bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2678: Targeting prostate cancer metastasis with novel small molecule agonists of EphA2
Authors: Wang Bingcheng , Petty Aaron 
Published: August 2015

Abstract
During tumor progression, EphA2 receptor can gain ligand-independent pro-oncogenic functions due to Akt activation and reduced ephrin-A ligand engagement. The effects can be reversed by ligand stimulation, which triggers the intrinsic tumor suppressive signaling pathways of EphA2 including inhibition of PI3/Akt and Ras/ERK pathways. These observations argue for development of small molecule agonists for EphA2 as potential tumor intervention agents. Through virtual screening and cell-based assays, we report here the identification and characterization of doxazosin as a novel small molecule agonist for EphA2 and EphA4, but not for other Eph receptors tested. NMR studies revealed extensive contacts of doxazosin with EphA2/A4, recapitulating both hydrophobic and electrostatic interactions recently found in the EphA2/ephrin-A1 complex. Clinically used as an α1-adrenoreceptor antagonist (Cardura®) for treating hypertension and benign prostate hyperplasia, doxazosin activated EphA2 independent of α1-adrenoreceptor. Similar to ephrin-A1, doxazosin inhibited Akt and ERK kinase activities in an EphA2-dependent manner. Treatment with doxazosin triggered EphA2 receptor internalization, and suppressed haptotactic and chemotactic migration of prostate cancer, breast cancer, and glioma cells. Moreover, in an orthotopic xenograft model, doxazosin reduced distal metastasis of human prostate cancer cells and prolonged survival in recipient mice. More potent and selective derivatives of doxazosin have been developed with enhanced efficacy against prostate cancer and glioblastoma. To our knowledge, this is the first example of small molecule agonists of a receptor tyrosine kinase that is capable of inhibiting malignant behaviors in vitro and in vivo.
Citation Format: Bingcheng Wang, Aaron Petty. Targeting prostate cancer metastasis with novel small molecule agonists of EphA2. [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 2678. doi:10.1158/1538-7445.AM2015-2678
Abstract 2706: Inhibition of PFKFB3/glycolysis overcomes chemoresistance in ovarian cancers
Authors: Mondal Susmita , Roy Debarshi , Kalogera Eleftheria , Khurana Ashwani , Tapolsky Gilles H. , Telang Sucheta , Chesney Jason , Shridhar Viji 
Published: August 2015

Abstract
Metabolic alterations in cancer are increasingly being recognized as important novel targets. Among different regulators of altered metabolism, 6-PhosphoFructo-2-Kinase/Fructose-2,6-Bisphosphatases 3 (PFKFB3) a glycolytic enzyme required for tumorigenic growth, and produces fructose-2,6-bisphosphate (F2,6BP), is recognized as important regulator of glycolysis. We determined that the active form of PFKFB3ser471 was overexpressed in chemo-resistant ovarian cancer (OVCA) cell lines and resistant patient derived xenograft (PDX) models compared to their isogenic chemo-sensitive cell lines and sensitive PDX models. These results suggest that targeting PFKFB3 will have beneficial effects in patients with OVCA. PFK-158 is a potent and selective inhibitor of PFKFB3 that is currently being investigated in a Phase 1 study in patients with advanced solid malignancies. Here we report for the first time, PFK-158 dose-dependently inhibits cell proliferation and colony formation ability in both carboplatin and paclitaxel (PTX) resistant cell lines. PFK-158 markedly suppresses glycolysis by reducing glucose uptake, ATP production, lactate dehydrogenase activity and lactate secretion. Interestingly, both Chou-Talalay synergy analysis and apoptosis assay by annexin V-PI staining showed PFK-158 strongly synergies with both PTX and carboplatin in PTX and cisplatin resistant cell lines respectively. PFK-158 induced apoptosis through a significant increase in caspase-3/7 activation and PARP cleavage. Moreover, in a highly metastatic PTX-resistant in vivo model, combination of PFK-158 with carboplatin and PTX significantly reduced tumor weight, ascites and metastasis compared to untreated and PFK-158, carboplatin or PTX alone treated mice. Since the majority of OVCA patients recur with chemo-resistant disease, our results suggest that PFK-158 in combination with standard chemotherapy may have clinical utility in late stage ovarian cancer patients.
Citation Format: Susmita Mondal, Debarshi Roy, Eleftheria Kalogera, Ashwani Khurana, Gilles H. Tapolsky, Sucheta Telang, Jason Chesney, Viji Shridhar. Inhibition of PFKFB3/glycolysis overcomes chemoresistance in ovarian cancers. [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 2706. doi:10.1158/1538-7445.AM2015-2706
Abstract 2715: Hepatotoxicity and oxidative stress biomarker study of peg-coated and non-coated gold nanoparticles in Sprague-Dawley rats
Authors: Patlolla Anita K. , Fountain Myeisha , Tchounwou Paul 
Published: August 2015

Abstract
Nanoparticles (NPs) offer a great possibility for biomedical application, not only to deliver pharmaceutics, but also to be used as novel diagnostic and therapeutic approaches. Currently, there are no data available regarding to what extent the degree of the toxicity and the accumulation of gold nanoparticles (GNPs) are present in in vivo model. The aim of this study was to assess the effects, after oral administration, of poly-ethylene-glycol (PEG) coated and non-coated GNPs on various hepatotoxicity and oxidative stress markers such as alanine (ALT), aspartate aminotransferases and alkaline phosphatase, lipid hydro peroxide (LHP) in the mouse model. Sprague -Dawley rats were exposed to four different concentrations of PEG-coated and non-coated GNPs (12.5, 25, 50 and 100 mg/kg BW) and a control. Samples were collected 24 hours after the last treatment following standard protocols. Exposure to PEG-coated and non-coated GNPs enhanced the activities of serum amino-transferases (ALT/AST), alkaline phosphatases (ALP) and concentration of lipid hydro peroxide compared to control. However, PEG-coated GNPs demonstrated enhanced hepatotoxic effect than non-coated GNPs. The scientific findings reported here suggest that both GNPs have the potential to induce hepatotoxicity in Sprague-Dawley rats through activation of the mechanisms of oxidative stress at a higher level of exposure. However, more studies to clarify the role of encapsulation in the in vivo toxicity of GNPs, are required and parallel comparison is preferred.
Keywords: gold nanoparticle (GNP), poly-ethylene-glycol, lipid hydroperoxide, serum aminotransferases, alkaline phosphatases, Sprague-Dawley rats, hepatotoxicity.
Citation Format: Anita K. Patlolla, Myeisha Fountain, Paul Tchounwou. Hepatotoxicity and oxidative stress biomarker study of peg-coated and non-coated gold nanoparticles in Sprague-Dawley rats. [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 2715. doi:10.1158/1538-7445.AM2015-2715
Abstract 2726: Dysregulation of host cellular genes targeted by HPV integration contributes to HPV related cervical carcinogenesis
Authors: Zhang Ruiyang , Chen Xiangmei , Lu Fengmin 
Published: August 2015

Abstract
The integration of HPV viral DNA into the human genome has been postulated as an important etiological event during cervical carcinogenesis. Several recent reports have indicated that this integration might cause functional dysregulation of the host cellular gene(s) involved, suggesting a possible role for such integration targeted cellular genes(ITGs) in cervical carcinogenesis. Therefore in this study, a comprehensive analysis of HPV integration events was undertaken using data collected from the scientific literature. 499 integration loci on human chromosomes were included. This systemic analysis first confirmed previous findings that the breakpointsof HPV genome are concentrated in E1, E2 and E2/E4 regions. The collected data revealed that HPV DNA preferred to integrate into intragenic regions, particularly gene-dense regions of human chromosomes. Intriguingly, the host cellular genes nearby the integration sites were found to be transcriptionally active compared to similar collection of genes picked at random locations across the human genome. Furthermore, Analysis of the integration sites in the human genome revealed that all chromosomes were represented with several integration hotspots. In addition, the ITGs identified were found to be enriched in tumor-related terms and pathways using gene ontology (GO) and KEGG analysis. Besides, functional analysis of MPPED2, one of above ITGs, demonstrated a role in blocking G1/S transition and cell proliferation retardation. Overall the results of this comprehensive analysis has implicated for the first time dysregulation of ITGs caused by viral integration as having a possible etiological involvement in cervical carcinogenesis.
Citation Format: Ruiyang Zhang, Xiangmei Chen, Fengmin Lu. Dysregulation of host cellular genes targeted by HPV integration contributes to HPV related cervical carcinogenesis. [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 2726. doi:10.1158/1538-7445.AM2015-2726
Abstract 2731: Establishment and characterization of immortalized nasopharyngeal epithelial cells with stable infection of Epstein-Barr virus
Authors: Jia Lin , Tsang Chi Man , Yip Yim Ling , Law Wai Tak , Zhang Jun , Tsao George SW 
Published: August 2015

Abstract
Nasopharyngeal carcinoma (NPC), with a remarkably distinctive ethnic and geographic distribution, has the highest incidence among Southern Chinese. Unlike other types of head and neck cancers, a unique feature of NPC is its close association with Epstein-Barr virus (EBV). EBV infection represents an early event during the pathogenesis of NPC. Latent EBV infection is found in every cancer cell of virtually all cases of undifferentiated NPC in endemic regions. Genetic alterations in the premalignant epithelium may support the EBV latency. Although EBV-encoded proteins in its latent infection, including LMP1, LMP2A, etc., have been identified with crucial functions to initiate or promote oncogenesis, to date the exact role of EBV infection in the malignant transformation of nasopharyngeal epithelial (NPE) cells remains unclear. We have previously generated a panel of immortalized NPE cells by ectopic overexpression of hTert (catalytic unit of human telomerase). However, reliable in vitro models of stable EBV infection are also necessary for further elucidating the regulatory network supporting the persistent latency of EBV in NPE cells, and also the potential roles of EBV in the pathogenesis of NPC. In the present study, we established NP361hTert-EBV cells with stable EBV infection via co-culture with Akata B cells harboring EBV, followed by the effective enrichment of EBV-infected cells by FACS sorting. The loss of EBV episome in NPE cells was fast initially upon infection, and relatively stable maintenance of EBV could be achieved after enrichment of EBV-positive cells for three times. Results of western blotting analysis showed that the protein expression level of cyclin D1 was increased in NP361hTert-EBV cells, as compared to the non-infected NP361hTert cells. Meanwhile, we also observed increased expression of phosphorylated protein kinase Akt (Ser473) in NP361hTert-EBV cells, suggesting that the Akt signaling was activated, and such activation might contribute to the persistence of EBV in NP361hTert cells. The stable EBV-infected NPE cells will serve as a powerful in vitro model for further study in elucidating the functional role of EBV in the carcinogenesis of NPC.
This work was partly supported by General Research Fund (HKU 779713M, HKU780911M), and the AoE NPC grant (AoE/M-06/08) from Hong Kong Research Grant Council; and Small Project Funding (201309176242) from The University of Hong Kong.
Citation Format: Lin Jia, Chi Man Tsang, Yim Ling Yip, Wai Tak Law, Jun Zhang, George SW Tsao. Establishment and characterization of immortalized nasopharyngeal epithelial cells with stable infection of Epstein-Barr virus. [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 2731. doi:10.1158/1538-7445.AM2015-2731
Abstract 2732: The role of protein P in hepatocellular carcinoma
Authors: Fu Hongyong , Guo Lianying , HUANG Lin 
Published: August 2015

Abstract
Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer and the third leading cause of cancer-related death worldwide. Although treatment options have improved in the past 30 years, 5-year survival rate remains below 20%. To improve the therapeutics of HCC, great efforts are needed in understanding the mechanisms underlying HCC. Protein P, plays an important role in the development of cancer. To clarify the role of P in the development of HCC, we investigated the expression level of P in HCC tissue chips. The results showed that P level is much higher in carcinoma than adjacent tissue, and the overall 5-year survival is much better in P low expression patients than in P high expression patients. P expression was also found to be increased in HCC cell lines, compared with the normal liver cell line. Further, the proliferation of HCC cell lines was suppressed significantly by siRNA-mediated P knockdown in both anchorage dependent and independent growth assays. These data suggested that P is a crucial factor in the development of HCC, which might therefore represent a novel therapeutic target for HCC.
Citation Format: Hongyong Fu, Lianying Guo, Lin HUANG. The role of protein P in hepatocellular carcinoma. [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 2732. doi:10.1158/1538-7445.AM2015-2732
Abstract 2752: Prevalence of BAP1 germline mutations in asbestos-exposed malignant mesothelioma cases and controls
Authors: Cheung Mitchell , Talarchek Jacqueline , Howard Suzanne E. , Howard Timothy , Peng Hongzhuang , Hesdorffer Mary , Rauscher Frank J. , Ohar Jill A. , Testa Joseph 
Published: August 2015

Abstract
Malignant mesothelioma (MM) is an uncommon but aggressive cancer that has been linked with asbestos exposure. Contributing genetic factors appear to play a role because familial clustering of MM has been observed and that only a small percentage of asbestos-exposed individuals have been documented to develop MM. Germline mutation of BAP1 has been identified as one such predisposing factor. However, the frequency of germline BAP1 mutations in MM cases is debatable due to small sampling sizes of studies from previous publications. Therefore, we decided to determine the prevalence of germline BAP1 mutations in a large set of asbestos-exposed MM cases and controls, the biggest such population study to date. BAP1 mutation status was compared between 150 MM cases with a family history of cancer and 153 asbestos-exposed controls without indications of familial cancers. Although no alterations of BAP1 were discovered in the controls, BAP1 mutations were identified in 9 of the MM cases (6%). These alterations included 2 splice site changes, 4 insertion/deletions, and 3 missense mutations. In vitro enzymatic assays showed decreased deubiquitinase activity for each of the three BAP1 missense mutant proteins. We observed a statistically significant lower age of MM onset as well as a higher incidence of peritoneal MMs among the 9 BAP1 mutation cases compared to the non-mutated MM cases. The other tumors identified in family members of the 9 individuals included additional MMs, ocular and cutaneous melanomas, renal, breast, lung, and gastric carcinomas, and lymphomas. Interestingly, six of the nine MM cases with a germline BAP1 mutation had two or more primary cancers, suggesting a widespread targeting of tissues of multiple organs caused by the mutation. In summary, these findings suggest that patients presenting with MM and a family history of cancer should be considered for BAP1 mutation testing to identify those who might benefit from screening and regular monitoring of family members to enable early detection and intervention.
Citation Format: Mitchell Cheung, Jacqueline Talarchek, Suzanne E. Howard, Timothy Howard, Hongzhuang Peng, Mary Hesdorffer, Frank J. Rauscher, Jill A. Ohar, Joseph Testa. Prevalence of BAP1 germline mutations in asbestos-exposed malignant mesothelioma cases and controls. [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 2752. doi:10.1158/1538-7445.AM2015-2752
Abstract 2762: LFSpro: A risk assessment tool to estimate TP53 mutation status in families with Li-Fraumeni syndrome
Authors: Peng Gang , Bojadzieva Jasmina , Ballinger Mandy L. , Thomas David M. , Strong Louise , Wang Wenyi 
Published: August 2015

Abstract
Li-Fraumeni syndrome (LFS) is a rare disorder and characterized by autosomal dominant mutation inheritance with frequent occurrence of multiple cancer types including soft tissue/bone sarcoma, breast cancer, leukemia, brain tumors and many others. A majority of LFS is caused by germ-line mutations in p53 tumor suppressor gene. Given the diverse cancer spectrum and incidence in Li-Fraumeni syndrome (LFS) and limitations of the clinical criteria, accurate identification of candidates for prospective TP53 mutation testing has been difficult. A more efficient prediction tool is needed for TP53 mutation carrier identification, which, followed by appropriate management and screening, may ultimately decrease mortality. To this date, we developed LFSpro, which is built on a Mendelian model and estimates TP53 mutation probability through the Elston-Stewart algorithm. With independent validation data from 765 families (19,530 individuals), we demonstrated the accurate prediction of TP53 mutation status using LFSpro. Family history of cancer evolves, and LFSpro is sensitive to mutation carriers in families newly presenting in high-risk clinics and in families followed for years. It is more broadly applicable than the current clinical criteria and therefore may improve clinical management for families with LFS.
Citation Format: Gang Peng, Jasmina Bojadzieva, Mandy L. Ballinger, David M. Thomas, Louise Strong, Wenyi Wang. LFSpro: A risk assessment tool to estimate TP53 mutation status in families with Li-Fraumeni syndrome. [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 2762. doi:10.1158/1538-7445.AM2015-2762
Abstract 2765: Evaluation of family history of cancer in first-degree relatives and increased cancer risk: A multinational study
Authors: Modali Laxmi , Lehman Teresa A. , Modali Ramakrishna , Ratnasinghe Luke D. 
Published: August 2015

Abstract
Family history of cancer is a known risk factor for several of the more prevalent cancer types. However, familial aggregation of cancer may not follow the genetic linkage pattern seen with most inherited cancer syndromes. In these instances, clustering may be due to unknown hereditary genetic mutations or to an aggregation of environmental risk factors and such clustering may still confer a significant risk. We assessed the association between family history of cancer in first-degree relatives and cancer risk among 9,122 cancer cases and 76,537 controls in a multinational study. Analyses also included evaluation of breast, colon and prostate cancer risk associated with family history of these respective cancer types. Cases were verified by physician diagnosis and all study participants were administered an in-depth survey to ascertain various demographic and lifestyle factors as well as a complete family history of cancer among first-degree relatives. Multivariable logistic regression was used to assess the association between family history of cancer and cancer risk. Among all subjects, the odds ratio (OR) for individuals with a family history of cancer was 1.79 [95% confidence interval = 1.7-1.9] after adjusting for age, gender, BMI, smoking pack years and ethnicity. Additionally, a greater cancer risk was associated with increasing number of first-degree relatives with a history of cancer. Ethnic groups studied included Caucasian-Americans, African-Americans, Hispanic/Latinas and Caucasian-Polish. All ethnic groups showed a significant association between family history of cancer and cancer risk with the highest adjusted OR of 2.65 [95% confidence interval = 2.0-3.6] among the Hispanic/Latina group. Further analyses indicated that family history of colon, breast and prostate cancer was significantly associated with an increased risk of these respective cancer types across studied ethnic groups. In particular, the adjusted ORs for breast, colon and prostate cancer risk in the Caucasian-Polish group were at least double the overall adjusted ORs for each cancer type. Our study shows that family history of cancer is a significant predictor of cancer risk especially among certain ethnic groups. In addition, family history of cancer can represent both a genetic predisposition and/or environmental exposure and risk associated with familial clustering of cancer.
Citation Format: Laxmi Modali, Teresa A. Lehman, Ramakrishna Modali, Luke D. Ratnasinghe. Evaluation of family history of cancer in first-degree relatives and increased cancer risk: A multinational study. [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 2765. doi:10.1158/1538-7445.AM2015-2765