bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-285: Bioinformatic identification of prognostic signature defined by copy number alteration and expression of CCNE1 in non-muscle invasive bladder cancer
Authors: Chu In-Sun , Leem Sun-Hee 
Published: July 2016

Abstract
Because non-muscle-invasive bladder cancer (NMIBC) is clinically heterogeneous, predicting disease progression for patients with bladder cancer still remains a major clinical challenge, despite numerous investigations for NMIBC. In this study we identify a prognostic signature to predict the heterogeneity of NMIBC using an integrative analysis of copy number and gene expression data. We analyzed the copy number and gene expression profile data of bladder cancer obtained from The Cancer Genome Atlas (TCGA) consortium. A prognostic signature based on copy number altered gene was developed and validated in three independent patient cohorts (n = 501). Diverse statistical methods were applied to identify and validate a signature. Of the fourteen significant copy number altered molecules reported previously, ten were significantly correlated between copy number and expression changes in the TCGA dataset. Among them, CCNE1 and its co-expressed genes were significantly associated with disease progression, which was validated in the independent cohorts. The CCNE1 signature was shown to be an independent risk factor by a multivariate analysis (HR 4.99, 95% CI = 1.054 to 23.659, P = 0.043). Lastly, gene network and upstream regulator analyses revealed that NMIBC progression might be mediated by CCND1-CCNE1-SP1 pathways. The prognostic molecular signature defined by copy number and expression changes of CCNE1 suggests a novel diagnostic tool for predicting the likelihood of progression in NMIBC.
Citation Format: In-Sun Chu, Sun-Hee Leem. Bioinformatic identification of prognostic signature defined by copy number alteration and expression of CCNE1 in non-muscle invasive bladder cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-285.
Abstract LB-288: Investigation on the interaction between human beta defensin type 3 (hBD-3) and ectodomain of EphA2 receptor using molecular dynamics simulation method
Authors: Zhang Liqun 
Published: July 2016

Abstract
Defensins are a family of cationic cysteine-rich small molecules. In general, human beta defensins (hBD) are produced by epithelial cells, and they are important to the human innate immune system. Experimental results showed that defensins can directly bind with receptors such as chemokine receptors and act through several mechanisms that may trigger antitumor immunity or facilitate the host's immune response (or evasion) and promote tumor progression. hBD type 3 (hBD-3) is newly discovered and is unique that it has a net charge density much higher than other family members, and has the ability to undergo oligomerization. On the other hand, EPH receptors and their corresponding ligands (ephrins) are membrane-bound proteins that require direct cell-cell interactions for the activation of the receptors. Eph-ephrin system plays a critical role in tumor and vascular functions during carcinogenesis. Once EPH receptor A2 (EphA2) is ligand-independent, it can over-express itself in many types of tumors, and behave like an oncogene. Besides, many studies suggested that mutations that affect EPH receptor function play a role in cancer initiation or progression. Therefore, the EphA2-ephrin5 system can be a novel target for the development of anti-tumorigenic and anti-angiogenic therapies, and understanding its interaction with other molecules is important to demystify the cancer mechanism.
Both EphA2 ectodomain (ECD) and hBD-3 exist outside of the cell membrane. In order to find out the interaction mechanism of hBD-3 with EphA2 receptor, initially blind docking using Cluspro software was performed to predict all the possible binding sites between hBD-3 oligomer and EphA2 ECD in the free and bound forms. After that, all atom molecular dynamics CHARMM simulations were performed to find out the most probable binding interfaces between hBD-3 oligomer and EphA2 ECD. It was found that hBD-3 has multiple stable binding sites on the EphA2 ECD, and its binding on the ligand-binding domain (LBD) of EphA2 could influence the binding of ephrin5 with EphA2. Those suggest the hBD-3 could play a role in cancer initiation.
Citation Format: Liqun Zhang. Investigation on the interaction between human beta defensin type 3 (hBD-3) and ectodomain of EphA2 receptor using molecular dynamics simulation method. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-288.
Abstract LB-296: Multi-target sDNA increases colorectal cancer screening among previously non-compliant patients: The USMD physician services experience
Authors: Prince Mark , Lester Lynn , Chinawala Rupal , Berger Barry M. 
Published: July 2016

Abstract
Background: The multi-target stool DNA test (mt-sDNA) is an FDA approved, high sensitivity, colorectal cancer screening test. We evaluated mt-sDNA in non-screening-compliant Medicare patients and assessed compliance and diagnostic colonoscopy usage and correlated positive mt-sDNA results with colonoscopy findings.
Methods: We performed a retrospective medical records review (October 2014 - September 2015) to identify mt-sDNA use in average-risk Medicare eligible patients treated by USMD Physician Services (Dallas, Tx) who were not previously compliant with colon cancer screening. We offered mt-sDNA to patients who were either &gt;10 years since last colonoscopy and/or &gt;1 yr. since last fecal occult blood test. Follow-up colonoscopy was advised for all patients with a positive result. Colonoscopy and pathology results were reviewed with patient classification based on the most significant pathology finding (index lesion). Size, location and total number of polyps and adenomas were tabulated.
Results: Over 12 months, 77 providers ordered 393 mt-sDNA studies with 347 completed (88.3% compliance). Patient mean age was 69.8 (50-85) and patients were 64% female. Mt-sDNA was negative in 85.3% (296/347) and positive in 14.7% (51/347). Follow-up colonoscopy was performed in 46 positive patients (90.2% colonoscopy compliance) with 3 patients refusing colonoscopy and two patients lost to follow up. Index findings included: colon cancer (4/46, 8.7%), advanced adenomas (21/46, 45.6%), non-advanced adenoma (9/46, 19.6%), and negative results (12/46,23.0%). The positive predictive value for advanced colorectal lesions was 54.3% and for any colorectal neoplasia was 73.9%.
Conclusions: The availability of mt-sDNA provided significant medical benefit to our previously screening non-compliant Medicare population. Patients with clinically critical advanced colorectal neoplasia were identified in this cohort due to high compliance with both mt-sDNA screening and follow-up diagnostic colonoscopy.
Citation Format: Mark Prince, Lynn Lester, Rupal Chinawala, Barry M. Berger. Multi-target sDNA increases colorectal cancer screening among previously non-compliant patients: The USMD physician services experience. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-296.
Abstract LB-310: NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 4-like 2 (NDUFA4L2) reduces oxidative stress to promote hepatocellular carcinoma
Authors: Lai Robin Kit-Ho , Xu Irix Ming-Jing , Chiu David Kung-Chun , Tse Aki Pui-Wah , Wei Larry Lai , Law Cheuk-Ting , Lee Derek , Wong Chun-Ming , Wong Maria Pik , Ng Irene Oi-Lin , Wong. Carmen Chak Lui 
Published: July 2016

Abstract
Background & Aims: Liver is a major metabolic organ, yet the detailed metabolic alterations driving hepatocellular carcinoma (HCC) remain elusive. The rapid growing nature of HCC results in oxygen deprivation or hypoxia in regions of tumors with insufficient blood supply. Hypoxia unbalances the electron flow through the electron transport chain (ETC) resulting in reactive oxygen species (ROS) accumulation. Here we aim at delineating the mechanisms by which HCC evades oxidative stress. Methods: We performed transcriptome sequencing to study the gene expression profile in both HCC patients and HCC cell line. The mRNA expression of 100 paired HCC and corresponding non-tumorous tissues were analyzed. Stable RNAi knockdown by shRNA and genetic knockout by TALEN were established in HCC cells for functional characterization. Results: We demonstrated that HCC cells specifically utilized the mitochondrial protein NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 4-like 2 gene (NDUFA4L2), in the complex I of the ETC, to survive hypoxia. NDUFA4L2 was drastically over-expressed in human HCC and closely associated with poor clinical outcomes in HCC patients. We confirmed that NDUFA4L2 was regulated by HIF-1α in HCC cells. Inactivation of HIF-1α/NDUFA4L2 in different HCC cell lines increased mitochondrial activity and oxygen consumption, resulting in ROS accumulation and ROS-mediated apoptosis in HCC cells. Knockdown of NDUFA4L2 markedly suppressed HCC growth and metastasis in vitro and in vivo. In addition, HIF inhibitors, digoxin and sorafenib, significantly suppressed growth of tumors that expressed high level of NDUFA4L2 in orthotopic HCC model. Conclusions: Our results have unprecedentedly uncovered the clinical relevance and oncogenic roles of NDUFA4L2 in HCC.
Citation Format: Robin Kit-Ho Lai, Irix Ming-Jing Xu, David Kung-Chun Chiu, Aki Pui-Wah Tse, Larry Lai Wei, Cheuk-Ting Law, Derek Lee, Chun-Ming Wong, Maria Pik Wong, Irene Oi-Lin Ng, Carmen Chak Lui Wong. NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 4-like 2 (NDUFA4L2) reduces oxidative stress to promote hepatocellular carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-310.
Abstract LB-313: Upregulation of lactate dehydrogenase A by 14-3-3ζ leads to increased glycolysis critical for breast cancer initiation and progression
Authors: Chang Chia-Chi , Zhang Chenyu , Sahin Ozgur , Zhang Qingling , Wang Hai , Zhang Jian , Rehman Sumaiyah , Li Ping , Yu Dihua 
Published: July 2016

Abstract
Metabolic reprogramming is a hallmark of cancer. Elevated glycolysis in cancer cells switches the cellular metabolic flux to produce more biological building blocks, thereby facilitating cellular adaptation to the adverse environment and sustaining rapid proliferation. Recently, new evidence has emerged that abnormal metabolic reprogramming may occur at the early-stages of neoplasia and critically contribute to early transformation and cancer initiation. Previously, we reported that 14-3-3ζ overexpression is an early event in human breast cancer, taking place as early as in the atypical ductal hyperplasia (ADH) stage. We therefore hypothesized that 14-3-3ζ overexpression in breast epithelial cells may trigger metabolic reprogramming by elevating glycolysis that contributes to cancer initiation. In the present study, our bioinfomatics analysis of microarray profiling data from the early-stages breast neoplastic lesions revealed that 14-3-3ζ expression is strongly correlated with the expression of genes of the canonical glycolytic pathway, particularly lactate dehydrogenase A (LDHA). Experimentally, increasing 14-3-3ζ expression in human non-transformed mammary epithelial cells (hMECs), MCF10A and MCF12A, transcriptionally up-regulated LDHA expression, elevated glycolytic activity, and promoted early transformation of hMECs. Conversely, knockdown of LDHA in the 14-3-3ζ-overexpressing hMECs significantly reduced glycolytic activity and inhibited transformation. Together, our data demonstrate that overexpression of 14-3-3ζ in early stage pre-cancerous breast epithelial cells may trigger an elevated glycolysis by activating the MEK-ERK-CREB signaling axis and transcriptionally up-regulating LDHA, thereby critically contributes to human breast cancer initiation.
Citation Format: Chia-Chi Chang, Chenyu Zhang, Ozgur Sahin, Qingling Zhang, Hai Wang, Jian Zhang, Sumaiyah Rehman, Ping Li, Dihua Yu. Upregulation of lactate dehydrogenase A by 14-3-3ζ leads to increased glycolysis critical for breast cancer initiation and progression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-313.
Abstract LB-320: Obligate lesions and diverse evolutionary patterns drive small cell bladder cancer
Authors: Penson Alexander , Chang Matthew T. , Desai Neil , Socci Nicholas D. , Shen Ronglai , Seshan Venkatraman E. , Kundra Ritika , Abeshouse Adam , Viale Agnes , Cha Eugene K. , Bochner Bernard H. , Rosenberg Jonathan E. , Bajorin Dean F. , Schultz Nikolaus , Berger Michael F. , Iyer Gopa , Solit David B. , Al-Ahmadie Hikmat , Taylor Barry S. 
Published: July 2016

Abstract
Small cell bladder cancer (SCBC) is a rare and aggressive neuroendocrine tumor with a dismal prognosis and limited treatment options. As SCBC is histologically indistinguishable from small cell lung cancer, a shared pathogenesis and cell of origin has been proposed. To determine whether SCBCs arise from a pre-existent urothelial carcinoma or share a molecular pathogenesis in common with small cell lung cancer, we performed integrative analysis of 61 SCBC patients to identify histology- and organ-specific similarities and differences with urothelial carcinomas and small cell lung cancers. SCBC has a high somatic mutational burden driven predominantly by an APOBEC-mediated mutational process. Obligate mutations in TP53, RB1, or the TERT promoter were present in nearly all samples. While these events arose early in all affected tumors, reflecting an evolutionary branch point that drove small cell lineage differentiation, they were not the founding transforming event, as they were often preceded by diverse and less common driver mutations many of which are common in bladder urothelial cancers but not small cell lung tumors. The majority of patient tumors (72%) also underwent whole-genome duplication (WGD). While arising at different chronological points in the evolution of the disease, WGD was often preceded by biallelic mutations in TP53 with retention of two intact copies. Together, our findings indicate that small cell cancers of the bladder and lung have a convergent but distinct pathogenesis and SCBCs likely arise from a cell of original shared with urothelial bladder cancer.
Citation Format: Alexander Penson, Matthew T. Chang, Neil Desai, Nicholas D. Socci, Ronglai Shen, Venkatraman E. Seshan, Ritika Kundra, Adam Abeshouse, Agnes Viale, Eugene K. Cha, Bernard H. Bochner, Jonathan E. Rosenberg, Dean F. Bajorin, Nikolaus Schultz, Michael F. Berger, Gopa Iyer, David B. Solit, Hikmat Al-Ahmadie, Barry S. Taylor. Obligate lesions and diverse evolutionary patterns drive small cell bladder cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-320.
Abstract LB-339: Mutation analysis of cell-free DNA captures heterogeneity of individual circulating tumor cells in metastatic breast cancer
Authors: Guttery David S. , Shaw Jacqueline A. , Hills Allison , Fernandez-Garcia Daniel , Page Karen , Rosales Brenda , Goddard Kate , Hastings Robert , Luo Jinli , Ogle Olivia , Woodley Laura , Ali Simak , Stebbing Justin , Coombes Charles 
Published: July 2016

Abstract
Circulating tumor cells (CTCs) are more technically challenging to isolate and characterize than circulating cell-free DNA (cfDNA). However, analysis of single CTCs may reveal more actionable information to guide targeted therapies than mutation tracking in cfDNA. Here, we compared CTC count with cfDNA levels in 113 patients with metastatic breast cancer. In 5 patients we compared mutations in 40 individual CTCs and matched cfDNA using targeted amplicon sequencing of 54 genes (∼2800 COSMIC mutations) at &gt;2500x mean read depth. Total cfDNA levels were significantly associated with overall survival (hazard ratio (HR), 2.2; 95% CI, 1.1 to 4.3; P = 0.021) and correlated with CTC counts (P = 0.002). Four patients had mutations detected in cfDNA, the levels of which tracked with levels of circulating tumor DNA (ctDNA). Mutational heterogeneity was seen across individual CTCs (including mutations in PIK3CA, ESR1 and KRAS) and was reflected in matched cfDNA, but cfDNA had other mutations not seen in CTCs (including TP53). Therefore, cfDNA reflects persisting CTCs and enables monitoring of the metastatic burden for clinical decision-making when CTCs cannot be obtained. Moreover, monitoring of total cfDNA levels could provide an inexpensive and simple measure of treatment response.
Citation Format: David S. Guttery, Jacqueline A. Shaw, Allison Hills, Daniel Fernandez-Garcia, Karen Page, Brenda Rosales, Kate Goddard, Robert Hastings, Jinli Luo, Olivia Ogle, Laura Woodley, Simak Ali, Justin Stebbing, Charles Coombes. Mutation analysis of cell-free DNA captures heterogeneity of individual circulating tumor cells in metastatic breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-339.
Abstract LB-358: Plasma HGF level is associated with obesity, increased risk and reduced survival of pancreatic cancer
Authors: Yan Dong , Chang Ping , Li Donghui 
Published: July 2016

Abstract
Background: Obesity is one of the modifiable risk factors for the development and progression of pancreatic cancer. However, the mechanisms of obesity-related pancreatic cancer has not been well defined. In our previous analysis of the genome-wide association data, we identified a significant interaction of obesity with cytokine signaling pathway. Methods: In the current study, we selected several genes from this pathway that code for secreted or membrane proteins and measured the protein levels in plasma samples of 100 pancreatic patients and 100 healthy controls drawn from a case-control study conducted at MD Anderson. Cases and controls were frequency matched by age, sex, race and body mass index (BMI). Plasma levels of HGF (hepatocyte growth factor), MIP-1β (microphage infiltration factor 1-beta), FasL (Fas ligand) and PLA2 (phospholipase A2) were measured using the Luminex and ELISA methods. The protein levels were analyzed in relation to cancer risk and patient survival using analysis of variance, non-parametric test, Kaplan Meier plot, log-rank test, and Cox proportional hazard regression models. Results: A significantly higher level of HGF and MIP-1β and lower level of FasL was observed in cancer patients than in controls, with the mean values of 365.7 vs. 146.2 pg/ml, P&lt; 0.001; 216.5 vs.122.3 pg/ml, P = 0.002, 23.1 versus 29.4 pg/ml, P&lt;0.001, respectively. Individuals with a high HGF or low FasL level had, respectively, 4.6-fold (95% confidence interval [CI] = 2.4-9.1, P&lt;0.001) and 2.9-fold (95% CI = 1.55-5.38, P = 0.001) increased risk of pancreatic cancer with adjustment for other known risk factors. Furthermore, a significant association of HGF level with BMI was observed in cases (R2 = 0.269, P = 0.005). The HGF level (mean ± SE pg/ml) was significantly higher in obese (682±204) than that in overweight (268±40) or normal weight patients (313±71), P = 0.01 and 0.005, respectively. Patients with higher levels of HGF had a significantly reduced overall survival than those with lower levels (9.3 vs. 13.3 months, P = 0.006). Cox proportional hazard regression analysis demonstrated that a higher level of HGF was an independent prognostic factor (Hazard Ratio = 2.61, 95% CI = 1.22-5.64, P = 0.01) after adjusting for BMI, disease stage and other clinical factors. Conclusion: A higher plasma level of HGF was related to obesity and overall survival in pancreatic adenocarcinoma, which may serve as a potential diagnostic and prognostic marker for pancreatic cancer.
Citation Format: Dong Yan, Ping Chang, Donghui Li. Plasma HGF level is associated with obesity, increased risk and reduced survival of pancreatic cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-358.
Abstract LB-364: Natural history of age-related lobular involution and impact on breast cancer risk
Authors: Radisky Derek , Visscher Daniel W. , Frank Ryan , Vierkant Robert A. , Winham Stacey J. , Stallings-Mann Melody L. , Hoskin Tanya L. , Nassar Aziza , Vachon Celine M. , Denison Lori A. , Hartmann Lynn C. , Frost Marlene H. , Degnim Amy C. 
Published: July 2016

Abstract
Background: Age-related lobular involution (LI) is a physiological process in which the terminal duct lobular units of the breast regress as a woman ages. Analyses of breast biopsies from women with benign breast disease (BBD) have found that extent of LI is negatively associated with subsequent breast cancer development. Here we assess the natural course of LI within individual women, and the impact of progressive LI on breast cancer risk.
Methods: The Mayo Clinic BBD cohort consists of 13,455 women with BBD from 1967-2001. The BBD cohort includes 1115 women who had multiple benign biopsies, 106 of whom had developed breast cancer. Within this multiple biopsy cohort, the progression of the LI process was examined by age at initial biopsy and time between biopsies. The relationship between LI progression and breast cancer risk was assessed using standardized incidence ratios (SIRs) and by Cox proportional hazards analysis.
Results: Women who had multiple biopsies were younger age and had a slightly higher family history of breast cancer as compared with the overall BBD cohort. Extent of LI at subsequent biopsy was greater with increasing time between biopsies and for women age 55+ at initial biopsy. Among women with multiple biopsies, there was a significant association of higher breast cancer risk among those with involution stasis (lack of progression, HR 1.63) as compared with those with involution progression, p = 0.036.
Conclusions: The multiple biopsy BBD cohort allows for a longitudinal study of the natural progression of LI. The majority of women in the multiple biopsy cohort showed progression of LI status between benign biopsies, and extent of progression was highest for women who were in the perimenopausal age range at initial biopsy. Progression of LI status between initial and subsequent biopsy was associated with decreased breast cancer risk.
Citation Format: Derek Radisky, Daniel W. Visscher, Ryan Frank, Robert A. Vierkant, Stacey J. Winham, Melody L. Stallings-Mann, Tanya L. Hoskin, Aziza Nassar, Celine M. Vachon, Lori A. Denison, Lynn C. Hartmann, Marlene H. Frost, Amy C. Degnim. Natural history of age-related lobular involution and impact on breast cancer risk. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-364.