tbuckley/cabot-search huggingface dataset:
Abstract 5244: Partial knockdown of RLIP76 prevents cancer susceptibility of p53 null mice
Authors: Sharad S. Singhal, Jyotsana Singhal, Joshua Tompkins, David Horne, Xiwei Wu, Arthur Riggs, Sanjay Awasthi
Journal: Cancer Research (2017)

Abstract P53 is a stress-responsive, genome protective, tumor suppressor whose functions are lost or altered in nearly all neoplasia. P53 homozygous knockout mice (p53-/-) develop spontaneous lymphoma and other malignancies in nearly 100% of cases by 6 months of life. In stark contrast, homozygous gene knockout of the stress-responsive, anti-apoptotic, mercapturic acid pathway transporter protein, RLIP76, results in marked protection from chemical carcinogenesis. P53 expression and activation is regulated by intermediary metabolites of this pathway, and p53 regulates the expression of key enzymes of this pathway. P53 can directly bind to RLIP76 through a CDK-interaction domain, and inhibit its transport activity as well as endocytosis stimulatory activity. These results indicate that RLIP76 is an effector of p53 in a manner analogous to its known function as the first known effector of the Ral pathways that regulate membrane plasticity, motility and invasion. This translates into reduced kinase signaling down-stream of membrane-receptor/ligand interactions. An inverse relationship between RLIP76 and p53 protein and mRNA expression has been observed in-vitro, and is confirmed by analysis of human cancer genomic analyses in the COH database. RLIP76 depletion causes apoptosis in cancer cells independent of p53 status, strengthening the view that RLIP76 is key down-stream effector of p53. We reasoned that if RLIP76 is necessary for cancer to develop in p53-deficient animals, its suppression will reduce the incidence of malignancy in 12-week old p53-/- mice treated with COHSA007 phosphorothioated antisense, 200 μg i.p.q.2wk till age 8 months. Results of our studies confirmed these predictions, since 4/4 scrambled antisense treated p53-/- mice developed T-cell lymphoma whereas 8/8 COHSA007 treated p53-/- mice survived to the end of the experiment without development of any malignancy. These findings demonstrate that RLIP76 is required for malignancy in the p53-/- mice. Taken in context of our previous studies showing that RLIP76-/- mice are highly resistant to inflammation and carcinogenesis in chemical carcinogenesis models of the skin and lung, the present findings strongly support the idea of an existential role of RLIP76 in the malignant phenotype, and strengthen the rationale for using targeted systemic depletion of RLIP76 for treatment of human neoplasia (Supported in part by the Department of Defense grant (W81XWH-16-1-0641) and USPHS grant CA 77495). Citation Format: Sharad S. Singhal, Jyotsana Singhal, Joshua Tompkins, David Horne, Xiwei Wu, Arthur Riggs, Sanjay Awasthi. Partial knockdown of RLIP76 prevents cancer susceptibility of p53 null mice [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 5244. doi:10.1158/1538-7445.AM2017-5244
Abstract 1937: Evolution of neuroblastoma patient-derived orthotopic xenografts through space and time
Authors: Noémie Braekeveldt, Susanne Fransson, Kristoffer von Stedingk, Ingrid Öra, Rosa Noguera, Tommy Martinsson, David Gisselsson Nord, Sven Påhlman, Daniel Bexell
Journal: Cancer Research (2017)

Abstract Background Recently, we established orthotopic neuroblastoma patient-derived xenografts (PDXs) which maintain the phenotypic, genomic, and stromal hallmarks of patient tumors. Here we examined how PDXs evolve following years of in vivo growth. Materials and Methods We established up to eight in vivo generations of neuroblastoma orthotopic PDXs through serial passaging in NSG mice. RNA sequencing, exome sequencing and SNP array analysis were used to analyze patient tumors and PDXs from different in vivo generations. Results Using SNP analysis, we found mostly a remarkable genomic stability at chromosomal level between patient tumors, early and late PDX generations. RNA-seq revealed that patient tumors expressed higher levels of genes involved in immune responses and ECM metabolism compared to PDXs. Different PDX samples clustered correctly into their respective tumor type. PDXs from all early generations did not separate from PDXs from late generations. Thus, gene expression levels are surprisingly often quite stable despite years of in vivo growth. To shed light on neuroblastoma intratumor heterogeneity, we implanted 10 different tumor fragments from a single patient tumor into mice. We classified the 10 mice into three groups based on the time periods required for tumor growth. RNA-seq showed that each of these groups had a distinct gene expression profile and pathways involved in neuroblastoma progression have been identified. Conclusions Neuroblastoma orthotopic PDXs are often very stable at chromosomal and gene expression levels despite years of in vivo growth. We utilized multiple PDXs to show functional intratumor heterogeneity coupled to distinct gene expression profile. Citation Format: Noémie Braekeveldt, Susanne Fransson, Kristoffer von Stedingk, Ingrid Öra, Rosa Noguera, Tommy Martinsson, David Gisselsson Nord, Sven Påhlman, Daniel Bexell. Evolution of neuroblastoma patient-derived orthotopic xenografts through space and time [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 1937. doi:10.1158/1538-7445.AM2017-1937
Effect of Endovascular Contact Aspiration vs Stent Retriever on Revascularization in Patients With Acute Ischemic Stroke and Large Vessel Occlusion
Authors: Bertrand Lapergue, Raphael Blanc, Benjamin Gory, Julien Labreuche, Alain Duhamel, Gautier Marnat, Suzana Saleme, Vincent Costalat, Serge Bracard, Hubert Desal, Mikael Mazighi, Arturo Consoli, Michel Piotin
Journal: JAMA (2017)

<h3>Importance</h3> The benefits of endovascular revascularization using the contact aspiration technique vs the stent retriever technique in patients with acute ischemic stroke remain uncertain because of lack of evidence from randomized trials. <h3>Objective</h3> To compare efficacy and adverse events using the contact aspiration technique vs the standard stent retriever technique as a first-line endovascular treatment for successful revascularization among patients with acute ischemic stroke and large vessel occlusion. <h3>Design, Setting, and Participants</h3> The Contact Aspiration vs Stent Retriever for Successful Revascularization (ASTER) study was a randomized, open-label, blinded end-point clinical trial conducted in 8 comprehensive stroke centers in France (October 2015-October 2016). Patients who presented with acute ischemic stroke and a large vessel occlusion in the anterior circulation within 6 hours of symptom onset were included. <h3>Interventions</h3> Patients were randomly assigned to first-line contact aspiration (n = 192) or first-line stent retriever (n = 189) immediately prior to mechanical thrombectomy. <h3>Main Outcomes and Measures</h3> The primary outcome was the proportion of patients with successful revascularization defined as a modified Thrombolysis in Cerebral Infarction score of 2b or 3 at the end of all endovascular procedures. Secondary outcomes included degree of disability assessed by overall distribution of the modified Rankin Scale (mRS) score at 90 days, change in National Institutes of Health Stroke Scale (NIHSS) score at 24 hours, all-cause mortality at 90 days, and procedure-related serious adverse events. <h3>Results</h3> Among 381 patients randomized (mean age, 69.9 years; 174 women [45.7%]), 363 (95.3%) completed the trial. Median time from symptom onset to arterial puncture was 227 minutes (interquartile range, 180-280 minutes). For the primary outcome, the proportion of patients with successful revascularization was 85.4% (n = 164) in the contact aspiration group vs 83.1% (n = 157) in the stent retriever group (odds ratio, 1.20 [95% CI, 0.68-2.10];<i>P</i> = .53; difference, 2.4% [95% CI, −5.4% to 9.7%]). For the clinical efficacy outcomes (change in NIHSS score at 24 hours, mRS score at 90 days) and adverse events, there were no significant differences between groups. <h3>Conclusions and Relevance</h3> Among patients with ischemic stroke in the anterior circulation undergoing thrombectomy, first-line thrombectomy with contact aspiration compared with stent retriever did not result in an increased successful revascularization rate at the end of the procedure. <h3>Trial Registration</h3> clinicaltrials.gov Identifier:NCT02523261
Abstract 5089: Antitumor activities elicited by direct intratumoral administration of a recombinant adenovirus expressing either IL-28A/IFN-λ2 or IL-29/IFN-λ1
Authors: Muneo Numasaki, Hiroki Tsukamoto, Yoshihisa Tomioka
Journal: Cancer Research (2017)

Abstract Interleukin (IL)-28A/IFN-λ2 and IL-29/IFN-λ1 have been demonstrated to elicit direct and indirect antitumor actions. In this study, we constructed an adenovirus vector expressing either IL-28A/IFN-λ2 (AdIL-28A) or IL-29/IFN-λ1 (AdIL-29) to evaluate the therapeutic properties of intratumoral injection of recombinant adenovirus to apply for the clinical implementation of cancer gene therapy. Despite the lack of antiproliferative effect on MCA205 and B16-F10 cells, a retarded growth of established subcutaneous tumors was observed following multiple injections of either AdIL-28A or AdIL-29 when compared with AdNull. In vivo cell depletion experiments displayed that both NK cells and CD8+ T cells play a major role in AdIL-28A-mediated tumor growth suppression. A significant increase in the number of infiltrating CD8+ T cells into the tumors treated with either AdIL-28A or AdIL-29 was observed. Moreover, specific antitumor cytotoxic T lymphocyte reactivity was detected in spleen cells from animals treated with either AdIL-28A or AdIL-29. In IFN-γ deficient mice, the antitumor activity of AdIL-28A was completely impaired, indicating that IFN-γ is critically involved in the tumor growth inhibition triggered by AdIL-28A. IL-12 provided an additive antitumor effect when combined with AdIL-28A. These results indicate that AdIL-28A and AdIL-29 could be successfully utilized as an alternative cancer gene therapy. Note: This abstract was not presented at the meeting. Citation Format: Muneo Numasaki, Hiroki Tsukamoto, Yoshihisa Tomioka. Antitumor activities elicited by direct intratumoral administration of a recombinant adenovirus expressing either IL-28A/IFN-λ2 or IL-29/IFN-λ1 [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 5089. doi:10.1158/1538-7445.AM2017-5089
Abstract 1441: A comprehensive cis-eQTL analysis revealed target genes in breast cancer susceptibility loci identified in genome-wide association studies
Authors: Xingyi Guo, Weiqiang Lin, Qiuyin Cai, Jiajun Shi, Yaqiong Sun, Xiao Pan, Mi-Ryung Han, Wanqing Wen, Bingshan Li, Jirong Long, Jianghua Chen, Wei Zheng
Journal: Cancer Research (2017)

Abstract Genome-wide association studies (GWAS) have identified approximately 107 common single nucleotide polymorphisms (index SNPs) for breast cancer risk. The target genes and underlying mechanisms for the large majority of the identified associations remain unknown. We conducted a cis-expression quantitative trait loci (cis-eQTL) analysis using transcriptome data from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) (N = 1,981), The Cancer Genome Atlas (TCGA) (N = 458), and the Genotype-Tissue Expression (GTEx) project (N = 183). We identified a total of 58 genes including SSBP4 at Benjamini-Hochberg adjusted P &amp;lt; 0.05 in at least one dataset and another gene, PAX9, at P &amp;lt; 0.05 with consistent association directions in all three datasets. Using data from the Encyclopedia of DNA Elements (ENCODE), we selected functional SNPs and showed that some alternative alleles could significantly change promoter activities of their target genes compared to reference alleles using luciferase reporter assays. The effects of target gene expression for those alleles were in line with eQTL observations. In addition, we validated the genes SETD9 and SSBP4 using Sequenom allelotype technique from 235 adjacent normal breast tissues and observed the allelic-specific expression associated with their index SNPs. This study revealed novel biological mechanisms for associations of genetic susceptibility risk loci for breast cancer. Citation Format: Xingyi Guo, Weiqiang Lin, Qiuyin Cai, Jiajun Shi, Yaqiong Sun, Xiao Pan, Mi-Ryung Han, Wanqing Wen, Bingshan Li, Jirong Long, Jianghua Chen, Wei Zheng. A comprehensive cis-eQTL analysis revealed target genes in breast cancer susceptibility loci identified in genome-wide association studies [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 1441. doi:10.1158/1538-7445.AM2017-1441
Abstract 1912: Actn4, a novel therapeutic target of dietary ellagic acid, promotes breast cancer metastasis <i>via</i> mediating cancer stem cells
Authors: Neng Wang, Zhiyu Wang, Xiaoming Xie
Journal: Cancer Research (2017)

Abstract Purpose: Pharmacology-based target identification has become a novel stratey leading to the discovery of novel pathological biomarkers. Ellagic acid (EA), a dietary polyphenol compound, exhibits potent anticancer activities, whereas the underlying mechanisms remain unclear. This study sought to determine the role and regulation of ACTN4 expression in human breast cancer metastasis and EA-based therapy. Experimental Design: The anti-metastasis ability of EA was validated by MMTV-PyMT mice and in vitro cell models. Drug affiity responsive target stability (DARTS) was utilized to identify ACTN4 as the direct target of EA in breast breast cancer stem cells (CSCs). The metastatic regulated mechanisms of ACTN4 were assessed by CSC-related assays including mammosphere formation, tumorigenic ability, reattachment differentiation and signaling pathway analysis. The clinical significance of ACTN4 was based on human tissue microarray analysis and TCGA database exploration. Results: EA inhibited breast cancer growth and metastasis via directly targeting ACTN4 in vitro and in vivo, accompanied with limited CSCs population. ACTN4 knockdown resulted in blockage of malignant cell proliferation, colony formation and ameliorated metastasis potency. ACTN4 positive CSCs exhibited higher ESA+ proportion, increased mammosphere-formation ability, as well as enhanced in vivo tumorigenesis ability. Increased ACTN4 expression was directly associated with later cancer stage, increased incidence of metastasis, and poor overall survival period. Conclusions: ACTN4 plays an important role in breast CSCs-related metastasis and is a novel therapeutic target of EA treatment. Note: This abstract was not presented at the meeting. Citation Format: Neng Wang, Zhiyu Wang, Xiaoming Xie. Actn4, a novel therapeutic target of dietary ellagic acid, promotes breast cancer metastasis via mediating cancer stem cells [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 1912. doi:10.1158/1538-7445.AM2017-1912
Abstract 3233: Design and synthesis of BPR1K653 and its derivatives targeting the back pocket of Aurora kinases for selective isoform inhibition
Authors: Ya-Hui Chi, Chun-Ping Chang, Yi-Yu Ke, Wen-Hsing Lin, Hsing-Pang Hsieh
Journal: Cancer Research (2017)

Abstract Guided by computational modeling addressing the back pocket of Aurora kinases, several novel chemical analogs of BPR1K653 were designed and synthesized in two steps with 30-66% yields. All synthesized compounds were evaluated by Aurora-A and Aurora-B enzymatic kinase activity assays, cellular phosphorylation inhibition assays and cell viability assays. Of them, compound 3a that exhibits no substitution at phenylurea showed similar inhibition activity to Aurora-A and -B. Compounds 3b and 3c which harbor tertiary amino group at meta position of phenylurea showed 10-15 fold inhibition selectivity for Aurora-A over Aurora-B in enzymatic assays. In addition, 3b and 3c were more than 200 fold superior in inhibiting T-loop autophosphorylation of Aurora-A compared to Aurora-B in HCT116 colon carcinoma cells. On the other hand, compound 3d with a 4-hydroxypiperidinyl group at ortho position preserves Aurora-B inhibition activity. Molecular docking study revealed that the various steric interaction between the compound and residues in the back pocket of Aurora kinases determines their inhibition selectivity. Citation Format: Ya-Hui Chi, Chun-Ping Chang, Yi-Yu Ke, Wen-Hsing Lin, Hsing-Pang Hsieh. Design and synthesis of BPR1K653 and its derivatives targeting the back pocket of Aurora kinases for selective isoform inhibition [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 3233. doi:10.1158/1538-7445.AM2017-3233
Abstract 3917: GenoCTC, a liquid biopsy device using microfluidic enrichment for affinity-based isolation of circulating tumor cells
Authors: Jiyeon Ryu, Do Hyung Kim, Gyeong-Mi Kim, Jin Soo Kim, Youngkee Shin, Jaeku Lee, Hun Seok Lee
Journal: Cancer Research (2017)

Abstract To achieve a complete remission of cancer is still challenging that most patients with solid cancer ultimately experience metastasis. Detection of circulating tumor cells (CTCs) from the peripheral blood is promising key to solve the cancer cell dissemination and make accurate diagnosis, therefore, many efforts have been made to isolate the CTCs. Here, we newly developed the liquid biopsy device, GenoCTC, with microfluidic chips isolating CTCs from the patient whole blood. To isolate CTCs, EpCAM+ CTCs in the whole blood are first bound with magnetic beads conjugated with human-EpCAM antibody, and GenoCTC and its chip can isolate the EpCAM+ CTCs through magnetic based method. With 7.5 mL whole blood from lung cancer patient, we isolated EpCAM+ CTCs, and these CTCs were validated by immunofluorescence assay using anti-CK and anti-CD45. We also enumerated EpCAM+ CTCs in 17 whole blood samples from 10 lung cancer patients that various number, 2 to 114, of CTCs were found from each patient. The number of CTCs is known to have a correlation with disease progression and chemo-resistance, so the clinical meaning of this result is needed to be investigated. Furthermore, some CTCs are also found to be EpCAM independent which is regarded to have clinical utility involved in EMT. We used plastin-3 as its marker, and it was confirmed with HS 578T breast cancer cell line which shows low expression of EpCAM but high expression of plastin-3. The various molecules expressed on CTCs can be isolated with GenoCTC for further study. The characterization of CTCs is not only limited to EpCAM expression that it is important to be elucidated the complex biology of CTCs to apply companion diagnosis for personalized medicine. Citation Format: Jiyeon Ryu, Do Hyung Kim, Gyeong-Mi Kim, Jin Soo Kim, Youngkee Shin, Jaeku Lee, Hun Seok Lee. GenoCTC, a liquid biopsy device using microfluidic enrichment for affinity-based isolation of circulating tumor cells [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 3917. doi:10.1158/1538-7445.AM2017-3917
Abstract 1373: The role of the ASH1L SET domain in leukemogenesis
Authors: David Rogawski, Hongzhi Miao, Katarzyna Kempinska, Lili Chen, Jen Chase, Ann Friedman, Xiaomei Yan, Kenichi Nishioka, Gang Huang, Patricia Ernst, Andy Muntean, Ivan Maillard, Tomasz Cierpicki, Jolanta Grembecka
Journal: Cancer Research (2017)

Abstract ASH1L (absent, small, or homeotic-like 1) is a histone lysine methyltransferase (KMTase) specific for histone 3, lysine 36 that has an emerging role in multiple types of cancer. During development, ASH1L activates HOX genes and regulates self-renewal potential of long-term hematopoietic stem cells. Interestingly, HOX genes are oncogenic drivers in a variety of cancer types. For example, overexpression of HOXA9 is highly associated with a poor prognosis in acute myeloid leukemia (AML). In addition, ASH1L is overexpressed in a variety of cancers, including breast and thyroid cancer, but its role in cancer remains poorly characterized. Recent data suggest that ASH1L promotes leukemogenesis in mixed-lineage leukemia by recruiting the MLL epigenetic regulator to target genes. However, ASH1L is a large protein with multiple chromatin-interacting domains, and which regions of the ASH1L protein are important in leukemia has not been reported. Specifically, the role of ASH1L’s KMTase activity in leukemogenesis remains unknown. To further investigate the function of ASH1L in leukemia, we knocked down expression of ASH1L in leukemia cell lines. We found that ASH1L knockdown slowed cell growth and caused a decrease in expression of HOXA genes and their collaborator MEIS1. To specifically investigate the role of ASH1L KMTase activity in leukemia, we used a mouse model with a targeted in-frame deletion of the ASH1L SET domain (ΔSET). ΔSET cells express a shorter version of ASH1L that does not contain the SET domain. We transduced bone marrow cells (BMCs) isolated from ΔSET and WT mice with several oncogenes relevant to AML to determine the role of the ASH1L SET domain in leukemic transformation. We found that ΔSET BMCs were significantly impaired in leukemic transformation compared to WT BMCs, as manifested by decreased colony-forming ability and reduced expression of HOXA genes. These findings suggest that the ASH1L SET domain plays an important role in leukemogenesis mediated by multiple different oncogenes. Future studies will further characterize ASH1L’s role in leukemia by identifying the complete set of genetic loci that it methylates and regulates, and will determine whether the ASH1L SET domain represents a viable therapeutic target. Citation Format: David Rogawski, Hongzhi Miao, Katarzyna Kempinska, Lili Chen, Jen Chase, Ann Friedman, Xiaomei Yan, Kenichi Nishioka, Gang Huang, Patricia Ernst, Andy Muntean, Ivan Maillard, Tomasz Cierpicki, Jolanta Grembecka. The role of the ASH1L SET domain in leukemogenesis [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 1373. doi:10.1158/1538-7445.AM2017-1373