bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3634: A gain-of-function mutation in tyrosine phosphatase SHP-2 enhances breast carcinoma malignant phenotypes
Authors: Hu Zhongqian , Fang Haoshu , Wang Siying 
Published: August 2015

Abstract
Breast cancer is the most common malignant tumor in women worldwide, and it is the second leading cause of cancer-related mortality in the US women. Evidences suggested that overexpression of Src homologous protein phosphotyrosyl phosphatase 2 (SHP2) has been observed in most of the breast cancer cell lines and in breast cancer tissues, and accompanied with lymph nodes metastasis. Inhibition of SHP2 in the breast cancer cell lines abolishes the growth and decrease survival of tumor cells, which leads to the differentiation of malignant cells into normal breast epithelial phenotype. These observations suggest that SHP2 promotes the tumor development though increase tumor formation and metastasis. However, the pathophysiologic role of SHP2 (overexpression or gain-of-function mutation) and its relevance to tumorigenesis are still largely unknow. In this study, we focused on the in vivo and in vitro effects of the gain-of-function mutant SHP-2 on phenotypes of breast cancer. Mutant PTPN11 cDNA (D61G) was transduced into MDA-MB231 and MCF-7 cells. The effects of D61G mutant on breast cancer tumorigenesis and malignant behaviours, such as cell adhesion, proliferation, migration and invasion were tested. The potential underlying molecular mechanisms, i.e., the activation of the Gab1-Ras-Erk axis were also examined. In vitro studies found that, in SHP2 D61G mutant groups, the tumour adhesion, proliferation, migration and invasion were increased significantly. Consistently, in vivo studies also found that the incidence of tumour and the tumour weights of the SHP-2 D61G-MB231 group were increased significantly (P&lt;0.001), which is also associated with tumour metastasis. Mechanistically, the PTPN11 D61G mutation resulted in the activation of Ras-ErK pathway. And interestingly, the interaction between Gab1 and mutant SHP2 was also significantly increased. The mutant SHP-2 significantly promoted tumour migration and invasion at least partially through the activation of Gab1-Ras-Erk axis. In conclusion, our findings clearly establish a role for the SHP-2 GOF mutant in breast tumour growth and provide novel insight into the mechanisms of SHP-2 GOF mutant-mediated tumor promotion. This finding could have direct implications for breast cancer therapy.
This study was supported by a grant from the National Natural Science Foundation of China (codes: 30873046, 30973424, and 81072663) and by the Fundamental Research Funds for the Central Universities (code:3290004402).
Note: This abstract was not presented at the meeting.
Citation Format: Zhongqian Hu, Haoshu Fang, Siying Wang. A gain-of-function mutation in tyrosine phosphatase SHP-2 enhances breast carcinoma malignant phenotypes. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3634. doi:10.1158/1538-7445.AM2015-3634
Abstract 3647: Targeting cancer-induced anemia with hepcidin lowering ALK2 inhibitors
Authors: Peterson Peter W. 
Published: August 2015

Abstract
Anemia of cancer (AOC) is a cytokine driven condition that frequently occurs in patients due to chronic inflammation associated with cancer development. It differs from chemotherapy-induced anemia because the anemia is a result of the disease itself and not a side effect of a treatment regimen, although the both causes can work in concert. AOC is caused by high levels of the liver peptide hormone, hepcidin, which sequesters iron in epithelial cells and macrophages, thereby limiting bioavailable iron required for erythropoiesis. Reducing elevated hepcidin levels in cancer patients can reverse the hypoferremia and anemia seen in AOC. Hepcidin levels are controlled by inflammatory cytokines through pathways dependent on bone morphogenetic proteins (BMP). BMPs up-regulate hepcidin by activating the SMAD signaling pathway through the activin-like kinase receptor 2 (ALK2). Therefore, ALK2 has emerged as an attractive therapeutic target to modulate hepcidin levels in cancer patients and treat their AOC. We have developed novel small molecule ALK2 inhibitors which have shown promising results in tissue culture models as well as a preclinical cancer model of AOC. The two most promising compounds downregulate hepcidin expression in BMP-induced cell culture studies at concentrations of 100 nM or lower. Importantly, this activity was observed at concentrations that exhibited little cytotoxicity suggesting the compounds have a clean selectivity profile. The two compounds have been tested in a TC-1 syngeneic mouse model of AOC where anemia is induced after tumor formation, in a manner similar to human cancer caused anemia. Treatment with the lead candidates reversed the induction of hepcidin expression and also decreased the symptoms of anemia as measured by serum iron and red blood cell levels. From these data, we have nominated a candidate to advance into IND-enabling studies that has favorable drug-like properties. We anticipate a clinical development strategy that focuses on AOC.
Citation Format: Peter W. Peterson. Targeting cancer-induced anemia with hepcidin lowering ALK2 inhibitors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3647. doi:10.1158/1538-7445.AM2015-3647
Abstract 3649: Broad profiling reveals opportunities for selective inhibition of disease-associated mutant kinases
Authors: Duong-Ly Krisna C. , Devarajan Karthik , Liang Shuguang , Horiuchi Kurumi , Wang Yuren , Ma Haiching , Peterson Jeffrey R. 
Published: August 2015

Abstract
Small molecule kinase inhibitors are promising therapeutic agents in a number of diseases, most notably cancer. However, mutations in kinases, both intrinsic and acquired, can drastically alter inhibitor sensitivity. To identify inhibitors of disease-associated mutant kinases, we conducted an unbiased functional screen of 182 small molecule kinase inhibitors against 76 mutated recombinant kinases arising from 21 cognate wild-type kinases. The results revealed novel lead compounds that were exquisitely selective for mutant kinases, including several that exhibited preferred inhibition of mutant kinases over their cognate wild-type kinases. This study provides a resource for the development of novel small molecule inhibitors against disease-associated mutant kinases and illustrates the potential of unbiased large-scale profiling as an approach to compound-centric kinase inhibitor discovery.
Citation Format: Krisna C. Duong-Ly, Karthik Devarajan, Shuguang Liang, Kurumi Horiuchi, Yuren Wang, Haiching Ma, Jeffrey R. Peterson. Broad profiling reveals opportunities for selective inhibition of disease-associated mutant kinases. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3649. doi:10.1158/1538-7445.AM2015-3649
Abstract 3671: Loading and molecular labeling of cell-specific exosomes by HDL-like AuNPs
Authors: Angeloni Nicholas L. , McMahon Kaylin M. , Thaxton C. Shad 
Published: August 2015

Abstract
Exosomes are 30-100 nm diameter lipid vesicles produced by most cells. Exosomes carry diverse cargo, such as RNA and proteins. Cancer cells produce an abundant amount of exosomes, which are released from cells of the primary tumor into the tumor microenvironment and the circulation. Data show that exosomes can promote cancer progression and metastasis by delivering, for instance, pro-metastatic factors to pre-metastatic sites. It is not currently possible to specifically separate tumor-derived exosomes from complex matrices. This ability would provide a better understanding of their contribution to tumorigenesis and cancer progression. Furthermore, the targeting properties of exosomes make them appealing vehicles for encapsulating and delivering therapeutic cargo. However, it is challenging to isolate and then load exosomes with specific drugs. Uniquely, our data reveal that synthetic high-density lipoprotein nanoparticles (HDL NPs) can be tailored to achieve cell-specific exosome labeling and loading of therapeutic cargo. HDL NPs are synthesized using a 5 nm diameter spherical gold nanoparticle. The gold NP serves as a template to control size and shape. Apolipoprotein A-I and phospholipids are conjugated to the gold surface, yielding a synthetic HDL NP similar in size, shape, surface chemistry, and function to some natural HDLs. Our data demonstrate that, upon addition of HDL NPs to cultured CWR 22Rv1 prostate cancer cells, they are packaged into exosomes that are secreted from these cells. Furthermore, HDL NPs made using phospholipids functionalized with either biotin or fluorophore molecules leads to the incorporation of the phospholipids into the exosomes. Thus, the specific cell-derived exosomes are labeled with gold, a molecular fluorophore label, and/or biotin. In each case, the specific exosomes are easy to isolate using methods such as fluorescent isolation or by the robust streptavidin-biotin interaction. Isolated exosomes retain the same size and molecular markers as exosomes from untreated cells. Overall, this unique method may provide control over exosomes for a myriad of diagnostic and therapeutic uses.
Citation Format: Nicholas L. Angeloni, Kaylin M. McMahon, C. Shad Thaxton. Loading and molecular labeling of cell-specific exosomes by HDL-like AuNPs. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3671. doi:10.1158/1538-7445.AM2015-3671
Abstract 3678: Imaging AZD1152HQPA Accurin™ nanoparticle accumulation in preclinical tumors
Authors: Goodwin Richard , Swales John , Nilsson Anna , Andren Per , Strittmatter Nicola , Takats Zoltan , Howes Colin , Taylor Paula , Ashton Susan , Jewsbury Philip , Barry Simon T. 
Published: August 2015

Abstract
AZD1152HQPA Accurin is a passively targeted nanoparticle containing the active metabolite of the Aurora B kinase prodrug AZD1152. In preclinical studies, AZD1152HQPA Accurin displays reduced bone marrow toxicity associated with AZD1152 together with increases in anti-tumour activity. Nanoparticles are proposed to enable delivery and retention of drug to the tumour thereby increasing efficacy and modifying therapeutic index. While it is possible to demonstrate increased duration of modulation of pharmacodynamic biomarkers and drug exposure by nanoparticle delivery, directly demonstrating that nanoparticles accumulate in the tumour is challenging. To investigate the intra tumoural distribution of AZD1152HQPA Accurin nanoparticles we have employed mass spectrometry techniques to image samples derived from human colorectal cancer SW620 studies in rats. We have separately identified the nanoparticle itself, drug encapsulated in nanoparticle, and drug released from nanoparticle; the latter by detecting a metabolite that is only generated from released drug. First MALDI (matrix assisted laser desorption ionization) which offers 20 μm spatial resolution, was used to detect AZD1152-hQPA (released and encapsulated). Second LESA (liquid extraction surface analysis), which offers 1000 μm spatial resolution, was used to detect drug and metabolite, enabling co-distribution to be demonstrated. Finally DESI (desorption electrospray ionization) which offers 100 μm spatial resolution was used to detect drug, metabolite and nanoparticle constituent showing the co-distribution in more detail. Using this combination of approaches it is possible to demonstrate the presence of nanoparticle-delivered AZD1152HQPA metabolite in the tumour at extended timepoints; co-located with nanoparticle and unchanged (encapsulated) drug. At these time points no drug remains if delivered as a simple IV infusion. Collectively this imaging mass spectrometry analysis demonstrates AZD1152HQPA Accurin accumulation in pre-clinical tumours and confirms that the Accurin accesses the tumour and achieves sustained drug release within the tumour.
Citation Format: Richard Goodwin, John Swales, Anna Nilsson, Per Andren, Nicola Strittmatter, Zoltan Takats, Colin Howes, Paula Taylor, Susan Ashton, Philip Jewsbury, Simon T. Barry. Imaging AZD1152HQPA Accurin™ nanoparticle accumulation in preclinical tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3678. doi:10.1158/1538-7445.AM2015-3678
Abstract 37: Role and regulation of CYP24A1 in endometrial cancer
Authors: Bokhari Amber A. , Lee Laura R. , Dewayne Raboteau , Hamilton Chad A. , Maxwell George L. , Rodriguez Gustavo C. , Syed Viqar 
Published: August 2015

Abstract
The cytochrome P450 enzyme, 24-hydroxylase, encoded by CYP24A1 is critical for the catabolism of 1,25(OH)2D3 (calcitriol). The unbalanced high levels of CYP24A1 seem to be a determinant of calcitriol resistance in tumors. We have previously shown that progesterone enhances calcitriol antitumor activity by upregulating vitamin D receptor expression and promoting apoptosis in endometrial cancer cells. In the present study, we evaluated CYP24A1 protein expression in normal and endometrial tumor tissues, assessed the effect of progesterone and calcitriol on CYP24A1 and its spliced variant expression in endometrial cancer cell lines and correlated this with tumor cell growth. Expression of CYP24A1 was assessed in tissue microarrays by immunohistochemistry. A grade-dependent increase of CYP24A1 expression was found in endometrial carcinomas. Endometrial cancer cells expressed high levels of CYP24A1 compared to immortalized endometrial epithelial cells. Furthermore, CYP24A1 is induced in cells in response to calcitriol. Regulation of CYP24A1 by progesterone, progestin derivatives, calcitriol and their combination was examined by RT-PCR and Western blotting following 8, 24, 72 and 120 h exposure of cells to hormones. In all cancer cell lines, progesterone, medroxyprogesterone acetate and norgestrol attenuated
calcitriol-induced CYP24A1, spliced variant CYP24SV transcripts and protein expression at 72 and 120 h of treatment. Furthermore, knockdown of CYP24A1 gene expression by siRNA sensitized endometrial cancer cells to the growth suppressive effect of calcitriol. The data suggest that CYP24A1 overexpression limits calcitriol anti-proliferative signaling in cancer cells, and provide evidence that progestins may be beneficial in preserving calcitriol action in endometrial cancer.
Citation Format: Amber A. Bokhari, Laura R. Lee, Raboteau Dewayne, Chad A. Hamilton, George L. Maxwell, Gustavo C. Rodriguez, Viqar Syed. Role and regulation of CYP24A1 in endometrial cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 37. doi:10.1158/1538-7445.AM2015-37
Abstract 3702: Cumulative incidence rates of breast cancer for Filipinos and Chamorros in Guam and the United States
Authors: Badowski Grazyna , Leon Guerrero Rachael , Simsiman Brayan , Novotny Rachel , Wilkens Lynne 
Published: August 2015

Abstract
Background
Breast cancer is the leading cause of cancer-related death among women on Guam. However incidence rates vary between Chamorros and Filipinos, the two predominant ethnic groups on Guam.
Objective
Our objective was to compare age-specific cumulative incidence rates among ethnic groups in Guam and US. Cumulative incidence rates are relatively stable and thus provide a good estimate of cumulative risk of breast cancer.
Methods
This study included all breast cancer cases (n = 576) reported to the Guam Cancer Registry from 2000 to 2009 and all breast cancer cases (n = 678,637) reported to the Surveillance, Epidemiology,and End Results (SEER) 18-Registry Database. Cumulative incidence rates were calculated for Filipinos and Chamorros for two time periods: 2000-2004 and 2005-2009. For comparison, cumulative incidence rates were also calculated for all women in Guam and the US, and for Filipino only in the US.
Results
Remarkable differences were seen in cumulative incidence rates by age and ethnicity. During the 2000-2004 time period, the cumulative incidence rates by age 40 in Filipinos on Guam were the highest (0.7%) and almost threefold higher than the rate in Chamorros (0.24%). But after age 40, the rates for Chamorros increased rapidly. The lifetime cumulative incidence rates (age 0-75) for Chamorros was highest in Guam (11.4%) and close to the US rate (12%). Interestingly, there was a marked difference in lifetime cumulative incidence rates between Filipino women in Guam and Filipinos in the US (7% and 10.9% respectively). Similar results were found for the 2005-2009 time period.
Conclusions
The observed disparity among ethnic groups suggests ethnic differences in exposure or response to certain risk factors. Further study is needed to examine possible differences in risk behaviors between Filipinos and Chamorros in Guam, as well as between Filipinos in Guam and Filipinos in the US.
Citation Format: Grazyna Badowski, Rachael Leon Guerrero, Brayan Simsiman, Rachel Novotny, Lynne Wilkens. Cumulative incidence rates of breast cancer for Filipinos and Chamorros in Guam and the United States. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3702. doi:10.1158/1538-7445.AM2015-3702
Abstract 3728: Rapid deployment of statewide tobacco cessation program for cancer patients
Authors: Petersen Laura , Baca Hilary , Brown Karen , Lindsay Jamie , Mott Sarah , Severson Jane , Schulze Anna , Warren Graham 
Published: August 2015

Abstract
Purpose
Tobacco use is not only associated with the development of cancer, but after a patient develops cancer, its continued use is associated with poorer cancer treatment outcomes. Despite this fact, most oncologists do not regularly provide tobacco cessation support. The purpose of this study was to implement an expedited process of patient identification and tobacco cessation for cancer patients.
Methods
The Michigan Oncology Quality Consortium (MOQC) collaborated with the Michigan Department of Community Health, Blue Cross and Blue Shield of Michigan, and the Michigan Cancer Consortium to enhance tobacco cessation support for cancer patients. A statewide tobacco cessation demonstration project using a lean engineering approach was developed to provide structured tobacco assessments, referral to state quitline resources, and provide tailored cessation support to cancer patients consisting of behavioral counseling and free pharmacotherapy where appropriate. These steps were rapidly deployed in over 30 locations including those in private oncology practices and cancer centers in the first year. Data were analyzed to evaluate participation, retention, and quit rates for cancer patients enrolled in the program.
Results
Previous reports have described high rates of patient contact and participation in the cessation program. In the 690 patients with at least 12 months since program enrollment, 200 (29%) participated in only 1 call, 313 (45%) participated in 1-2 follow-up calls, and 177 (26%) participated in 3 or more follow-up calls. Follow-up 30 day quit rate data was obtained in 198, 138, and 199 patients at 3, 6, and 12 months respectively. Self-reported quit rates remained largely consistent with 29.8% at 3 months, 27.5% at 6 months, and 30.2% at 12 months.
Conclusions
The MOQC demonstration project represents a model partnership between payors, clinicians, and statewide quitlines that maintained consistent and moderate quit rates in cancer patients. Large-scale deployment of this model program may provide a clinically efficient and effective mechanism to enhance widespread tobacco cessation efforts for cancer patients.
Citation Format: Laura Petersen, Hilary Baca, Karen Brown, Jamie Lindsay, Sarah Mott, Jane Severson, Anna Schulze, Graham Warren. Rapid deployment of statewide tobacco cessation program for cancer patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3728. doi:10.1158/1538-7445.AM2015-3728
Abstract 3756: Identification of prognostic gene signatures of glioblastoma: a study based on TCGA data analysis
Authors: Kim Yong-Wan 
Published: August 2015

Abstract
The Cancer Genome Atlas (TCGA) project is a large-scale effort with the goal of identifying novel molecular aberrations in glioblastoma (GBM). Here, we describe an in-depth analysis of gene expression data and copy number aberration (CNA) data to classify GBMs into prognostic groups to determine correlates of subtypes that may be biologically significant. To identify predictive survival models, we searched TCGA in 173 patients and identified 42 probe sets that could be used to divide the tumor samples into 3 groups and showed a significantly improved overall survival. Kaplan-Meier plots showed that the median survival of group 3 was markedly longer (127 weeks) than that of groups 1 and 2 (47 and 52 weeks, respectively). We then validated the 42 probe sets to stratify the patients according to survival in other public GBM gene expression datasets (eg, GSE4290 dataset). An overall analysis of the gene expression and copy number aberration using a multivariate Cox regression model showed that the 42 probe sets had a significant prognostic value independent of other variables. By integrating multidimensional genomic data from TCGA, we identified a specific survival model in a new prognostic group of GBM and suggest that molecular stratification of patients with GBM into homogeneous subgroups may provide opportunities for the development of new treatment modalities. [This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MEST) (NRF-2013R1A1A2063115) and the MSIP (Ministry of Science, ICT and Future Planning), Korea, under the “IT Consilience Creative Program” (NIPA-2014-H0201-14-1002) supervised by the NIPA (National IT Industry Promotion Agency)]
Citation Format: Yong-Wan Kim. Identification of prognostic gene signatures of glioblastoma: a study based on TCGA data analysis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3756. doi:10.1158/1538-7445.AM2015-3756