tbuckley/cabot-search huggingface dataset:
Abstract 3902: A novel biologic ADI-TRAIL fusion protein benefits from structural and functional complementarity of its components arginine deiminase and TRAIL, induces cancer cell apoptosis in vitro, and inhibits tumor growth in vivo
Authors: Elena Brin, Katherine Wu, Yudou He, Wei-Jong Shia, Mario M. Kuo, Li-Chang Chen, Eleanor Dagostino, Richard Hickey, Bob Almassy, Richard Showalter, Jim Thomson
Journal: Cancer Research (2018)

Abstract TNF-related apoptosis-inducing ligand (TRAIL) receptor agonists have shown good safety profile and efficacy in preclinical cancer models. However, clinical success has been limited due to poor PK and/or development of resistance to death receptor-induced apoptosis. To address these issues we have conceived and produced a fusion protein of arginine deiminase (ADI) and TRAIL. ADI is an enzyme that converts arginine into citrulline. Arginine deprivation can inhibit growth of arginine auxotrophic cancers that lack key enzymes enabling normal cells to produce arginine from citrulline. ADI is currently being evaluated in clinical trials and is well-tolerated. We (and others) observed synergy between ADI and TRAIL in inducing apoptosis in a number of cancer cell lines including those that are otherwise resistant to rhTRAIL. We have explored potential mechanisms of synergy and will present our findings. Using in silico modeling we predicted structural complementarity between ADI and TRAIL with each modality stabilized when part of the fusion protein. We were able to produce multiple ADI-TRAIL fusion protein variants and have tested their activity in enzymatic and cell-based assays. Our experimental data confirmed in silico predictions of the structural advantages for ADI and TRAIL in the fusion protein. ADI enzymatic activity improved when part of the fusion protein and the fusion protein appeared to have higher potency than the combination of the two separate proteins in inducing cancer cell death. In mice ADI-TRAIL fusion protein exhibited extended half-life and was efficacious in HCT116 xenograft model, superior to rhTRAIL administered at the same molar amounts. Serum concentrations of the fusion protein had an inverse correlation with the tumor volume. ADI-TRAIL is a novel biologic that benefits from structural and functional synergies between its components and is showing promise as a cancer therapeutic in preclinical studies. Citation Format: Elena Brin, Katherine Wu, Yudou He, Wei-Jong Shia, Mario M. Kuo, Li-Chang Chen, Eleanor Dagostino, Richard Hickey, Bob Almassy, Richard Showalter, Jim Thomson. A novel biologic ADI-TRAIL fusion protein benefits from structural and functional complementarity of its components arginine deiminase and TRAIL, induces cancer cell apoptosis in vitro, and inhibits tumor growth in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3902.
Abstract 5235: An investigation of the potential effects of the atypical PKC-ι inhibitor ICA-1 on ovarian cancer proliferation and survival, in estrogen dependent and independent systems
Authors: Tracess Smalley, Mildred Acevedo-Duncan
Journal: Cancer Research (2018)

Abstract Ovarian cancer is the most lethal gynecological cancer diagnosis. There is no efficient screening process for ovarian cancers and the average stage of diagnosis is stage III. Atypical PKCs (PKC-ζ and PKC-ι/λ) have been shown to be overexpressed in various malignant cells lines and to be linked to pathways for cellular proliferation and survival. Many investigations suggest that the hormone estrogen regulates cellular proliferation in an ERα dependent manner. Little research shows the effects of estrogen on ERα and β negative cells and its role in cellular proliferation. In this investigation, ovarian cell lines (HEY, COV644, T80) were treated with the atypical PKC-ι inhibitor ICA-1 nucleoside variant in two different systems, with and without estrogen, and assayed to determine the effects on proliferation and cellular survival. These assays included protein quantification, cell proliferation, and wound healing. Our preliminary data suggests that PKC-ι is a novel target in carcinogenesis and inhibition of this protein decreases the rate of proliferation. Our results also suggest that estrogen has a significant effect on cell proliferation, even in estrogen receptor negative cells. Citation Format: Tracess Smalley, Mildred Acevedo-Duncan. An investigation of the potential effects of the atypical PKC-ι inhibitor ICA-1 on ovarian cancer proliferation and survival, in estrogen dependent and independent systems [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5235.
Abstract LB-153: KY1055, a novel ICOS-PD-L1 bispecific antibody, efficiently enhances T cell activation and delivers a potent anti-tumour response in vivo
Authors: Richard C. Sainson, Nahida Parveen, Gwenoline Borhis, Miha Kosmac, Tracey OKell, Emma Taggart, Joana Carvalho, Matthew McCourt, Hanif Ali, Hannah Craig, Aksana Labokha
Journal: Cancer Research (2018)

Abstract Antibodies blocking the PD-1/PD-L1 axis present significant breakthroughs in the treatment of hitherto untreatable cancers. However, despite the highly encouraging progress that has been made, multiple tumour types demonstrate limited response to these therapies. The emerging picture is that combination with other therapies is required to improve response rates and/or the durability of response. Additional benefit could be achieved by combining an anti-PD-L1 approach with another modulator of T cell activation. ICOS is a co-stimulatory molecule expressed on activated T cells such as TEff and TReg cells present in the tumour microenvironment (TME). ICOS agonism has been demonstrated to improve TEff cell survival and IFNγ release, resulting in the activation of T cell-dependent eradication of the tumour. In addition, the high expression of ICOS observed on TReg cells in the TME allows these highly immunosuppressive cells to be selectively depleted when using the appropriate antibody format. With the aim of targeting both ICOS and PD-L1, we have developed a bispecific mAb² (KY1055) as a human IgG1 format that consists of fully human Fab arms targeting ICOS and a modified Fc (Fcab) containing binding sites to PD-L1. We demonstrate potent (single digit nM) binding to ICOS via the Fab and to PD-L1 via the Fcab. Furthermore, in vitro studies reveal that KY1055 can bridge together ICOS- and PD-L1-expressing cells and can activate ICOS signalling through this cross-presentation. Functionality of the Fcab was validated by demonstrating that it blocks the PD-1-PD-L1 inhibitory pathway, resulting in the up-regulation of IFNγ in monocyte:T cell co-culture assays. We also demonstrate the ability of KY1055 to deplete ICOShigh cells in vitro by ADCC. In vivo, we confirm the anti-tumour efficacy of KY1055 in several syngeneic models that are poorly responsive to the respective monotherapies and further demonstrate improved anti-tumour efficacy when combined with anti-CTLA4 and anti-PD-1 in vivo. Finally, we demonstrate that KY1055 depletes TRegs and improves the TEff : TReg ratio in vivo in a CT26 model of tumour growth. Altogether, these data warrant further development of KY1055 for the treatment of solid tumours. Citation Format: Richard C. Sainson, Nahida Parveen, Gwenoline Borhis, Miha Kosmac, Tracey OKell, Emma Taggart, Joana Carvalho, Matthew McCourt, Hanif Ali, Hannah Craig, Aksana Labokha. KY1055, a novel ICOS-PD-L1 bispecific antibody, efficiently enhances T cell activation and delivers a potent anti-tumour response in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-153.
Nitric Oxide Regulates Transforming Growth Factor-β Signaling in Endothelial Cells
Authors: MartaSaura, CarlosZaragoza, BeatriceHerranz, MercedesGriera, LuisaDiez-Marqués, DiegoRodriguez-Puyol, ManuelRodriguez-Puyol
Journal: Circulation Research (2005)

Many forms of vascular disease are characterized by increased transforming growth factor (TGF)-β1 expression and endothelial dysfunction. Smad proteins are a key step in TGF-β–initiated signal transduction. We hypothesized that NO may regulate endothelial TGF-β–dependent gene expression. We show that NO inhibits TGF-β/Smad–regulated gene transactivation in a cGMP-dependent manner. NO effects were mimicked by a soluble analogue of cGMP. Inhibition of cGMP-dependent protein kinase 1 (PKG-1) or overexpression of dominant-negative PKG-1α suppressed NO/cGMP inhibition of TGF-β–induced gene expression. Inversely, overexpression of PKG-1α catalytic subunit blocked TGF-β–induced gene transactivation. Furthermore NO delayed and reduced phosphorylated Smad2/3 nuclear translocation, an effect mediated by PKG-1, whereas NG-nitro-l-arginine methyl ester augmented Smad phosphorylation and gene expression in response to TGF-β. Aortas from endothelial NO synthase–deficient mice showed enhanced basal TGF-β1 and collagen t...
Abstract 260: Apigenin nanoparticle suppresses sphere formation in CD133+/ALDH1high prostate cancer stem cells through downregulation of stem cell markers
Authors: Rajnee Kanwal, Sanjeev Shukla, Agata A. Exner, Andreas G. Tzakos, Sanjay Gupta
Journal: Cancer Research (2018)

Abstract The recurrence of prostate cancer after definitive treatment(s) is thought to be due to the potential of rare cancer stem cells (CSCs) to withstand therapy and initiate tumor formation. CSCs are a subpopulation of cancer cells capable of self-renewal and plastic adaptation mediating tumorigenesis, metastasis, and therapy resistance. CSCs are associated with cancer progression and clinical outcome in cancer patients. In the present study, we isolated CSCs from various human prostate cancer 22Rv1, DU145 and PC-3 cells by applying selection of cluster of differentiation 133 cell surface marker and high ALDH1 activity (CD133+/ALDH1high). Next we aimed to identify CD133+/ALDH1high CSCs isolated from human prostate cancer cells and compare their profiles with non-CSCs as bulk counterparts of the population. Subsequently, the CSC population continued to grow in the three-dimensional multicellular spheroids. Differentiation investigated with stem cell-related genomic characteristics exhibited significant increase in genes viz. CD44, Nanog, β-catenin, c-Myc, SOX2 and Oct4 in CSCs at the message level. In further studies we determine the effect of natural plant flavone apigenin on CSC population. Apigenin is abundantly present in common fruits and vegetables and possess remarkable anticancer, anti-angiogenic and anti-metastatic properties. Apigenin loaded polyethylene glycol nanoparticles (Ap-NP) was characterized for particle size, morphology, zeta potential, drug release and encapsulation. Cellular entry and intracellular localization of Ap-NP were assessed by transmission electron microscopy. Treatment of CD133+/ALDH1high CSCs with Ap-NP inhibited cell viability and sphere formation at higher extent in time dependent manner, compared to the non-CSCs counterparts. Furthermore, Ap-NP exposure resulted in the downregulation of Nanog, β-catenin, c-Myc, SOX2 and Oct4 in the CSCs. Taken together, our study demonstrate overexpression of potential CSC markers and the ability to target these CSCs by the use of non-toxic agent apigenin killing this rare population that may lead to the total abolition of tumor recurrence and/or metastasis. Citation Format: Rajnee Kanwal, Sanjeev Shukla, Agata A. Exner, Andreas G. Tzakos, Sanjay Gupta. Apigenin nanoparticle suppresses sphere formation in CD133+/ALDH1high prostate cancer stem cells through downregulation of stem cell markers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 260.
Abstract 1422: NEBNext Direct® Custom Ready myeloid genes for NGS target enrichment
Authors: Scott M. Adams, Kruti M. Patel, Amy B. Emerman, Sarah K. Bowman, Charles D. Elfe, Evan Mauceli, Andrew Barry, Theodore Davis, Cynthia L. Hendrickson
Journal: Cancer Research (2018)

Abstract Comprehensive genetic evaluation of patients with blood cancer can be imperative for identifying and classifying myeloid malignancies in a patient. Since liquid tumors comprise of highly variable percentages of normal cells or multiple tumor clones, this type of screening is critical for early stage disease patients where a cytogenetic profile informs diagnosis or disease stratification, prognosis, and treatment options. For patients with late-stage disease, genetic testing can assist in choosing options for alternative treatments, including targeted therapies. Thus, next generation sequencing technologies are needed that can provide the sensitivity and specificity to identify these genetic complexities. Here we introduce a selection of over 50 genes from the NEBNext Direct® Custom Ready gene catalog that are known to be involved in myeloid malignancies. The NEBNext Direct® technology uses a novel approach to selectively enrich nucleic acid targets, and rapid customized panels can be generated by combining one to several hundred genes from the Custom Ready catalog. Unlike alternative hybridization methods, NEBNext Direct® does not require upfront library preparation. The approach rapidly hybridizes both strands of genomic DNA to biotinylated baits, captures the targets on streptavidin beads, enzymatically removes off-target sequence, and directly converts captured molecules into Illumina-compatible sequencing libraries in a single day protocol. A 12-base unique molecular identifier (UMI) tags each individual molecule prior to the final PCR amplification to enable identification of PCR duplicates, and an 8-base barcode is added to each library during PCR for high-throughput pooling. With 100ng of DNA input the panel provides highly uniform coverage and approximately 95% of sequence reads map to the targeted myeloid genes. The NEBNext Direct® Custom Ready myeloid genes demonstrate a high-throughput and cost-effective approach for the rapid and sensitive analysis of exon coding regions (~200kb) for over 50 oncogenic genes important in the pathogenesis of these types of blood disorders. These gene mutations are powerful prognostic markers that can be used as a guide for effective patient management. Citation Format: Scott M. Adams, Kruti M. Patel, Amy B. Emerman, Sarah K. Bowman, Charles D. Elfe, Evan Mauceli, Andrew Barry, Theodore Davis, Cynthia L. Hendrickson. NEBNext Direct® Custom Ready myeloid genes for NGS target enrichment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1422.
Abstract 3741: Deciphering the regulome of androgen receptor variants in prostate cancer
Authors: Mark L. Daniel, Theresa E. Hickey, Jason S. Carroll, Wayne D. Tilley, Luke A. Selth, Scott M. Dehm
Journal: Cancer Research (2018)

Abstract Prostate cancer is an androgen-dependent disease. Androgen function is controlled by the androgen receptor (AR), and treatments targeting AR are effective at preventing disease progression. Despite this, resistance and emergence of castration resistant prostate cancer (CRPC) is responsible for virtually all prostate cancer-related death. Constitutively active AR variants (AR-Vs) have been implicated as drivers of CRPC. AR-Vs consist of the unstructured AR NH2-terminal domain (NTD), and the AR DNA binding domain, but lack the ligand binding domain (LBD), which is targeted by all current therapies. While our understanding of proteins that regulate the AR LBD is mature, there is less known about the molecular regulation of the NTD. This represents a gap in knowledge given that the AR NTD is essential for AR/AR-V transcriptional activity. To address this, we used a technique termed Rapid Immunoprecipitation Mass spectrometry of Endogenous proteins (RIME) with a pair of isogenic prostate cancer cell lines that were manipulated via genome engineering to express either full-length AR or AR-V. RIME identified several candidate proteins that interact with the AR NTD including BCL9, a β-catenin transcriptional coactivator. Interrogation of public databases revealed that BCL9 mRNA is overexpressed in metastatic prostate cancer compared with localized disease. Additionally, knockdown of BCL9 in cell lines expressing full-length AR inhibited expression of AR target genes as well as β-catenin target genes. Interestingly, knockdown of BCL9 did not affect these same genes in cell lines expressing AR-Vs, indicating that AR truncation could represent a mechanism of escape from BCL9 regulation. Collectively, these findings identify a new mechanism of AR regulation by BCL9 in prostate cancer. Citation Format: Mark L. Daniel, Theresa E. Hickey, Jason S. Carroll, Wayne D. Tilley, Luke A. Selth, Scott M. Dehm. Deciphering the regulome of androgen receptor variants in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3741.
Abstract 2482: RanBP17 retards the epithelial-mesenchymal transition (EMT) and malignant progression of glioblastoma cells by regulating the exportation of beta-catenin from cell nucleus
Authors: Yi Wang, Penyi Guo, Xiaozai Xie, Sina Zhang, Haitao Yu, Lijun Wu, Ziyan Chen, Gang Chen
Journal: Cancer Research (2018)

Abstract Background: Glioblastoma multiforme (GBM) is the most common and lethal primary human brain tumor and exhibits multiple molecular aberrations. In this study, we attempted to explore the role of a nuclear transport receptor RanBP17 in carcinogenesis and its underlying mechanisms in GBM. Methods: The relevant information retrieved from the Human Integrated Protein Expression Database (HIPED), TCGA, and Rembrandt was analyzed to evaluate and compare RanBP17 expression in various tissues and cancer types. Next U87 and U251 were used to investigate the effects of RPS15A on epithelial-mesenchymal transition (EMT) and malignant behaviors of glioma cells. Further, RPS15A-associated signaling pathways were screened based on the data from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database and verified by using RT-PCR and Western blot (WB) assays. Results: RanBP17 was highly expressed in normal brain tissue, and loss or downregulation of RanBP17 was observed in GBM tissue (83/105, 79.05%) and associated with worse survival of patients. Overexpression of RanBP17 suppressed proliferation, migration and invasion of GBM cells in vitro and remarkably inhibited tumor growth in vivo. In addition, RanBP17 silencing promoted EMT of glioma cells via activating the expression of transcriptional factor Snail. Further experiments confirmed that RanBP17 overexpression promoted the export of β-catenin from cell nuclei and retarded wnt/β-catenin signaling. Conversely, knockdown of RanBP17 gene resulted in accumulation of β-catenin in glioblastoma cell nuclei, which, in turn, promoted expression of EMT-related proteins and malignant progression of glioblastoma by combining other transcript genes. Conclusions: RanBP17 expression is significantly lower in GBM compared to normal brain tissue. Silencing RanBP17 accelerates the EMT process and malignant progression of glioblastoma due to the suppressed export of β-catenin from glioblastoma cell nuclei and the resulting inhibition of wnt/β-catenin signaling. Therefore, loss or downregulation of RanBP17 can be considered a negative prognostic factor for survival of GBM patients. Citation Format: Yi Wang, Penyi Guo, Xiaozai Xie, Sina Zhang, Haitao Yu, Lijun Wu, Ziyan Chen, Gang Chen. RanBP17 retards the epithelial-mesenchymal transition (EMT) and malignant progression of glioblastoma cells by regulating the exportation of beta-catenin from cell nucleus [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2482.
Abstract 13036: Pressure and Pulsatility Jointly Impact the Prognosis of Stroke
Authors: Shao-YuanChuang, Hong-MinCheng, Chyi-HueyBai, Wen-TingYeh, Jiunn-RongChen, Wen-HarnPan
Journal: Circulation (2014)

Introduction: High blood pressure is major cause of cardiovascular events. Pulsatility of vessel velocity may associate with cardiovascular events. However, the combined effect of blood pressure and pulsatility for stroke remain unclear. Hypothesis: Therefore, we investigated the joined influence of central blood pressure and pulsatility index for cardiovascular events. Methods: Baseline data from 2063 adults (30 years or older) in the Cardiovascular Diseases Risk Factor Two-Township Study were linked to incidental total stroke status derived from insurance claims and death certificate records. Hazard ratios for risk of total stroke for high central systolic blood pressure (CSBP) and high plausibility index (PI) was calculated by peak systolic velocity, end diastolic velocity and mean vessel velocity which measured in common carotid artery were calculated using Cox proportional hazard models. Results: With 9.81 years (median) of follow-up, 139 persons had stroke develop. The incidence rates of stroke were...
Abstract 3305: Cell-of-origin differentiation stages define methylation-based subtypes of human colorectal adenomas and carcinomas
Authors: Felix Bormann, Manuel Rodríguez-Paredes, Felix Lasitschka, Dominic Edelmann, Axel Benner, Yehudit Bergman, Claudia R. Ball, Hanno Glimm, Heinz G. Linhart, Frank Lyko
Journal: Cancer Research (2018)

Abstract Introduction: Colorectal adenomas are precursor lesions of colorectal cancers and represent clonal amplifications of single cells from colonic crypts. DNA methylation patterns specify cell-type identity during cellular differentiation and therefore provide novel opportunities for tumor subclassification and patient stratification. Methods: Infinium 450k and EPIC data from of non-malignant colorectal adenomas was applied to a consensus clustering algorithm. This defined epigenetic subtypes that were subsequently tested for clinico-pathological features, such as morphology and mutation status. Additionally, the subtypes were compared with Infinium 450k data from colonic crypt sections and also colorectal cancer samples provided by The Cancer Genome Atlas. Finally, clinical significance was addressed by testing for subtype specific overall survival rates. Results: The analysis of the adenoma dataset defined 3 distinct epigenetic subtypes of human premalignant lesions. These 3 subtypes also reflect 3 of 4 epigenetic subtypes identified in colorectal cancer. The fourth, cancer-specific subtype represents the previously known subclass defined by microsatellite instability phenotype and the CpG island methylator phenotype. Comparisons to Crypt section methylomes and to other reference methylomes revealed that the other 3 subtypes represent epigenetic programs reflecting various intestinal crypt cell differentiation stages. Patient survival correlated with the differentiation stages with a particular poor prognosis for patients with stem cell-related epigenetic signatures. Conclusion: Our results establish a novel and clinically relevant approach for colorectal adenoma and cancer classification and illustrate how differences in the cell-type of origin shape the tumor methylome. Citation Format: Felix Bormann, Manuel Rodríguez-Paredes, Felix Lasitschka, Dominic Edelmann, Axel Benner, Yehudit Bergman, Claudia R. Ball, Hanno Glimm, Heinz G. Linhart, Frank Lyko. Cell-of-origin differentiation stages define methylation-based subtypes of human colorectal adenomas and carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3305.