bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4627: A novel computational re-analysis of published GWAS data suggests new risk loci for melanoma susceptibility
Authors: Cymerman Rachel M. , Bigio Benedetta , Seybold Martin P. , Polsky David , Wittkowski Knut M. 
Published: August 2015

Abstract
Purpose: Multiple melanoma GWAS have identified significant associations between single nucleotide polymorphisms (SNPs) and melanoma. As multiple variants within a given genetic locus may contribute to disease risk in different individuals, a novel computational approach to analyzing GWAS data by ‘wide-locus’ region has been shown to increase analytical power, and, in other diseases, has led to the discovery of new susceptibility loci. To date, this approach has not been applied to the study of germline genetic risk factors for melanoma. We applied this method to publically available melanoma GWAS data to identify novel germline risk factors for melanoma.
Methods: We re-analyzed data from the M.D. Anderson Cancer Center melanoma GWAS study (dbGap accession: phs000187.v1.p1). In the original study, 1,977 cases and 1,047 controls of European ancestry were genotyped on an Illumina OMNI1-Quad chip. We age-matched cases and controls using “age-censoring” to account for differences in melanoma risk across different age groups. Biostatistical analysis of ‘wide-loci’ was performed across all SNPs to evaluate risk loci based on the influence of neighboring SNPs. The re-analysis was performed by individuals blinded to specific results of the original study. Genome-wide significance for each wide locus was based on number of regions examined, and was set at p&lt;10−6.16.
Results: Using the ‘wide-locus’ approach, we identified 21 risk loci on 16 chromosomes that met genome-wide significance. Firstly, we replicated all of the genome-wide significant findings of the original, single-SNP analysis, identifying specific SNPs at HERC2 and wide loci at MC1R and AFG3L1 that met genome-wide significance. Secondly, we identified additional SNPs not replicated to genome-wide significance in the original analysis but previously discovered in other populations. These additional SNPs reside in the MC1R, OCA2, CPNE7, DBNDD1, and AFG3L1 loci. Finally, we identified 15 new candidate loci meeting genome-wide significance, with the most significant findings located at KLK12 (associated with carcinogenesis in other cancers), PDE8 (involved with cAMP intra-cellular signaling and immune activation), and LY86 (involved in immune cell activation).
Conclusion: Applying ‘wide-locus’-based statistical analysis to melanoma GWAS data replicated the findings of prior single-SNP analyses and identified multiple, new candidate risk loci worthy of further investigation.
Citation Format: Rachel M. Cymerman, Benedetta Bigio, Martin P. Seybold, David Polsky, Knut M. Wittkowski. A novel computational re-analysis of published GWAS data suggests new risk loci for melanoma susceptibility. [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 4627. doi:10.1158/1538-7445.AM2015-4627
Abstract 4654: Antitumorigenic activity of trans-chalcone in osteosarcoma
Authors: Silva Gabriel da , Marins Mozart , Fachin Ana Lúcia , Baek Seung J. 
Published: August 2015

Abstract
Background and Aims: Osteosarcoma is the most common bone cancer, and it affects mostly teenagers and children. Although the emergence of multidrug therapies has improved available treatments for osteosarcoma, approximately 30% of patients will still develop metastasis. Thus, there is a clear need to identify new anticancer therapies. Currently, much anticancer therapy uses drugs that affect molecular targets, such as up-regulation of p53 and down-regulation of Sp1. Building on this knowledge, our aims in this work were to evaluate the ability of trans-Chalcone to reduce viability, induce apoptosis, and to alter the levels of p53 and Sp1 in human osteosarcoma cell lines. Chalcones are secondary metabolites of plants and have been demonstrated to induce apoptosis in human cancer cells. Methods: Osteosarcoma cell viability and apoptosis were evaluated by MTT assay and flow cytometry, respectively. The expression of p53 and sp1 was assessed by Western blotting. Transcriptional and post-translational regulation were measured by luciferase assay and proteasomal inhibitor experiments. Results: We identified that cell growth was inhibited by trans-Chalcone in a dose- and time-dependent manner, with a significant inhibition at 10 μM after 48 hours. After 24 hours of treatment with trans-Chalcone, apoptosis was induced in a dose-dependent manner-fold induction at 1.9 and 3.6 at 10 μM and 50 μM, respectively, compared to control. Western blot analysis indicated that trans-chalcone reduced Sp1 and induced p53 expression, compared to control cells. Further experiments suggest that trans-Chalcone affected Sp1 down-regulation at the transcriptional level, whereas trans-chalcone up-regulated p53 expression at the post-translational level. These results were confirmed by a luciferase assay of the MDM2 promoter and a proteasomal degradation assay using several inhibitors. Conclusions: Trans-Chalcone inhibits cell growth and induces apoptosis in osteosarcoma cells and targets p53 tumor suppressor and Sp1 oncogenic proteins in osteosarcoma. Thus, trans-chalcone could be the focus of future clinical trials to develop an anti-cancer drug for osteosarcoma patients.
Support: The University of Tennessee Center of Excellence in Livestock Diseases and Human Health and a grant (No. process: BEX 3159/14-0) from the CAPES Foundation, an agency under the Ministry of Education of Brazil.
Citation Format: Gabriel da Silva, Mozart Marins, Ana Lúcia Fachin, Seung J. Baek. Antitumorigenic activity of trans-chalcone in osteosarcoma. [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 4654. doi:10.1158/1538-7445.AM2015-4654
Abstract 4661: Preventive effects of branched-chain amino acid supplementation on the spontaneous development of hepatic preneoplastic lesions in C57BL/KsJ-db/db obese mice
Authors: Ideta Takayasu 
Published: August 2015

Abstract
In the present study, the effects of BCAA supplementation on the spontaneous development of hepatic premalignant lesions, foci of cellular alteration, in db/db obese mice were examined. Male db/db mice were given a basal diet containing 3.0% of either BCAA or casein, a nitrogen-content-matched control of BCAA, for 36 weeks. On killing the mice, supplementation with BCAA significantly inhibited the development of foci of cellular alteration when compared with casein supplementation by inhibiting cell proliferation, but inducing apoptosis. BCAA supplementation increased the expression levels of peroxisome proliferator-activated receptor-γ(PPARγ), p21(CIP1) and p27(KIP1) messenger RNA and decreased the levels of c-fos and cyclin D1 mRNA in the liver. BCAA supplementation also reduced both the amount of hepatic triglyceride accumulation and the expression of interleukin (IL)-6, IL-1β, IL-18 and tumor necrosis factor-α mRNA in the liver. Increased macrophage infiltration was inhibited and the expression of IL-6, TNF-α, and monocyte chemoattractant protein-1 mRNA in the white adipose tissue were each decreased by BCAA supplementation. BCAA supplementation also reduced adipocyte size while increasing the expression of PPARα, PPARγand adiponectin mRNA in the white adipose tissue compared with casein supplementation. These findings indicate that BCAA supplementation inhibits the early phase of obesity-related liver tumorigenesis by attenuating chronic inflammation in both the liver and white adipose tissue. BCAA supplementation may be useful in the chemoprevention of liver tumorigenesis in obese individuals.
Citation Format: Takayasu Ideta. Preventive effects of branched-chain amino acid supplementation on the spontaneous development of hepatic preneoplastic lesions in C57BL/KsJ-db/db obese mice. [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 4661. doi:10.1158/1538-7445.AM2015-4661
Abstract 467: Oxidized lipids contribute to the suppression function of myeloid derived suppressor cells in cancer
Authors: Veglia Filippo , Tyurin Vladimir , Kagan Valerian , Gabrilovich Dmitry 
Published: August 2015

Abstract
Immune evasion is an emerging hallmark of cancer progression. It is established that the defects in the function of antigen presenting cells and the accumulation of myeloid derived suppressive cells (MDSCs) are critical drivers of tumor mediated immune evasion. MDSCs represent a heterogeneous population of immature and pathologically activated myeloid cells that are expanded in many cancers and suppress immune responses by several defined mechanisms. Our recent findings indicate that the massive accumulation of oxidized lipids in dendritic cells (DCs) resulted in profound defects in their ability to mount antitumor responses. In this study we observed that MDSCs from tumor bearing mice and from cancer patients have higher amount of lipids than their counterpart in tumor free mice and healthy donors, respectively. The content of lipids in MDSC was even much higher in MDSCs infiltrating the tumor, and the accumulation of lipids in MDSC seems be caused by the uptake of extracellular lipids. MDSCs with a highest content of lipids showed a stronger ability to suppress antigen specific CD8 T cell responses than MDSCs with a normal content of lipids. By using mass-spectrometry we identified different oxidized species in lipids accumulated in MDSC from both tumor bearing mice and patients with cancer. Myeloperoxidase (MPO) and reactive oxygen species (ROS) were responsible for the oxidation of lipids in MDSCs. Lack of MPO or ROS in MDSC almost completely abrogated the oxidation of lipids in these cells. Furthermore the reduced amount of oxidized lipids in MDSC from MPO KO mice or following the pharmacological inhibition of their oxidative machinery resulted in a profound defect in MDSC suppressive activity. In line with these findings, unsaturated fatty acids, highly susceptible to oxidation, favored the expansion of highly suppressive MDSC from hematopoietic progenitors in vitro, as oppose to non-oxidizable saturated fatty acids. Together, our data suggest that MDSCs have increased ability to pick up lipids from the microenvironment and to oxidize them via their potent oxidative machinery. In turn oxygenated lipids contribute to the suppressive activity of MDSC. The regulation of the oxidation of lipids in MDSC could be an attractive therapeutic strategy in cancer.
Citation Format: Filippo Veglia, Vladimir Tyurin, Valerian Kagan, Dmitry Gabrilovich. Oxidized lipids contribute to the suppression function of myeloid derived suppressor cells in 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 467. doi:10.1158/1538-7445.AM2015-467
Abstract 4699: Preclinical activity of the AKT inhibitor AZD5363 in PTEN-deficient mouse models of prostate cancer
Authors: De Velasco Marco A. , Hatanaka Yuji , Kura Yurie , Fukushima Emiko , Ando Naomi , Davies Barry R. , Yamamoto Yutaka , Oki Takashi , Shimizu Nobutaka , Yoshimura Kazuhiro , Nozawa Masahiro , Yoshikawa Kazuhiro , Nishio Kazuto , Uemura Hirotsugu 
Published: August 2015

Abstract
Increased phosphoinositide 3-kinase (PI3K) pathway activity is commonly observed in human prostate cancer and constitutes a potential target for therapeutic intervention. AZD5363 is a potent pan-AKT kinase inhibitor that is currently being investigated in phase 1 and 2 clinical trials in solid cancers including prostate. AZD5363 has demonstrated strong anti-tumor activity against human prostate cancer cells in vitro and in vivo. Genetically engineered mouse models mimic the genetic and biological evolution of human prostate cancer and address deficiencies encountered with xenograft models. In the present study, we examined in vivo target validation, pharmacodynamics, and antitumor responses of AZD5363 monotherapy in a PTEN-deficient mouse model of prostate cancer, and show the survival benefit in an advanced prostate cancer model driven by PTEN/P53 inactivation. Downstream targets of AKT were inhibited in a dose-dependent manner and activity of AZD5363 at was observed up to 8 hours after a single dose of 100 mg/kg. Tumor cell proliferation and the induction of apoptosis paralleled the activity of AZD5363. Compared to vehicle treated mice, chronic administration of AZD5363 at 100 mg/kg B.I.D. 5 times per week for 4 weeks inhibited growth of castration-naïve and castration-resistant prostate cancers by 15.9% ±4.3 and 20.2% ±4.4, respectively. Inhibition of S6 phosphorylation was effectively maintained the after chronic administration of AZD5363 and was accompanied by decreased proliferation rates and increase in apoptosis. Furthermore, in a long-term survival study of PTEN/P53 double knockout mice, treatment with AZD5363 significantly improved survival rates from 24 to 37 days, P&lt;0.011. In conclusion, our findings indicate that AZD5363 is effective against autochthonous models of mouse prostate cancer and support further investigation of the AKT inhibitor for the treatment of PTEN-deficient prostate cancer.
Citation Format: Marco A. De Velasco, Yuji Hatanaka, Yurie Kura, Emiko Fukushima, Naomi Ando, Barry R. Davies, Yutaka Yamamoto, Takashi Oki, Nobutaka Shimizu, Kazuhiro Yoshimura, Masahiro Nozawa, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura. Preclinical activity of the AKT inhibitor AZD5363 in PTEN-deficient mouse models of prostate 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 4699. doi:10.1158/1538-7445.AM2015-4699
Abstract 4715: Regulation of the PI3K pathway through a p85α monomer-homodimer equilibrium
Authors: Cheung Lydia WT , Walkiewicz Katarzyna W. , Besong Tabot , Hawke David , Arold Stefan T. , Mills Gordon B. 
Published: August 2015

Abstract
The canonical action of the p85α regulatory subunit of phosphatidylinositol 3-kinase (PI3K) is mediated by association with the p110 catalytic subunit to allow stimuli-dependent activation of the PI3K pathway. Although the best-characterized role of p85α is p110-dependent, intermolecular interactions of p85α protomers have been suggested to result in p85α homodimerization. However, the function of the p85α homodimer remains to be elucidated. Through structural modeling and biochemical analyses, we demonstrate the p110α-independent role of homodimerized p85α in the positive regulation of PTEN. p110α-free p85α homodimerizes via SH3:proline rich domain and BH:BH intermolecular interactions to selectively bind unphosphorylated activated PTEN. p85α homodimer competes for PTEN binding with the E3 ligase WWP2. As a consequence, homodimeric but not monomeric p85α suppresses the PI3K pathway by protecting PTEN from WWP2-mediated proteasomal degradation. Further, p85α homodimer enhances the lipid phosphatase activity and membrane association of PTEN. Importantly, the homodimerization surface and the PTEN-interaction interface are targeted in cancer patient-derived p85α mutants, providing a plausible mechanism for tumor development. These p85α mutants are oncogenic by destabilizing PTEN and inducing PI3K pathway activation. Together, we provide a mechanistic model of how p85α plays a dual role in regulating the PI3K pathway through forming p85α homodimer or p110-bound heterodimer. Our data suggest that the monomer-dimer equilibrium of p85α regulates the PI3K pathway and thereby associates with cancer development.
Citation Format: Lydia WT Cheung, Katarzyna W. Walkiewicz, Tabot Besong, David Hawke, Stefan T. Arold, Gordon B. Mills. Regulation of the PI3K pathway through a p85α monomer-homodimer equilibrium. [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 4715. doi:10.1158/1538-7445.AM2015-4715
Abstract 472: Galectin-3 modulates glioblastomas (GBM) tumor microenvironment, and is linked to glioblastoma invasion
Authors: Wesley Umadevi V. , Resad Esat , Clark Paul , Larrain Carolina , Kuo John , Dempsey Robert J. 
Published: August 2015

Abstract
Malignant glioblastomas (GBM) are lethal form of brain tumors, and are difficult to treat due to their invasion into the brain parenchyma. Aggressive and invasive nature of GBM is at least partly attributable to GBM associated stem cells (GSC). Soluble factors released by GBM and GSC can recruit inflammatory cells, including brain resident microglia to tumor micro-environment (TME) that support angiogenesis and invasion. We have previously shown that exogenous Galectin-3 (Gal-3), a carbohydrate binding lectin increases the migratory potential of BV2 microglial cells, and promotes the formation of pro-angiogenic structures in an in vitro HUVEC culture and 3D matrigel model. Furthermore, Gal-3 supports the survival of microglial cells under hypoxic environment. In this study, we investigated the role of Gal-3 in GBM by utilizing the biochemical and molecular approaches. Using well characterized GBM tumor cell lines, and GSC lines that exhibit various degrees of invasive potential, we have identified that the expression of the Gal-3 is significantly up-regulated in GSCs that are highly invasive as compared to those that form only focal tumors in a mouse xenotransplantation model. Gal-3 is also highly expressed in microglia that accumulated in and around the GSC tumors in mouse brain, as indicated by co-localization of Gal-3 and Iba1, the maker for activated microglia. Furthermore, Gal-3 expression is significantly increased in GBM tumor cells when exposed to in vitro hypoxic conditions. Importantly, Gal-3 increased the migratory potential of GBM tumor cells in vitro, indicating its role as a chemo-attractant. Taken together, these results suggest that Gal-3 plays a critical role in promoting GBM invasion through modulating the interaction of microglia in TME and GBM. Thus Gal-3 may be a potential therapeutic target for GBM.
Citation Format: Umadevi V. Wesley, Esat Resad, Paul Clark, Carolina Larrain, John Kuo, Robert J. Dempsey. Galectin-3 modulates glioblastomas (GBM) tumor microenvironment, and is linked to glioblastoma invasion. [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 472. doi:10.1158/1538-7445.AM2015-472
Abstract 4722: Inactivation of neogenin promotes castration resistance and bone metastasis in prostate cancer models
Authors: Chakraborty Goutam , Gadiya Mayur , Kossai Myriam , Gao Dong , Su Weijing , Gao Hua , Chen Yu , Scher Howard I. , Rubin Mark A. , Giancotti Filippo 
Published: August 2015

Abstract
Increasing evidence suggests that exposure to new generation agents targeting the AR promotes the emergence of castration-resistant stem-like clones ultimately leading to treatment failure. In order to develop improved therapies for castration-resistant prostate cancer (CRPC), it is important to understand the origin and biology of these stem-like clones. We have observed significantly diminished levels of Neogenin (encoded by NEO1) in CRPC. Neogenin functions as a neuronal guidance receptor but has also been implicated in epithelial branching morphogenesis and is homologous to DCC, which functions as a suppressor of tumor progression in breast and colorectal cancer. We found that silencing of neogenin induces androgen receptor (AR) dependent prostate cancer cells to undergo an epithelial to mesenchymal transition (EMT) and acquire neuroendocrine (NE) differentiation features. In addition, the neogenin-silenced cells expressed high levels of the stem cell markers β4 integrin and CD44 and formed rapidly growing tumor spheres in vitro. Intriguingly, these cells had become castration resistant due to loss of AR expression and were able to efficiently colonize the bone upon intracardiac injection in immunodeficient mice. Genomic and molecular pathology studies indicated that NEO1 expression is lost in CRPC and NEPC. To examine the relationship between the acquisition of the castration resistant phenotype and loss of neogenin, we have generated a series of casodex- and enzalutamide-resistant clones from LNCaP cells. Interestingly, we observed that a significant fraction of these clones have lost expression of neogenin and acquired expression of the β4 integrin and are highly metastatic in immunodeficient mice, similar to the characteristics of CRPC observed in the clinic. To validate these results, we sought to identify a population of β4-positive cells in the peripheral blood of patients with CRPC. By using immunofluorescent staining and FACS analysis, we were able to identify β4-positive circulating tumor cells (CTCs) from the peripheral blood of CRPC patients. These cells were not detected in the blood of healthy normal donors but their numbers increased with disease progression. These findings identify a novel tumor progression pathway that is likely to operate in at least a fraction of CRPC cases.
Citation Format: Goutam Chakraborty, Mayur Gadiya, Myriam Kossai, Dong Gao, Weijing Su, Hua Gao, Yu Chen, Howard I. Scher, Mark A. Rubin, Filippo Giancotti. Inactivation of neogenin promotes castration resistance and bone metastasis in prostate cancer models. [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 4722. doi:10.1158/1538-7445.AM2015-4722