tbuckley/cabot-search huggingface dataset:
Abstract 3347: Exploring the role of ASXL family of genes in enabling oncogenic AR-signaling in prostate cancer
Authors: Abhijit Parolia, Xuhong Cao, Arul Chinnaiyan
Journal: Cancer Research (2017)

Abstract Prostate cancer (PCa) is the second leading cause of cancer-related mortality in North American men. In recent years, there has been mounting evidence establishing the centrality of epigenetic mechanisms in PCa initiation and progression. Accordingly, various epigenetic genes have been described to collaborate with the androgen receptor (AR) in enabling its oncogenic transcriptional program and aberrantly restoring its activity in metastatic castration resistant PCa (mCRPC). Concordantly, our lab has recently described two epigenetic genes, BRD4 &amp; MLL2, as key co-activators of the AR signaling complex. Furthermore, we have demonstrated the therapeutic benefits of inhibiting the activity of these genes in advanced PCa. Thus, in a setting where invariably all metastatic PCa patients progress to evolve resistance to anti-AR therapy, epigenetic genes emerge as potent co-targets with the promise to improve patient outcomes. To To identify novel AR-collaborating genes, as part of a multi-institutional consortium, our lab had performed comprehensive molecular profiling of 150 mCRPC patient tumors. This study revealed multiple genetic aberrations in chromatin modifier genes. Interestingly, this list comprised of recurrent mutations in the ASXL family of genes in about ~5% of the cases. ASXL family members are epigenetic scaffolding proteins that assemble chromatin modifiers and transcription factors to specific genomic loci with histone modifications. Although intricately involved in the genesis of acute myeloid leukemia, hitherto, no study has comprehensively described the role of ASXL genes in PCa biology. Two members of this family, ASXL1 and ASXL2, are robustly expressed in PCa. Co-immunoprecipitation assays revealed that these proteins also reside in the AR-signaling complex. Notably, siRNA-mediated inhibition of these genes dramatically attenuated proliferation of AR-dependent PCa cells, but had minimal effect on non-neoplastic prostate cells. These preliminary results strongly implicate ASXL genes in the oncogenic re-programming of AR-activity and warrant further investigation towards exploring of their therapeutic value in currently incurable mCRPC. Citation Format: Abhijit Parolia, Xuhong Cao, Arul Chinnaiyan. Exploring the role of ASXL family of genes in enabling oncogenic AR-signaling in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3347. doi:10.1158/1538-7445.AM2017-3347
Abstract 4930: Genetic and epigenetic characteristics of esophageal cancer tissues with microbiome fusobacterium nucleatum
Authors: Yoshifumi Baba, Kensuke Yamamura, Shigeki Nakagawa, Kosuke Mima, Takatsugu Ishimoto, Masaaki Iwatsuki, Yasuo Sakamoto, Naoya Yoshida, Hideo Baba
Journal: Cancer Research (2017)

Abstract Background: Research into the microbiome is a rapidly advancing field in human cancers. The gut microbiome has recently been shown to play an important role in health, as well as in diseases such as obesity, inflammatory bowel disease, diabetes, non-alcoholic fatty liver disease, and several types of cancers. Fusobacterium nucleatum is a component of the human microbiome that primarily inhabits the oral cavity. It causes periodontal disease and has also been implicated in the development of human cancers. We have recently reported that Fusobacterium nucleatum in esophageal cancer tissues was associated with shorter survival, suggesting a potential role as a prognostic biomarker. In addition, our KEGG enrichment analysis using microarray data showed that Fusobacterium nucleatum might also contribute to aggressive tumor behavior through activation of chemokines such as CCL20. Nonetheless, molecular features of Fusobacterium nucleatum-positive esophageal cancers have been still unknown. Methods: Using 325 esophageal cancers, we detected Fusobacterium nucleatum DNA in 74 tumors (23%). We assessed other genetic and epigenetic events including mutations in KRAS, BRAF, PIK3CA gene, p53 expression, phosphorylated-AKT expression, LINE-1 methylation level (global DNA methylation level), IGF2 DMR0 methylation, MGMT methylation, and MLH1 methylation. Results: The LINE-1 methylation levels of Fusobacterium nucleatum-positive tumors was significantly lower compared with that of Fusobacterium nucleatum-negative tumors (P&amp;lt;0.0001). In addition, Fusobacterium nucleatum was significantly associated with PIK3CA wild type (P=0.010). There was no relationship of Fusobacterium nucleatum with KRAS, BRAF mutation, p53 expression, p-AKT expression, IGF2 DMR0 methylation, MGMT methylation, or MLH1 methylation. Conclusion: Fusobacterium nucleatum was related with LINE-1 hypomethylation and PIK3CA wild type. Our findings may shed lights on understanding the mechanism by which Fusobacterium nucleatum affects aggressive tumor behavior. . Citation Format: Yoshifumi Baba, Kensuke Yamamura, Shigeki Nakagawa, Kosuke Mima, Takatsugu Ishimoto, Masaaki Iwatsuki, Yasuo Sakamoto, Naoya Yoshida, Hideo Baba. Genetic and epigenetic characteristics of esophageal cancer tissues with microbiome fusobacterium nucleatum [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4930. doi:10.1158/1538-7445.AM2017-4930
A Retrospective Study of Venous Thromboembolism in Acute Leukemia Patients during Prolonged Hospital Stay. the Princess Margaret Cancer Centre Experience
Authors: Hassan Sibai, Umberto Falcone, Arjun Datt Law, Ali Hosni, Carmen Tan, Naoko Sakurai, Andre C. Schuh, Mark D. Minden, Steven M. Chan, Karen W.L. Yee, Vikas Gupta, Aaron D. Schimmer, Jack T Seki
Journal: Blood (2016)
Dual inhibition of receptor tyrosine kinases of PDGFR and EGFR abolishes prostate cancer cell growth in culture and in a mouse xenograft model by complete dephosphorylation of PKB/Akt
Authors: Daruka Mahadevan, Wenqing Qi, Laurence Cooke, Robert Calaluce, David Bearss
Journal: Cancer Research (2007)

5421   Hormone resistant and metastatic prostate adenocarcinomas are incurable despite current therapeutic advances. New therapies based on well validated targets are urgently needed to compliment existing treatment modalities. Receptors to epidermal derived growth factor (EGF) and platelet derived growth factor (PDGF) have been established as oncologic (drugable) targets in many cancers including prostate adenocarcinoma. We utilized a structure-based drug design approach to identify a novel PDGFR tyrosine kinase inhibitor, MP470 which also effectively inhibits c-Kit, c-Met and c-Ret. In this study we hypothesized that dual inhibition of EGFR with Tarceva and PDGFR with MP470 in LNCaP prostate cancer cells in culture and in a mouse xenograft model would be more effective than individual therapy. Cellular cytotoxicity assays demonstrated that MP470 was more effective in inhibiting cell proliferation with an IC 50  ~5µM than Tarceva (IC 50  ~10μM). Apoptosis was induced in a dose-dependent manner by MP470 alone and the combination with Tarceva was synergistic as demonstrated by morphology, flow cytometry and PARP cleavage. However, necrosis was elicited by MP470 treatment alone in two other prostate cancer cells PC-3 and DU-145. MP470 alone was more effective in inhibiting phosphorylation of Akt on Ser473 compared to Tarceva or Imatinib (Gleevec: PDGFR inhibitor) or Tarceva plus Imatinib. Moreover, MP470 plus Tarceva completely inhibited Akt phosphorylation in LNCaP cells stimulated by PDGF-BB. Consistent with these results, the combination of MP470 and Tarceva treatment was shown to abolish prostate tumor growth in an LNCaP xenograft mouse model. Individual therapy with MP470 or Tarceva was modestly effective in reducing tumor growth. Histo-pathological evaluation of the xenograft tumors at the midpoint and end of study by H+E and immunohistochemistry staining showed significantly increased apoptosis (active Caspase-3), decreased Akt phosphorylation, decreased angiogenesis (CD31) and decreased proliferation (Ki-67) in the MP470 plus Tarceva arm compared to control or MP470 or Tarceva arms. Taken together, these data demonstrate that MP470 is more effective in inhibiting cell survival and blockade of both EGFR and PDGFR pathways may represent a useful treatment modality for advanced prostate cancer.
Abstract 1807: Exosomal NM23 facilitates pro-angiogenic communication between triple-negative breast cancer cells and their vascular targets
Authors: Suzann Duan, Senny Nordmeier, Iain L. Buxton
Journal: Cancer Research (2017)

Abstract Functional interactions between primary tumor cells and their vascular targets orchestrate the formation of a metastatic milieu enriched with oxygen and metabolic substrates. These interactions have been largely attributed to the activation of VEGF receptor pathways through localized tumor-mediated release of VEGF, in addition to indirect receptor phosphorylation. However, pro-angiogenic events are known to occur in the absence of VEGF and alternative pathways resulting in dual activation of neovascularization and enhanced vascular permeability are of growing interest. Our lab has previously shown that triple-negative human breast cancer (MDA-MB-231) cells elaborate exosomes carrying NM23, a nucleoside diphosphate kinase (eNDPK) that is suggested to act as an upstream mediator of vasodilation and pro-angiogenic activity through its action of elevating extracellular ADP/ATP levels. To further elucidate the role of eNDPK in breast cancer signaling and metastasis, we show that 231-exosomes induce a pro-angiogenic phenotype in both human umbilical vein and murine pulmonary endothelial cells. Treatment with an NDPK-specific inhibitor and an antagonist to the ADP/ATP-activated P2Y1 receptor results in amelioration of pro-angiogenic characteristics. Further, we report the development and application of a novel murine implant model to demonstrate increased specificity of 231 exosome targeting to pulmonary endothelial cells over unrelated cell lines. These results suggest the involvement of exosomes and eNDPK in pro-angiogenic communication between metastatic breast cancer cells and their vascular targets. Exosomes elaborated by these cells specifically target pulmonary endothelium in vivo, mirroring the organotropic nature of breast cancer metastasis. Implication of eNDPK in angiogenesis and metastasis may challenge current and invasive treatment methods in favor of developing novel small molecule inhibitors of eNDPK signaling. Lastly, eNDPK can be explored as a potential biomarker for early detection of metastatic breast cancer as it uniquely appears in the serum of patients with breast cancer and not in the serum of individuals with unrelated pathologies. Citation Format: Suzann Duan, Senny Nordmeier, Iain L. Buxton. Exosomal NM23 facilitates pro-angiogenic communication between triple-negative breast cancer cells and their vascular targets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1807. doi:10.1158/1538-7445.AM2017-1807
Abstract 4341: Mesenchymal stem cells promote epithelial-mesenchymal transition of colon cancer cells via direct cell-to-cell contact
Authors: Hidehiko Takigawa, Yasuhiko Kitadai, Toshio Kuwai, Ryo Yuge, Shinji Tanaka, Kazuaki Chayama
Journal: Cancer Research (2017)

Abstract We previously reported that in an orthotopic nude mouse model of human colon cancer, bone marrow-derived mesenchymal stem cells (MSCs) migrated to tumor stroma and promoted tumor growth and metastasis. We evaluated the proliferation and migration ability in directly and indirectly co-culture assay to clarify the mechanism of interaction between cancer cells and MSCs. Proliferation and migration ability of cancer cells were increased by direct co-culture with MSCs but not by indirect co-culture of MSCs. Thus, we thought that direct contact between cancer cells and MSCs is important to their interaction. We performed microarray analysis of gene expression in KM12SM colon cancer cells directly co-cultured with MSCs. Expression of epithelial-mesenchymal transition (EMT) related genes such as fibronectin (FN), SPARC and Galectin 1 was increased by direct co-culture with MSCs. We also confirmed the upregulation of these genes with real time PCR, and these genes were not increased in cancer cells indirectly co-cultured with MSCs. Among these EMT related genes upregulated by direct co-culture with MSCs, we examined immune localization of FN, well-known EMT marker. In co-culture assay in chamber slides, expression of FN in cancer cluster was seen only at the edge where cancer cells directly contacted with MSCs. FN expression by cancer cells was increased at the tumor periphery and invasive edge in orthotopic nude mice tumors and human colon cancer tissues, respectively. These results suggest that mesenchymal stem cells induce epithelial-mesenchymal transition of colon cancer cells via direct cell-to-cell contact and may play an important role of colon cancer metastasis. Citation Format: Hidehiko Takigawa, Yasuhiko Kitadai, Toshio Kuwai, Ryo Yuge, Shinji Tanaka, Kazuaki Chayama. Mesenchymal stem cells promote epithelial-mesenchymal transition of colon cancer cells via direct cell-to-cell contact [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4341. doi:10.1158/1538-7445.AM2017-4341
Abstract 855: Ube2v1 promotes epithelial mesenchymal transition and metastasis in colorectal cancer by epigenetically transcriptional suppression of autophagy
Authors: Tong Shen, Dong Ling Cai, Hong Yu Liu, Juan Wen Gan, Ming Li, Ru Jing Wang, Da Peng Guo, Qun Zhou, Xing Xing Lu, Shi Li, Na Li Sun, Ming Jian Li
Journal: Cancer Research (2017)

Abstract Ubiquitination is one of the basic post-translational modifications for cellular homeostasis. The conjugating enzyme (E2) family plays as a bridge linking the first step mediated by E1 with the final step mediated by E3 in the ubiquitin-proteasomesystem. However, the role of Ube2v1, one of Ubiquitin-conjugating E2 enzyme variant proteins (Ube2v), in colorectal cancer (CRC) and autophagy is unclear. Here, we found that Ube2v1 is elevated in tumor samples of CRC patients and correlated with poorer survival of CRC patients. Furthermore, Ube2v1 promotes migration and invasion of CRC cells in vitro and boosts tumor growth and metastasis of CRC cells in vivo. Interestingly, Ube2v1 suppresses autophagy program and promotes EMT and metastasis of CRC cells in an autophagy dependent pattern in vitro and in vivo. Moreover, Rapamycin attenuates the enhanced in vitro migration and invasion and in vivo lung metastasis of Ube2v1 overexpression by inducing the autophagy pathway. Mechanistically, Ube2v1 increases histone H4 lysine 16 acetylation by down-regulating expression of Sirt1 and epigenetically suppresses gene expression of autophagy genes in colorectal cancer. In conclusion, Ube2v1 functions as a globalregulator for autophagy by epigenetically transcriptional suppression of autophagy, and consequently promotes EMT and metastasis of CRC. Our study functionally links Ube2v1, one member of E2 family in the ubiquitin-proteasome system toautophagy program in CRC progression and metastasis. Note: This abstract was not presented at the meeting. Citation Format: Tong Shen, Dong Ling Cai, Hong Yu Liu, Juan Wen Gan, Ming Li, Ru Jing Wang, Da Peng Guo, Qun Zhou, Xing Xing Lu, Shi Li, Na Li Sun, Ming Jian Li. Ube2v1 promotes epithelial mesenchymal transition and metastasis in colorectal cancer by epigenetically transcriptional suppression of autophagy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 855. doi:10.1158/1538-7445.AM2017-855
Abstract 2722: Next generation targeted sequencing reveals four unknown mutations in the Mexican population with Gorlin syndrome
Authors: Fragoso Veronica, Natalia Espinosa, Julieta Dominguez, Felipe Vaca-Paniagua, Luis A. Herrera, Rosa M. Alvarez
Journal: Cancer Research (2017)

Abstract Aim: Nevoid Basal Cell Carcinoma Syndrome (NBCCS), an autosomal dominant disorder, is characterized by the presence of a variety of developmental anomalies, and predisposition to multiple basal cell carcinomas (BCCs), and other neoplasias. NBCCS mainly results from germinal mutations in the PTCH1 gene, that encodes a transmembrane glycoprotein, component of the hedgehog signalling pathway. The incidence of NBCCS in general population is estimated at 1 in 150000. Data related to NBCCS in Mexican patients is reduced to clinical case reports, without molecular testing. Therefore, we conducted next-generation sequencing (NGS) of PTCH1, in 9 Mexican patients with diagnosis of NBCCS. Material and methods: NGS of PTCH1 was performed, in the context of a hereditary cancer gene panel. The PTCH1 regions with insufficient coverage (&amp;lt;30× read depth), were complemented by Sanger sequencing, to ensure 100% coverage of the gene. In-silico analysis was perfomed for missenses mutations. The identified pathogenic mutations were verified by capillary sequencing. Results: Targeted analysis of PTCH1 gene, looking for deletions, insertions, splice-site alterations, nonsense and missense mutations, was done. Four PTCH1 mutations (4/9) were identified: a deletion (c.1044delG); one insertion (c.631dupA); a non-sense mutation (c.3406G&amp;gt;T), and a missense mutation (c.1488C&amp;gt;A). None of the mutations had been previously reported. Conclusions : NGS of PTCH1 gene in 9 Mexican patients with clinical criteria for NBCCS allowed the identification of four novel pathogenic mutations (44% frequency). This is the first molecular overview of PTCH1 in NBCCS patients of our population. The perspectives of the current study lie in the molecular testing of other genes involved in NBCCS (PTCH2, SUFU), and other mechanisms (whole gene deletion), as well as the review of possible phenotype-genotype correlations. Citation Format: Fragoso Veronica, Natalia Espinosa, Julieta Dominguez, Felipe Vaca-Paniagua, Luis A. Herrera, Rosa M. Alvarez. Next generation targeted sequencing reveals four unknown mutations in the Mexican population with Gorlin syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2722. doi:10.1158/1538-7445.AM2017-2722
Abstract 1661: Humanized mouse models for immune-oncology biotherapeutics: Development, validation and applications
Authors: Gang Chen, Bin Cai, Feng Zhou, Jerry Zhou, Jie Liu, Xin Dong
Journal: Cancer Research (2017)

Abstract With clinical success and FDA approval of Ipilimumab, Nivolumab, Pembrolizumab and Atezolizumab, developing biotherapeutics against immune checkpoint targets, like CTLA-4, PD-1/PDL-1 and others, becomes hot pursuits for big pharma and biotech. However, traditional syngeneic models with surrogate murine reagents or human immune cell re-constitution in immune deficient mice are useful but not reliable and robust due to the species specificity and highly variable responses. It is crucial to establish additional preclinical models for efficacy assessment of investigational immune-oncology antibodies before entering clinic. Establishing human therapeutic target engineered mouse models by replacing mouse gene with human counterpart while maintaining intact mouse immunity is a practical approach for in vivo studies. Applying CRISPR-Cas9 and other gene editing techniques, we have engineered genetically a series of single and double human immune-checkpoint genes, like PD-1/PDL-1, CTLA-4, TIM3, CD137 and others, knock-in model expressing chimeric human/mouse targets composed of human extracellular domains, with intact mouse signal peptide and intracellular domain. FACS analysis of immune cells derived from homozygous knock-in mice showed that activated cells only express chimeric targets reactive to anti human target antibodies, but not mouse gene specific antibodies. We have been testing the efficacy of reference antibodies by treating these homozygous knock-in mice inoculated with syngeneic murine tumor cells. Other applications, like target validation, combination therapy and biomarker discovery, are also explored. Note: This abstract was not presented at the meeting. Citation Format: Gang Chen, Bin Cai, Feng Zhou, Jerry Zhou, Jie Liu, Xin Dong. Humanized mouse models for immune-oncology biotherapeutics: Development, validation and applications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1661. doi:10.1158/1538-7445.AM2017-1661
Abstract 033: Cardio-Cerebro-Vascular Diseases: Prevention in Metabolic Syndrome Patients
Authors: Günter Siegel, Eugeny Ermilov
Journal: Circulation Research (2013)

Background: ALP and GGT are indispensable constituents of brain microvessel endothelial cells, expressed and induced by IL-6. High values are entangled in affecting blood-brain barrier functionality. Since SOD bound to brain basement membrane and matrix heparan sulfate proteoglycan, is implicated in β-amyloid efflux, we examined in a pilot study of 11 patients with metabolic syndrome (MS) whether these biomarkers can be beneficially influenced through an antioxidant phytochemical approach with Ginkgo biloba (EGb 761, 2 × 120 mg/d). Also, MS is associated with an increased risk of developing diabetes and cardio-cerebro-vascular diseases (CCVD) (Figure). Methods: Photometric methods, ELISAs, EIAs and laser ellipsometry were applied. Results: A 2-month medication led to brain/liver biomarker changes: ALP -14.8% (p &lt; 0.004), GGT -11.3% (p &lt; 0.010). Antioxidative biomarker changes: SOD +17.7% (p &lt; 0.009), GPx +11.6% (p &lt;0.001), oxLDL/LDL -21.0% (p &lt; 0.002), 8- iso -PGF 2α -39.8% (p &lt; 0.003), MPO -29.6% (p &lt; 0.014). Antiinflammatory biomarker changes: IL-6 -12.9% (p &lt; 0.041), Lp(a) -26.3% (&lt; 0.001), hs-CRP -39.3% (&lt; 0.005), WBC -6.3% (&lt; 0.023), MMP-9 -32.9% (&lt; 0.042). Vasodilator biomarker changes: cAMP +43.5% (&lt; 0.001), cGMP +32.9% (&lt; 0.001), nanoplaque formation -14.3% (p &lt; 0.008), nanoplaque size -23.4% (p &lt; 0.0004). Conclusion: Since under ginkgo ALP and GGT were downregulated and SOD upregulated, and plasma biomarkers of oxidative stress, plaque stability and progression, inflammation, vasodilatory second messengers and lipid composition beneficially altered, this phytochemical may be estimated as complementary drug with potentially preventive character for CCVD.
The evolvement of discrete representations from continuous stimulus properties: A possible overarching principle of cognition
Authors: Nurit Gronau
Journal: Behavioral and Brain Sciences (2017)

Abstract Leibovich et al. propose that non-symbolic numerosity abilities develop from the processing of more basic, continuous magnitudes such as size, area, and density. Here I review similar arguments arising in the visual perception field and further propose that the evolvement of discrete representations from continuous stimulus properties may be a fundamental characteristic of cognitive development.