bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2644: No evidence for increased risk of cancers other than testicular cancer among first-degree relatives of testicular germ cell tumor (TGCT) patients from multiple-case TGCT families
Authors: McMaster Mary L. , Heimdal Ketil R. , Greene Mark H. 
Published: August 2012

Abstract
Familial aggregation of testicular germ cell tumors (TGCT) has been reported, but it is unclear whether other cancers co-aggregate in multiple-case TGCT families. METHODS: We performed an observed-to-expected (O/E) analysis in a cohort of TGCT families with documented family cancer history assembled in Norway and the U.S. All bloodline first-degree relatives of TGCT cases were eligible. Relatives with missing vital status, gender, or dates of birth and/or death were excluded. We used population-based, age-adjusted cancer incidence rates from Norway and the Surveillance, Epidemiology and End Results (SEER) Program of the National Cancer Institute, respectively, to calculate expected numbers of cancer cases. Only non-TGCT cancers were analyzed. RESULTS: A total of 130 TGCT families with 84 reported cancers and 31,556 person-years at risk were included in the analysis. Overall, there was no excess cancer risk, all non-TGCT sites combined, observed among first-degree relatives of TGCT cases (O/E = 0.89; 95%CI 0.71 - 1.10), either collectively or stratified by center. Although numbers were small, site-specific increased risks were observed for soft tissue cancers (n=4; O/E=7.14; 95%CI 1.95 - 18.29) and leukemia (n=9; O/E=6.48; 95%CI 2.96 - 12.29), and site-specific decreased risk was observed for breast cancer (n=6; O/E=0.44; 95%CI 0.16 - 0.95). These risks were statistically significant overall and in Norway, but not in the U.S. CONCLUSION: In this, the largest study of site-specific cancer risk within multiple-case TGCT families yet performed, we found no excess risk of non-TGCT cancers overall among first-degree relatives of TGCT cases. There was limited evidence supporting altered site-specific risks for soft tissue cancer, leukemia and breast cancer; however, cancer numbers were small, and the results were not consistent between centers, suggesting that differences in cancer reporting among families, case validation methods, or other factors, rather than an etiologic association, explain these findings. Familial testicular cancer appears to be a site-specific syndrome.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2644. doi:1538-7445.AM2012-2644
Abstract 2651: Association of p53 codon72 polymorphism, BCCIP & CDKN2A with melanoma risk. A p53-dependent mechanism
Authors: Andavolu Radhika G. , Rubakovic Svetlana , Rubin Jacob , Bir Jaski , Shu Shinger , Andavolu Murthy , Murray James Mac 
Published: August 2012

Abstract
Cancers arise due to accumulation of mutations in genes critical for cell proliferation, differentiation, and cell death. Direct interaction with cell cycle regulators characterizes growth suppression by several tumor suppressor genes. Mutation or polymorphisms that occur in the promoter or coding regions may affect gene expression and may thus have the potential to be of phenotypic or even of pathological significance. In our previous studies, we showed the differential gene expression patterns and gene interactions/ association of of BCCIP and/or CDKN2A gene1, TNF and/or CCR52 with respect to genotypes, melanoma types and family history. We reported a significant interaction between BCCIP and CDKN2A genotypes among melanoma cases and a significant difference between cases and controls for the BCCIP/CDKN2A haplotype, when adjusted with age and sex, possibly confering different levels of susceptibility to melanoma. In the same report we also had a finding of CDKN2A mutant genotype showing significant association with Melanoma type 1 followed by type 2 suggesting this gene to be critical only in cases with family history and /or with other malignancy. Previous reports have shown that BCCIP as an important component in maintaining the tumor suppression function of wild type p53.Without BCCIP, p53 fails to form tetramers, cannot bind with its target promoter sequences, and is defective in transactivation activity. The p53 pathway responds to cellular stresses that threaten the fidelity of DNA replication, genome stability, chromosome separation and cell division. Many of the cellular stresses can be oncogenic in nature and in skin, the most damaging stresses in carcinogenesis is UV radiation. In this follow up study we show a strong association of p53 codon72 polymorphism (p&lt;0.003) with melanoma (N=126) as compared to controls (N=172). Positive correlations of p53 gene with BCCIP polymorphism (p&lt;.013), BCCIP(p&lt;0.010) & CDKN2A(p&lt;0.032) gene expressions from tumor tissues from melanoma patients suggest the possible functional role of these reported gene interactions in causation or in disease progression. A 12 gene panel (TNF, CCR5 and other CDK pathway genes) and their possible interactions showing clinical relevance of these markers in melanoma development and/or progression through p53-dependent mechanism are discussed.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2651. doi:1538-7445.AM2012-2651
Abstract 27: Chemotherapy-induced Akt survival signaling is regulated by CD44- Ezrin/Radaxin Moesin (ERM) scaffolding, dependent on EGFR activity
Authors: Goldman Aaron J. , Shunmugam Ishwarya , Kulkarni Ashish , Rivera Fernando , Sengupta Shiladitya 
Published: August 2012

Abstract
Akt survival signaling has emerged as a predictor of poor prognosis in tumors resistant to chemotherapy. Despite the firm correlation between enhanced Akt survival signaling in resistant tumor tissue, there is a poor understanding of the exact mechanisms which elicit this robust pathway activation. In the present study we sought to uncover the full pathway of Akt activation in response to chemotherapy in order to fully elucidate mechanisms and proteins involved in chemotherapy resistance. Using breast and ovarian cancer cells, immunoprecipitations revealed that the CD44 glycoprotein initiates a unique scaffolding effect with the Ezrin/Radixin/Moesin (ERM) proteins and Akt in response to the anti-tubulin chemotherapies, docetaxel and vincrisine. Knockdown of CD44 using siRNA revealed that the activation of Akt(ser473) and ERM(tyr353) by chemotherapy are abolished in a time and dose dependent manner. Flow cytometry, caspase activation and cell viability assays confirmed that loss of Akt signaling sensitizes cancer cells to chemotherapy-induced apoptosis and a similar sensitivity was observed in the absence of CD44 expression. Furthermore, immunoprecipitations revealed that inhibition of EGFR using the small molecule inhibitor, Erlotinib, prevented CD44/ERM/Akt scaffolding in response to chemotherapy. In summary, CD44 and ERM scaffolding is responsible for the activation of Akt survival signaling induced by chemotherapy, in-vitro. Loss of CD44 sensitizes cancer cells to apoptosis. This scaffolding effect is dependent on the activity of EGFR, suggesting that a unique interaction exists between this ErbB1 receptor tyrosine kinase and the CD44 glyco-protein. This is the first evidence for cell surface events which precipitate survival signaling in cancer cells as a consequence of chemotherapy. These findings elucidate novel biomarker interactions for translation in the clinical setting.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 27. doi:1538-7445.AM2012-27
Abstract 2833: The protein ps20 increases tumourigenic potential in prostate cancer epithelial cells
Authors: Hickman Oliver , Vyakarnam Annapurna , Smith Richard A.G. , Dalgleish Angus G. , Dasgupta Prokar , Galustian Christine 
Published: August 2012

Abstract
Introduction The protein ps20 encoded by the WFDC1 gene contains a highly conserved whey 4-disulphide core (WFDC) domain and is a member of a protein family that regulates inflammation. Ps20/WFDC1 is expressed by prostate cancer stromal cells but its expression by cancerous prostate epithelium is associated with tumour progression in patients. The aim of this study was to determine how WFDC1expression by prostate cancer cells alters their tumourigenic properties. Methods The cell-lines LNCAP and PC3 were transfected with WFDC1 vector or empty vector (EV) and their growth, adhesive and migratory characteristics were investigated by MTT proliferation, transwell migration and ICAM-1 adhesion assays. Results PC3 and LNCAP cells transfected with WFDC1 increased in numbers by 3148 +/−151% and 523+/−311% after 48 hours respectively compared to EV transfected cell lines (p &lt;0.01 by unpaired T test). WFDC1-transfected cells became smaller and tightly clustered with greater cell-cell contact (See Figure 1). WFDC1 transfected cell migration through 8µM transwells was increased by 73% in PC3s and 57% in LNCaP compared to EV cells (p&lt;0.05 by paired t-test). ICAM-1 expression increased by 67% in WFDC1-LNCAP and by 50% in WFDC1-PC3s compared to EV-cells (p&lt;0.05 by paired t-test). VEGF (vascular endothelial growth factor) was also strongly detectable in the WFDC1-PC3 and LNCaP cells by western-blot whereas none was detectable in EV cells. Conclusions WFDC1 transfection of prostate cancer epithelial cells increases proliferation, migration and ICAM-1 expression, and also induces VEGF, which is a potent angiogenic growth factor. WFDC-1/ps20 may therefore be a critical target for prostate cancer therapeutics.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2833. doi:1538-7445.AM2012-2833
Abstract 2844: Inhibiting androgen receptor and JunD protein interaction to prevent prostate cancer progression
Authors: Schmidt Joseph , Kegel Stacy , Mehraein-Ghomi Farideh , Saphner Elizabeth , Reuter Quentin , Church Dawn , Hoffmann F Michael , Basu Hirak S. , Wilding George 
Published: August 2012

Abstract
Development of an effective therapy to prevent prostate cancer (PCa) progression to castrate-resistant PCa (CRPCa) remains an unmet medical need, mainly due to a poor understanding of the mechanism of PCa progression. Reactive oxygen species (ROS) are produced in high amounts in PCa cells. ROS play a major role in the development and progression of PCa. We have published that the activated androgen receptor (AR)-JunD complex induces spermidine/spermine N1-acetyl transferase (SSAT). SSAT is the first, and a regulatory, enzyme in a major polyamine catabolism pathway that leads to an over-production of ROS, specifically in the polyamine-rich PCa cells. A focus of our current research is to identify compounds that specifically target and block steps in this newly discovered ROS production pathway downstream to AR activation. Such compounds have the potential to become new targeted therapeutic agents offering minimal side effects for preventing progression to CRPCa in patients with early stage progressing PCa. Here we present data on drug-like small molecule inhibitors of the AR-JunD interaction that initiates this ROS-generating pathway in PCa. A novel high throughput assay based on Gaussia Luciferase enzyme reconstitution via protein-protein interaction was used to screen NCI Diversity Set and Life Chemicals libraries of drug-like small molecules to identify inhibitors of the AR-JunD interaction. The 27 selected hits were categorized as antiandrogens or non-antiandrogens through the use of a published fluorescence polarization assay. Sixteen non-antiandrogens, acting downstream of AR activation, were chosen for further study. In vitro studies entailed the measurement of the ability of the compounds to inhibit androgen-independent and dependent growth as well as androgen-induced ROS in human PCa cells. The top four compounds exhibited significant inhibition of growth and androgen-induced ROS at concentrations of 5 uM or less. Immunocytochemistry (ICC) studies were performed to determine the ability of the selected compounds to specifically inhibit the AR-JunD co-translocation to the nuclei. Based on the cell culture and ICC data, lead compounds were selected for pharmacokinetics studies to determine oral bioavailability. Detailed pharmacokinetic data of selected top compounds showing their bioavailability after intra venous and oral administration will be presented.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2844. doi:1538-7445.AM2012-2844
Abstract 2847: PECAM-1 targeting extends overall survival in various advanced metastatic mouse tumor models
Authors: Handumrongkul Chakkrapong , Collins Chris , DeLisser Horace , Kashani-Sabet Mohammed , Nadel Cory , Nosrati Mehdi , Keyt Bruce , Haqq Christopher , Fong Sylvia , Debs Robert J. 
Published: August 2012

Abstract
Objectives: Patients who die from cancer succumb to advanced metastatic progression (AMP). While targeted therapies are available that address tumor cell derived regulators of metastasis, few therapeutics are being developed to address the molecular mechanisms of AMP. Our group has previously shown that vascular endothelial cell (VEC) PECAM-1 is a critical molecular master switch which regulates AMP by controlling the release of VEC-derived, paracrine growth factors that drive its progression. Anti-PECAM-1 monoclonal antibody (mAb) effectively and safely treats even pre-terminal cancers in AMP-bearing mice. The current experiments were performed to assess whether, to what extent and how widely targeting PECAM-1 can improve overall survival in mice bearing advanced metastases. Methods: Groups of wildtype (WT) C57Bl/6 mice, together with age and gender matched PECAM-1 knockout (KO) mice were intravenously injected with 25,000 murine B16-F10 melanoma cells, 30,000 murine EL4 lymphoma cells or 1,000,000 murine MC38 colon cancer cells. We then injected matched groups of PECAM-1 KO vs WT mice with 1,000,000 B16-F10 cells, to model maximally aggressive AMP. All groups were assessed for overall survival, using IACUC approved guidelines. Results: In all cases, overall survival (OS) was significantly prolonged in PECAM-1 KO vs WT controls (Kaplan-Meier ranged from p = 0.018 to p = 0.0002). Targeting microenvironmental PECAM-1 was as effective in increasing OS in mice receiving the very high tumor burden of 1,000,000 B16-F10 cells as in mice receiving 25,000 cells, further confirming the efficacy of targeting PECAM-1 against the most advanced models of metastasis that can be achieved preclinically. Furthermore, anti-PECAM-1 mAb-based therapy of B16-F10 metastase was as effective as the PECAM-1 KO genotype in increasing OS. Conclusion: To date, many approved mAb- and small molecule-inhibitor based targeted-therapies have shown limited abilities to either prolong OS as single agents, or to effectively treat multiple different solid tumor types. These results suggest that anti-PECAM-1 mAb therapy, which specifically targets VEC and paracrine factors they produce, has the potential to significantly increase OS in the setting of lethal advanced metastatic progression, independent of tumor type. Anti-PECAM-1 mAb therapy is as effective as a PECAM-1 knockout in improving OS. Phase 1 clinical trials are planned within 2 years.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2847. doi:1538-7445.AM2012-2847
Abstract 2867: A novel WT1-derived peptide induces cellular senescence and inhibits tumor growth in a human melanoma cell line and xenograft model
Authors: Massaoka Mariana Hiromi , Matsuo Alisson Leonardo , Pereira Felipe Valença , Figueiredo Carlos Rogerio , Scutti Jorge Augusto , Girola Natália , Travassos Luiz Rodolpho 
Published: August 2012

Abstract
Malignant melanoma is the most aggressive and deadly type of skin cancer. The Wilms tumor protein 1 (WT1) is a transcription factor that has been associated with melanoma oncogenesis and proliferation, hence could be a target of tumor control procedures. A lysine-arginine rich peptide (WT1 pTj) based on WT1 C-terminal zinc finger domain was synthesized and tested for anti-proliferative effects on human and murine melanoma cell lines (A2058 and B16F10-Nex2, respectively), including inhibition of cell growth and colony formation, cell cycle arrest and induction of cell senescence. Internalization of WT1 pTj into A2058 cells was established by confocal microscopy, using biotinylated peptide and staining by streptoavidin-FITC. An effect on p53 activity was measured by a luciferase reporter assay. Competitive ELISA assay was performed to verify whether the peptide interferes with p53-WT1 interaction. In vivo, athymic nude mice and C57Bl/6 were inoculated with A2058 and B16F10-Nex2 cells, respectively, and treated for 5 consecutive days with C-amidated WT1 pTj. Here, we show that WT1 pTj decreased, in a dose and time dependent manner, the number of melanoma viable cells. The anti-proliferative activity of WT1 pTj was linked to an irreversible G1 cell cycle arrest and induction of senescence as suggested by positive staining for beta-galactosidase. Treatment with WT1 pTj reduced the total number of soft-agar colonies by A2058 melanoma cells. The peptide entered the cell within 15 minutes and was diffusely distributed throughout the cell, including the nucleus. Moreover, WT1 pTj enhanced p53 activity and competed with WT1 protein for binding to p53. In vivo, WT1 pTj reduced the number of lung nodules in the B16F10-Nex2 syngeneic model of metastatic melanoma and prolonged survival of mice in the A2058 subcutaneous xenograft model. In conclusion, WT1 pTj peptide entered cancer cells and promoted antitumor activity in vitro and in vivo. The data support the hypothesis that WT1 pTj may prevent important interactions between WT1 protein and its partners via a zinc finger motif, inhibiting melanoma development. Therefore, WT1 pTj is a promising agent against WT1-expressing malignancies (e.g. MCF-7 but not SK-BR-3 breast cancer or normal human fibroblasts; and also HL60 acute myeloid leukemia). WT1 pTj may act also as a trojan carrier peptide for potential drug delivery. Supported by FAPESP grant 2010/51423-0 and the Brazilian National Research Council (CNPq)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2867. doi:1538-7445.AM2012-2867
Abstract 2877: Perifosine alone and in combination with antimetabolites interferes with NF-kB pathway activation in colon cancer cell lines
Authors: Aicher Babette , Schmidt Peter , Engel Jürgen , Guenther Eckhard G. , Teifel Michael 
Published: August 2012

Abstract
Background: Perifosine, a novel, first-in-class, oral Akt inhibitor, in combination with the antimetabolite Capecitabine is currently in Phase III clinical trials for the treatment of refractory advanced colorectal cancer. We have shown previously that Perifosine in combination with antimetabolites displayed synergistic cytotoxicity and apoptosis in colon cancer and other cell lines [1]. Constitutive NF-kB activation is frequently observed in colorectal cancer and, moreover, is associated with resistance to chemotherapy [2]. Hence we analysed, wether downregulation of the NF-kB pathway contributes to Perifosine mechanism of action and to the observed synergism with antimetabolites in colon cancer cell lines. Methods: Cellular NF-kB activation in nuclear extracts was measured by the TransAm NF-kB p65 ELISA (Active Motif, USA) monitoring binding of NF-kB to its response element. To allow for higher throughput of NF-kB pathway analysis a monoclonal SW620 colon cancer cell line ectopically expressing a NF-kB response element driven reporter gene (Promega, USA) was established. Cellular cytotoxicity and apoptosis assays as well as western blotting were performed according to standard procedures. The analysis of drug combinations was conducted by CalcuSyn software (Biosoft, UK) [3]. Results: Perifosine pretreatment decreased TNFα-induced NF-kB activation in SW620 cells in both independent assay sytems with IC50 values of about 7-10 µM. This effect seems to be specific, since the results were not mimicked by cytotoxic effects of Perifosine. Some of the antimetabolites alone upregulated NF-kB activity in the reporter gene assay. In the presence of these antimetabolites Perifosine was still capable to downregulate NF-kB activity. Conclusions: In summary, these results demonstrate that downregulation of the NF-kB pathway may contribute to the mechanism of action of Perifosine. Moreover, cotreatment with Perifosine has the potential to interfere with the development of antimetabolite resistance due to NF-kB activation in colon cancer. Further experiments addressing Perifosine's mechanism of action in combination with antimetabolites in gastric cancer cell lines are ongoing. References [1] Aicher et al. (2010), Perifosine in combination with antimetabolites induces synergistic effects on cytotoxicity and apoptosis in human colon, multiple myeloma, breast, renal, and liver tumor cell lines. AACR-NCI-EORTC International Conference, Berlin, Germany. [2] Sakamoto and Maeda (2010), Expert. Opin. Ther. Targets 14, 593-601 [3] Chou (2006), Pharmacological Reviews 58, 621-681
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2877. doi:1538-7445.AM2012-2877
Abstract 289: Hydrogen bond surrogate (HBS) helices as orthosteric regulator of hypoxia inducible transcription
Authors: Kushal Swati , Bullock Brooke , Henchey Laura , Arora Paramjit , Olenyuk Bogdan 
Published: August 2012

Abstract
Hypoxia-Inducible Factor (HIF-1) is a heterodimeric transcriptional activator which plays a critical role in tumorigenesis and therefore is an important therapeutic target. Transcriptional activation of HIF-1 is known to involve the interaction between cysteine-histidine rich region1 (CH1) of a coactivator protein p300 or Creb Binding Protein (CBP) and C-terminal activation domain (C-TAD) of its α-subunit (HIF-1α C-TAD). Based on the hydrogen bond surrogate (HBS) approach, we have rationally designed stabilized alpha helix that can disrupt the binding interface between C-TAD domain of HIF-1α and CH1 domain of p300/CBP. We have shown by fluorescence polarization that such stabilized alpha helix mimetics can directly bind to the CH1 domain of p300 and also can disrupt the HIF-1α/p300 complex. HBS helix mimetics are also shown to selectively downregulate the hypoxia inducible genes in cell culture. Thus, orthosteric inhibition of the HIF-1 transcriptional complex by rationally designed helix mimetics offers a novel approach to downregulate the expression of key hypoxia inducible genes responsible for tumor progression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 289. doi:1538-7445.AM2012-289