tbuckley/cabot-search huggingface dataset:
Abstract 1216: Overcoming cisplatin resistance through the combination treatment with CK2 inhibitor, CX-4945, in gastric cancer
Authors: Hyun Myong Kim, Inhye Jeong, Kyu Hyun Park, Tae Soo Kim, Woo Sun Kwon, Hei-Cheul Jeung, Minkyu Jung, Sun Young Rha
Journal: Cancer Research (2017)

Abstract Platinum-based antineoplastic drugs are chemotherapeutic agents to usually treat gastric cancer (GC) include cisplatin. However, the majority of cancer patients will eventually relapse with cisplatin-resistant disease. Especially, increased DNA repair is drug targetable mechanism and useful in the treatment strategy of cisplatin-resistant cancer. Casein kinase 2 (CK2) has critical role of multiple cellular processes with DNA repair. For this reason, research for CK2 expression correlated with DNA repair mechanism is important in gastric cancer. Combination of cisplatin and CK2 inhibitor (CX-4945, also known as Silmitasertib, Senhwa Biosciences, USA) may improve cisplatin-induced DNA damage for GC treatment. In this study, we screened sensitivity of cisplatin and CX-4945 in 49 GC cell lines by MTT assay. For molecular profiling, we analyzed variants and gene expression using whole exome sequencing and RNA sequencing. RNA and protein expression of CK2 subunits (α/α’) using real-time RT-PCR and Western blot. Also, activity of CK2α was measured by ELISA. Combination treatment performed different schedules including concurrent and sequential. Synergistic effect was analyzed by Bliss Independence model. As CK2 profiling, CK2α’ mRNA expression was a tendency to correlated with CX-4945 sensitivity(p=0.0504). Moreover, CK2α’ protein expression was a correlated with CX-4945 sensitivity(p=0.0252). Other molecular profiling did not reveal any clear correlations. Twenty one (Group1: cisplatin extremely resistant and CK2 high, Group2: cisplatin intermediate resistant regardless of CK2 expression) cell lines were performed combination treatment. Both YCC-21 and YCC-28 cell lines show synergistic effect (+20% and +22%, respectively) in concurrent schedule. Only MKN-74 cell line show synergistic effect (+11%) in Pre-addition. The 4 cell lines (YCC-18, YCC-38, SNU-1 and -216) were show synergistic effect (+10%, +37%, +11% and +19%, respectively) in Post-addition. In conclusion, early inhibition of CK2 shows synergistic effect in group 1, because CK2 is high expression. In group 2, late inhibition of CK2 demonstrated synergistic effect. It means CK2-related DNA repair is up-regulating for repair to cisplatin-induced DNA damage. Personalized the treatment schedule for inhibit CK2-induced DNA repair is a new strategy to restore cisplatin resistant in GC. Citation Format: Hyun Myong Kim, Inhye Jeong, Kyu Hyun Park, Tae Soo Kim, Woo Sun Kwon, Hei-Cheul Jeung, Minkyu Jung, Sun Young Rha. Overcoming cisplatin resistance through the combination treatment with CK2 inhibitor, CX-4945, in gastric 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 1216. doi:10.1158/1538-7445.AM2017-1216
Abstract 4688: AVID200: a novel computationally-designed TGF beta trap promoting anti-tumor T cell activity
Authors: Maureen D. O'Connor-McCourt, Anne E. Lenferink, John Zwaagstra, Traian Sulea, Catherine Collins, Renu Singh, Yves Durocher, Christiane Cantin, James Koropatnick
Journal: Cancer Research (2017)

Abstract AVID200 is a computationally-designed, avidity-enhanced, receptor ectodomain-based trap that binds and neutralizes TGF-beta 1 and 3 with low pM potency. Of the three TGF-beta isoforms, blockade of TGF-beta 2 has been shown to promote cancer metastasis. Therefore, AVID200 is designed to inhibit TGF-beta 1 and 3 only. TGF-beta is a strongly immunosuppressive molecule that, when expressed by cancers, mediates escape from immune surveillance. Increased TGF-beta ligand promotes cancer progression by suppressing anti-tumor immunity, predominantly by suppressing recruitment and activation of anti-tumor T cells. Consequently, TGF-beta is an important therapeutic target in cancer.AVID200 immunotherapy blocks the capacity of TGF-beta 1 and 3 ligands to interact with their receptors. That blockage induces T cell infiltration into tumors, thereby promoting a "T cell-inflamed" tumor state. Multiple trap formats with differing in vitro blocking potency, biophysical traits, and circulating half-lives in rodents have been designed, synthesized, and tested. On the basis of favorable characteristics, the AVID200 molecule was selected for in vivo assessment of efficacy in inhibiting growth of syngeneic 4T1 triple negative breast cancer (TNBC) homografts in immunocompetent host mice. In addition, CD4+ and CD8+ T cells isolated from draining lymph nodes of 4T1 tumor-bearing mice, treated and untreated with AVID200 and other candidate TGF-beta traps, were assessed for activities important in anti-tumor immune activity. We report that AVID200 immunotherapy decreased T-cell apoptosis, stimulated T-cell proliferation in response to tumor cell lysate-loaded dendritic cells, and enhanced the capacity of T-cells to specifically recognize and kill 4T1 tumor cells in ex vivo 2D cultures. The effect of combining AVID200 with immune checkpoint inhibitors in the treatment of syngeneic homografts in immune-competent mice is being assessed. AVID200 is a promising new immunotherapy to selectively inhibit the TGF-beta 1 and 3 isoforms, thereby enhancing desirable anti-tumor immunity while avoiding the tumor-promoting effects resulting from TGF-beta 2 neutralization. Citation Format: Maureen D. O'Connor-McCourt, Anne E. Lenferink, John Zwaagstra, Traian Sulea, Catherine Collins, Renu Singh, Yves Durocher, Christiane Cantin, James Koropatnick. AVID200: a novel computationally-designed TGF beta trap promoting anti-tumor T cell activity [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 4688. doi:10.1158/1538-7445.AM2017-4688
Abstract 5727: A functional polymorphism in DTX1 gene of Notch pathway predicts the prognosis of surgically resected non-small cell lung cancer
Authors: Shin Yup Lee, Janghyuck Lee, Kyung Min Shin, Ji Woong Son, Jae Yong Park
Journal: Cancer Research (2017)

Abstract Notch signaling pathway has been implicated in the prognosis of non-small cell lung cancer (NSCLC). This study was conducted to determine the association between single nucleotide polymorphisms (SNPs) in the Notch pathway genes and survival outcomes of surgically resected NSCLC. Among the 64 SNPs analyzed in the discovery set, 8 SNPs were significantly associated with overall survival (OS) or disease-free survival (DFS). Among the 8 SNPs, the association was consistently observed only for DTX1 rs1732786A&amp;gt;G in the validation sets. In combined analysis, the rs1732786A&amp;gt;G was significantly associated with better OS and DFS (adjusted HR aHR for OS, 0.81; 95% CI, 0.68-0.95; P = 0.01; aHR for DFS, 0.82; 95% CI, 0.72-0.94; P = 0.003; under codominant model). To verify the functional relevance of the rs1732786A&amp;gt;G in DTX1 promoter region, we conducted dual-luciferase reporter assays. The G allele showed significantly higher luciferase activity than the A allele (P &amp;lt; 0.005) in lung cancer cell lines. The relative expression level of DTX1 mRNA was significantly lower in tumor tissues than in nonmalignant lung tissue (P = 0.003). Moreover, the level of DTX1 mRNA expression in tumor tissue increased as the number of G allele increased (P trend = 0.02). Higher levels of DTX1 mRNA expression were significantly correlated with a better OS and DFS (P = 0.03 and P = 0.002). Our results suggest that the DTX1 rs1732786 A&amp;gt;G polymorphism may affect DTX1 expression and may be a useful marker for predicting the prognosis of patients with early stage NSCLC. Citation Format: Shin Yup Lee, Janghyuck Lee, Kyung Min Shin, Ji Woong Son, Jae Yong Park. A functional polymorphism in DTX1 gene of Notch pathway predicts the prognosis of surgically resected non-small cell lung 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 5727. doi:10.1158/1538-7445.AM2017-5727
Endoscopic ultrasound-guided gastrojejunostomy: a novel technique
Authors: Amy Tyberg, Manuel Perez-Miranda, Steven Zerbo, Todd Baron, Michel Kahaleh
Journal: Endoscopy (2017)

Endoscopic ultrasound (EUS)-guided gastroenterostomy with placement of a lumen-apposing metal stent has emerged as a novel, minimally invasive therapeutic option for patients with gastric outlet obstruction (GOO) [1] [2] [3]. The most challenging aspect of the procedure is immobilizing the jejunal loop in order to create the fistulous tract and deploy the stent. Several different techniques have been described [1] [2] [3]. We present a novel approach involving the use of a second endoscope that is advanced through a previously placed percutaneous gastrostomy (PEG) site to within the target jejunal lumen in order to provide traction on the wire, and to facilitate fistula creation and stent placement.
Abstract 2179: Targeted delivery of nanoparticulate cytochrome c into GL261 glioma cells through the proton-coupled folate transporter
Authors: Yuriy Kucheryavykh, Jescelica Ortiz-Rivera, Michael Inyushin, Luis Cubano, Moraima Morales-Cruz, Alejandra Cruz-Montañez, Kai Griebenow, Lilia Kucheryavykh
Journal: Cancer Research (2017)

Abstract In this study we identified the proton-coupled folate transporter (PCFT) as a route for targeted delivery of drugs to glioma cells. Using the techniques of confocal imaging, western blotting, and siRNA knockdown against the PCFT (encoded by the SLC46A1 gene), we demonstrated that Gl261 glioma cells, but not primary cultured astrocytes, express the PCFT, which provides selective internalization of folic acid (FA)-conjugated cytochrome c-containing nanoparticles (FA-Cyt c NPs), followed by glioma cell death. FA-Cyt c NPs, used at a concentration of 100 µg/ml, had no cytotoxic effects in astrocytes but caused 40% death in GL261 cells. Whole-cell patch clamp recording revealed FA-induced membrane currents, with maximum activity at pH 6.0, which is specific for the PCFT. Currents were reduced by siRNA PCFT knockdown in a similar manner as by application of FA-Cyt c NPs, indicating that the PCFT is a major carrier of FA and a route for internalization of FA-conjugated NPs in GL261 cells. We conclude that the PCFT provides a mechanism for targeted delivery of FA-conjugated nanodrugs to glioma cells with high specificity for GL261 cells, effectively causing apoptosis in these cells, and provides a starting point for the development of efficient methods for treating gliomas. The research was supported by NIH grants SC2GM102040, SC2GM095410, G12MD007583, R25GM110513, and US Department of Education Grant P031S130068. Citation Format: Yuriy Kucheryavykh, Jescelica Ortiz-Rivera, Michael Inyushin, Luis Cubano, Moraima Morales-Cruz, Alejandra Cruz-Montañez, Kai Griebenow, Lilia Kucheryavykh. Targeted delivery of nanoparticulate cytochrome c into GL261 glioma cells through the proton-coupled folate transporter [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 2179. doi:10.1158/1538-7445.AM2017-2179
Abstract 5467: Phosphoproteomic analysis of pyruvate dehydrogenase in response to environmental stress
Authors: Wendi O'Neill, Tereza Golias, Martin Benej, Nicholas Denko
Journal: Cancer Research (2017)

Abstract Pyruvate dehydrogenase is a mitochondrial enzyme that regulates the flux of carbohydrates into oxidative phosphorylation. The activity of PDH is largely regulated by reversible phosphorylation. The pyruvate dehydrogenase kinases add inhibitory phosphorylations to PDH on the E1α subunit at positions 232, 293, and 300. Interestingly, there is a family of 4 related PDHK genes with overlapping affinity for the 3 phosphorylation sites. PDHK1 and PDHK3 have been identified as hypoxia-inducible at the transcriptional level, and PDHK1 has been shown to be important for the growth of model tumors. This work attempts to more carefully define the functions of PDHK1 and 3 using CRISPR technology in colorectal cancer lines in vitro and genetically engineered mice in vivo. Using antibodies specific for the phosphorylated sites on E1α, we find that PDHK1 is essential for the phosphorylation of the 232 site in response to hypoxia and partially responsible for the hyperphosphorylation of 293 and 300. The level of phosphorylation in response to hypoxia is also sensitive to nutrients in the environment, with high levels of glucose enhancing E1α phosphorylation in hypoxia. Analysis of the number of phosporylations on individual E1α molecules using isoelectric focusing shows a range of events, with some molecules having 2 or 3 phosphorylations, while a large fraction of the E1α remains unphosphorylated in hypoxia. This type of pattern suggests a non-random phosphorylation of the multiple sites. Analysis of PDH activity supports the in vitro findings that any single phosphorylation event is sufficient to inhibit PDH complex activity. Preliminary mitochondrial oxygen consumption experiments show that colorectal cancer cells are less dependent on PDHK1 for regulating mitochondrial function compared to published data in pancreatic and head and neck cancer. Finally, analysis of PDH phosphorylation in mice supports a role for PDHK1 in the regulation of PDH activity in response to fasting and blood glucose levels. In conclusion, regulation of PDH in normal and cancerous colonocytes appears to be sensitive to environmental oxygen and nutrients. PDHK1 is the PDHK family member with the greatest influence on the addition of non-random inhibitory phosphorylation events. These in vitro findings will be analyzed with respect to the findings obtained using the new PDHK1 fl/fl villin Cre mouse. Citation Format: Wendi O'Neill, Tereza Golias, Martin Benej, Nicholas Denko. Phosphoproteomic analysis of pyruvate dehydrogenase in response to environmental stress [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 5467. doi:10.1158/1538-7445.AM2017-5467
Abstract 1291: Mutation analysis of endometrial cancer in a population-based study by targeted next-generation sequencing
Authors: Maxine Chen, Marta Crous-Bou, Michael J. Downing, Evan L. Busch, Kimberley Glass, Jennifer Prescott, George L. Mutter, Immaculata De Vivo
Journal: Cancer Research (2017)

Abstract Endometrial carcinoma (EC), a malignancy that arises from the epithelial lining of the uterus, is heterogeneous at histologic and molecular levels. Risk factors and outcomes also differ by type. Though prior studies characterized the genomic landscape of endometrial carcinoma, few integrated histologic, clinical, and prospectively collected epidemiologic data into the analysis. We collected formalin-fixed paraffin embedded tumor tissue from women enrolled in the Nurses’ Health Study who were diagnosed with EC between 1976 and 2012. We targeted 50 cancer related genes for high-throughput sequencing to identify genetic variants in 37 ECs and correlate findings with immunohistochemical, histologic, and epidemiologic data. Case selection was designed to include maximal power to discover genetic changes associated with p53 immunohistochemical status and clinical stage of disease at diagnosis. Mutations most frequently occurred in TP53 (57%), PTEN (46%), and PIK3CA (38%). TP53 mutations were seen in 83% of ECs that immunostained positive for mutant p53, with the most frequent TP53 mutations occurring in R248. Well-differentiated endometrioid tumors had elevated frequencies of PTEN and PIK3CA mutations compared to less differentiated tumors (p &amp;lt; 0.05). The mutation profiles of these samples are consistent with previous studies, supporting the viability of archival paraffin-embedded tissue in mutation detection. This study’s interdisciplinary approach to tumor characterization may help inform future development of personalized models for EC. Citation Format: Maxine Chen, Marta Crous-Bou, Michael J. Downing, Evan L. Busch, Kimberley Glass, Jennifer Prescott, George L. Mutter, Immaculata De Vivo. Mutation analysis of endometrial cancer in a population-based study by targeted next-generation sequencing [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 1291. doi:10.1158/1538-7445.AM2017-1291
Abstract 1389: Effects of geinstein on histone modifying enzyme expression in prostate cancer
Authors: Lanni Aquila, Nick Smothermon, Lisa Morey
Journal: Cancer Research (2017)

Abstract The present study sought to examine the expression of two histone modifying enzymes, SET8 and SIRT1, in human prostate cancer cell model when exposed to increasing concentrations of genistein. Genistein is a phytoestrogen found mainly in soy-based foods and is of importance due to the varying intake levels worldwide. This compound is thought to have chemopreventive properties and it is hypothesized to exert its affects by epigenetically modifying chromatin organization within cells. As an estrogen-like compound, genistein may exert effects similar to that of estrogen. For this reason, SET8, a histone methyltransferase, and, SIRT1, a histone deacetylase, were studied. Previously, these histone modifying enzymes were found to play a role in estrogen signaling. In the present study, cells were treated either for 24 hours (acute) or 5 days (chronic), total RNA was extracted, followed by an RT-PCR, and amplification of the genes of interest via PCR. Changes in gene expression were quantitated using ImageJ. Overall, it was concluded that the exposure to genistein impacts the gene expression of both SET8 and SIRT1 within human prostate cancer cells. Note: This abstract was not presented at the meeting. Citation Format: Lanni Aquila, Nick Smothermon, Lisa Morey. Effects of geinstein on histone modifying enzyme expression 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 1389. doi:10.1158/1538-7445.AM2017-1389
Abstract 2429: Generation of a transcriptome of oncogenic mutant p53 in triple-negative breast cancer
Authors: Rebecca E. Steele, Simon S. McDade, Paul B. Mullan
Journal: Cancer Research (2017)

Abstract The purpose of this study was to generate a transcriptional profile specific for mutant p53 in triple-negative breast cancer (TNBC), representing potential novel therapeutic targets. The highly heterogeneous TNBC tumor subgroup is established as having a poor clinical outcome. There are currently no targeted therapies for women with TNBC; consequently, there is an unmet clinical need to identify targetable pathways. Approximately 75% of these tumors are known to harbour a mutation in Tp53 (mutp53). Chromatin Immunoprecipitation Sequencing (ChIP-Seq) for mutp53 and ETS-1 (a known mutp53 interactor) was carried out using the D0-1 (sc-126) and sc-20 antibodies respectively, in the MDA-MB-468 TNBC cell line. The aim of these ChIP-seq experiments was to identify sites bound by endogenous R273H mutp53 and ETS-1 and to confirm that target genes were co-regulated. We identified 282 novel mutp53 specific genomic binding sites and 37 mutant p53 and ETS1 shared binding sites. In-house data analysis and peak calling generated a list of potential transcriptionally co-regulated genes adjacent to these genomic sites. PDGFβ, TRIB3, BTRC, TNFSF18 &amp; PI3 were successfully validated as being transcriptionally regulated by R273H mutp53 and not wild-type p53 (as shown by MCF7 ChIP-seq comparisons). A number of these genes are known to be aberrantly expressed in TNBC patient tumors and harbor interesting immune biology, providing potential opportunities for novel therapeutic strategies. In addition, DNA damaging chemotherapy-resistant MDA-MB-468 derivatives express elevated levels of mutp53 protein and altered expression of our validated transcriptional targets, suggesting that they may also have roles in promoting resistance to current chemotherapy treatments, downstream of mutp53. In conclusion, we have identified a cohort of ‘mutp53 specific’ transcriptional targets which may have roles in modulating immune responses to TNBCs, driving resistance to current chemotherapies and could provide opportunities for the development of novel treatments for TNBCs. Citation Format: Rebecca E. Steele, Simon S. McDade, Paul B. Mullan. Generation of a transcriptome of oncogenic mutant p53 in triple-negative breast 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 2429. doi:10.1158/1538-7445.AM2017-2429
Endocuff-assisted colonoscopy is associated with a lower adenoma miss rate: a multicenter randomized tandem study
Authors: Konstantinos Triantafyllou, Dimitrios Polymeros, Periklis Apostolopoulos, Catarina Lopes Brandao, Paraskevas Gkolfakis, Alessandro Repici, Ioannis Papanikolaou, Mario Dinis-Ribeiro, George Alexandrakis, Cesare Hassan
Journal: Endoscopy (2017)

Background and study aims The Endocuff (ARC Medical Design, Leeds, UK) is a device that, when mounted on the tip of an endoscope, may assist with inspection of a greater surface of the colonic mucosa by pulling backwards, flattening, and stretching the colonic folds as the endoscope is gradually withdrawn. We aimed to compare the adenoma miss rates of Endocuff-assisted colonoscopy with those of conventional colonoscopy. Patients and methods The included patients underwent same-day, back-to-back, (Endocuff-assisted colonoscopy as the index procedure followed by conventional colonoscopy or vice versa, randomly assigned 1:1) colonoscopies, performed by six endoscopists with documented adenoma detection rates > 35 %, in four tertiary endoscopy facilities. Results We randomized 200 patients (mean age 61.2 years [standard deviation 9.8]; 86.5 % colorectal cancer screening surveillance cases). Overall, there were seven incomplete examinations using Endocuff and one with conventional colonoscopy (P = 0.03). Times for endoscope insertion (5.0 minutes [0.8 - 21.0] vs. 5.0 minutes [1.0 - 16.0]; P = 0.49) and withdrawal (6.0 minutes [3.2 - 29.0] vs. 6.0 minutes [3.1 - 17.0]; P = 0.06) were similar for Endocuff-assisted and conventional colonoscopy. We detected one cancer and 195 adenomas; 84 in the proximal colon. Endocuff-assisted colonoscopy showed significantly lower overall and proximal colon adenoma miss rates compared with conventional colonoscopy (14.7 % [8.0 % - 21.0 %] vs. 38.4 % [28.1 % - 48.6 %] and 10.4 % [1.8 % - 19.1 %] vs. 38.9 % [23.0 % - 54.8 %], respectively). No difference between the two arms was shown regarding advanced adenoma miss rates, either overall or in the proximal colon. There were no serious adverse events related to the procedures. Conclusions In comparison with conventional colonoscopy, Endocuff-assisted colonoscopy has a significantly lower adenoma miss rate when performed by high-detector endoscopists. However, the incomplete colonoscopy rate with Endocuff is higher.ClinicalTrials.gov Identifier: NCT02340065.