically resistant to conventional treatments, and targeting signaling pathways in T-ICs provides potential therapeutic targets for HCC. In our established enriched T-IC population, we identified the activation of a lipogenesis pathway in which expression of stearoyl-CoA desaturase-1 (SCD1), an enzyme involved in the conversion of saturated into monounsaturated fatty acids, was most significant. SCD1 overexpression is frequently found in HCC samples and is significantly associated with poorer patient survival. Using overexpression and knockdown approaches, SCD1 was found to regulate the traits of T-ICs, including tumorigenicity, self-renewal, differentiation, drug resistance and the expression of liver T-IC markers. Interestingly, SCD1 was markedly upregulated in our established sorafenib-resistant cell lines as well as patient-derived xenografts (PDTXs), and its overexpression predicts the clinical response of HCC patients to sorafenib treatment. Consistently, pharmacological inhibition of SCD1 suppressed T-IC phenotypes and enhanced sensitivity to sorafenib treatment. Using a patient-derived xenograft model, we found that a novel SCD1 inhibitor (SSI-4) in combination with sorafenib demonstrated a maximal tumor suppressive effect. Induction of endoplasmic reticulum (ER) stress-mediated T-IC differentiation can account for the enhanced sensitivity towards sorafenib treatment upon SCD1 suppression. In conclusion, SCD1-induced ER stress may specifically increase the sensitivity of liver T-ICs to the effects of sorafenib treatment. Targeting SCD1 in combination with sorafenib therapy may be a novel therapeutic regimen against HCC.
Citation Format: Kin Fai Ma, Eunice Yuen Ting Lau, Irene Oi Lin Ng, Kin Wah Lee. Stearoyl-CoA Desaturase (SCD1) regulates liver tumor initiating cells through modulating ER stress [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 4772. doi:10.1158/1538-7445.AM2017-4772