tbuckley/cabot-search huggingface dataset:
Abstract 3316: Hypermethylation at the SMPD3 promoter is frequently detected in hepatocellular carcinoma tumor tissue and corresponding plasma circulating DNA, and potentially differs by tumor subtype
Authors: Sandi Alexander Kwee, Karolina Peplowska, Maarit Tiirikainen, Min-Ae Song, Linda L. Wong
Journal: Cancer Research (2018)

Abstract Background: Circulating plasma DNAs may exhibit altered methylation reflective of aberrant epigenetics in tumor tissues, which may present a clinical opportunity for non-invasive assessment of tumor molecular phenotype. Hypermethylation at the promoter region of SMPD3 (Sphingomyelin phosphodiesterase 3), a tumor suppressor gene, has been identified in several genome-wide DNA methylation studies involving tissue specimens of hepatocellular carcinoma (HCC) (Shen et al., 2012; Song et al., 2013). The purpose of this study was to measure and compare SMPD3 promoter hypermethylation (specifically at cg10426893) in tumors, adjacent liver tissue, and circulating cell-free DNA (cfDNA) to examine its potential as a biomarker of HCC corresponding with tumor molecular subtype. Methods: Blood and liver tissue specimens were collected following written informed consent from 54 patients undergoing partial liver resection for BCLC stage A HCC. DNA methylation was quantified through pyrosequencing analysis of bisulfite-treated DNAs from corresponding tumor tissue, adjacent liver tissue, plasma, and buffy-coat samples. Results were compared within patients using paired t-test. Transcriptomic molecular sub-classification based on the Hoshida classification system (2009) was performed on a subset of 39 tumors to explore potential associations between SMPD3 promoter hypermethylation and HCC molecular subtype. Results: Levels of SMPD3 promoter methylation were significantly higher in tumor tissue compared to adjacent liver tissue (37.0% vs. 8.8%, p &amp;lt; 0.0001) as well as when compared to cfDNA samples (32.9% vs. 14.3%, p &amp;lt; 0.0001). SMPD3 promoter methylation levels in cfDNA and tumor tissues were also significantly higher than in corresponding buffy-coat samples (p = 0.0146 and p &amp;lt; 0.0001, respectively). Tumors belonging to the S3 molecular sub-class (n = 22) exhibited significantly higher SMPD3 promoter methylation levels than non-S3 tumors (n = 17) (44.1 % vs. 24.1%, p = 0.0166). Conclusions: Significant increases in DNA methylation involving the promoter region of SMPD3 in HCC tumor tissues are reflected in cfDNA, supporting potential clinical liquid biopsy applications. Preliminarily, this epigenetic alteration appears to be associated with the S3 (differentiation) molecular subtype of HCC. Citation Format: Sandi Alexander Kwee, Karolina Peplowska, Maarit Tiirikainen, Min-Ae Song, Linda L. Wong. Hypermethylation at the SMPD3 promoter is frequently detected in hepatocellular carcinoma tumor tissue and corresponding plasma circulating DNA, and potentially differs by tumor subtype [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 3316.
Abstract 4654: A cell-based translocation assay system identifies active fractions from plant that inhibit growth of FGFR3 overactivation cancers
Authors: Yi-Ching Lee, Yun-Wen Lin
Journal: Cancer Research (2018)

Abstract Fibroblast growth factor receptor 3 (FGFR3) is one of four tyrosine kinase receptors that bind and respond to fibroblast growth factors (FGFs). Gain-of-function mutations in FGFR3 cause a group of skeletal dysplasias. The overactivation of FGFR3 in somatic cells is reported to be associated with human cancers, including multiple myeloma (MM), urothelial bladder carcinoma, cervical carcinoma, as well as benign seborrheic keratosis. Patients with FGFR3 overactivation have demonstrated an overall poor prognosis, and the treatment remains a substantial challenge. Several tyrosine kinase inhibitors (TKIs) have been proposed for treatment of FGFR3-activating cancers and some of them are currently in clinical trials. However, the side effects and a modest efficacy of the compounds towards FGFR3 promote the need to identify high-selectivity and high-potency specific FGFR3 inhibitors. We established a cell-based protein translocation assay system that can monitor FGFR3 activity and be used for high-throughput screening of complex mixtures. With this system we identified plant ethanol extract as a FGFR3 inhibitor and performed bioassay-guided fractionation to identify potent active fractions. The functionality of extract and active fractions was validated in vitro in FGFR3-activated primary multiple myeloma cells. The active fractions can preferentially inhibit the proliferation of MM with FGFR3 activation compared with MM without FGFR3 activation and inhibit the FGFR3 downstream signaling pathways. Furthermore, we demonstrated that the active fractions enhance FGFR3 degradation but not FGFR1, 2, 4 in a Western blot analysis. Our results demonstrate the applicability of this discovery approach. The identified plant extracts and active factions hold therapeutic potential for the treatment of FGFR3-activated skeletal dysplasias and cancers. Citation Format: Yi-Ching Lee, Yun-Wen Lin. A cell-based translocation assay system identifies active fractions from plant that inhibit growth of FGFR3 overactivation cancers [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 4654.
Abstract 2205: Prediction model of CA125 among premenopausal women
Authors: Naoko Sasamoto, Ana Babic, Bernard A. Rosner, Allison F. Vitonis, Daniel W. Cramer, Shelley S. Tworoger, Kathryn L. Terry
Journal: Cancer Research (2018)

Abstract Background: Cancer antigen 125 (CA125) is a membrane-bound glycosylated mucin that has been reported to be the most promising biomarker for ovarian cancer screening, although results from two large randomized trials comparing screening using CA125 and transvaginal ultrasound to usual care have shown no clinically significant difference in ovarian cancer mortality. A major limitation of CA125 as an ovarian cancer screening biomarker has been low specificity and variation between individuals by personal characteristics. Identifying personal characteristics that influence CA125 levels could be used to create personalized thresholds for CA125 for each individual, thereby improving its performance as an ovarian cancer screening biomarker. However, reports on factors that influence CA125 among premenopausal women are limited. Methods: We evaluated the association between reproductive and lifestyle factors and CA125 among 828 premenopausal population-based controls enrolled in the New England Case-Control study between 1992 and 2008. CA125 was measured using the CA125II assay at the CERLab at Boston Children's Hospital. We developed a prediction model of log-transformed CA125 using stepwise linear regression with &amp;lt;0.15 as significance level for entry and stay considering factors associated with CA125 in postmenopausal women and ovarian cancer risk factors, such as age, body mass index (BMI), race, smoking status, age at menarche, oral contraceptive use and its duration, parity, endometriosis, tubal ligation, unilateral oophorectomy, hysterectomy, family history of ovarian cancer, previous history of cancer, genital powder use, and caffeine intake as candidate predictors. Results: In our univariate analyses, older age and endometriosis were associated with significantly higher CA125 while tubal ligation, hysterectomy, and time since last menstrual period were associated with significantly lower CA125 (p&amp;lt;0.05). Age, endometriosis, tubal ligation, hysterectomy, smoking status, caffeine intake, and interval days since last menstrual period were selected in our final prediction model, which explained 6% of the total variability of log-transformed CA125 levels. Conclusion: Efforts to validate this CA125 prediction model in an independent cohort of premenopausal women and evaluate whether using the personalized CA125 cutoff based on this prediction model discriminates cases and controls better than the single 35 cutoff are ongoing. Citation Format: Naoko Sasamoto, Ana Babic, Bernard A. Rosner, Allison F. Vitonis, Daniel W. Cramer, Shelley S. Tworoger, Kathryn L. Terry. Prediction model of CA125 among premenopausal women [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 2205.
Angiotensin II Inhibits Protein Kinase A–Dependent Chloride Conductance in Heart via Pertussis Toxin–Sensitive G Proteins
Authors: KazuhikoObayashi, MinoruHorie, Lai-HuaXie, KunihikoTsuchiya, AkiraKubota, HitoshiIshida, ShigetakeSasayama
Journal: Circulation (1997)

Background Angiotensin II receptors are reported to be abundant in the guinea pig ventricle; their coupling to adenylate cyclase in the heart, however, remains controversial. Therefore, we investigated the effect of angiotensin II on Cl− conductance activated by cAMP-dependent protein kinase. Methods and Results After minimizing the contribution of other ionic currents, exposure of single guinea pig ventricular cells to isoproterenol (40 to 50 nmol/L; 36°C) elicited a typical protein kinase A–dependent Cl− conductance. Subsequent application of angiotensin II reduced the isoproterenol-induced conductance with an IC50 of 0.24±0.08 nmol/L. Angiotensin II also inhibited the Cl− currents, which were activated through stimulation of adenylate cyclase by forskolin and histamine receptors. CV-11974 (1 μmol/L), an antagonist selective for the angiotensin type 1 receptor, prevented the effect of angiotensin II. Angiotensin II did not inhibit the current that had been persistently activated by intracellular GTPγS (...
Prognostic Value of Preoperative Right Ventricular Geometry and Tricuspid Valve Tethering Area in Patients Undergoing Tricuspid Annuloplasty
Authors: Kai-HangYiu, ArthurWong, LijunPu, Man-FungChiang, Ko-YungSit, DanielChan, Hou-YeeLee, Yui-MingLam, YanChen, Chung-WahSiu, Chu-PakLau, Wing-KokAu, Hung-FatTse
Journal: Circulation (2014)

Background—Patients who undergo tricuspid annuloplasty during left-side heart valve surgery have a poor postoperative clinical outcome. However, preoperative right ventricular (RV) echocardiography parameters that predict adverse events in these patients are poorly understood. Methods and Results—We studied 74 patients (age, 58±10 years; men, 27%) with significant tricuspid regurgitation who consequently underwent tricuspid annuloplasty during left-side heart valve surgery. A total of 26 adverse events (22 heart failures and 4 cardiovascular deaths) occurred during a median follow-up of 26 months. RV midcavity diameter (hazard ratio=2.44; 95% confidence interval=1.48–4.02; P<0.01), RV longitudinal dimension (hazard ratio=1.64; 95% confidence interval=1.10–2.45; P=0.02), and tricuspid valve tethering area (hazard ratio=3.25; 95% confidence interval=1.71–6.19; P<0.01) were independently associated with adverse events after adjustment for age and New York Heart Association class III/IV. Receiver-operator cha...
Abstract 195: Electrochemical treatment produces pH changes in the tumor microenvironment that are toxic to cancer cells
Authors: Nicholas Perkons, Elliot Stein, Chike Nwaezeapu, Joseph Wildenberg, Daniel Ackerman, Gregory Nadolski, Stephen Hunt, Terence Gade
Journal: Cancer Research (2018)

Abstract Background: Locoregional therapy is playing an increasingly central role in the management of hepatocellular carcinoma (HCC), where ablation is distinguished among these techniques by its capacity to effect cure. Electrochemical treatment (EChT), a technique that facilitates necrosis via the application of direct current at low voltages shows promise; however, widespread use has been limited as studies of the underlying biology and the mechanism of action have been limited. Methods: A novel assay for the study of EChT mechanism was designed, wherein HCC cells (2.5e5 cells/mL) were embedded in low-melting temperature agarose (1.5%). EChT was performed on these assays between nitinol cathodes (d = 0.5 mm) and platinum anodes (d = 0.5 mm) in a variety of geometries. Buffering capacity of the encapsulation assay was varied via the addition of HEPES buffer at final concentrations of 10mM, 50mM, or 200mM. Either during or immediately following EChT, the following measurements were recorded: cell viability, pH, ROS burden, transmembrane potential, and temperature. Results: Following EChT, acidic pH was appreciated surrounding the anodes and basic pH surrounding the cathodes in regions where cell death was observed by fluorescence microscopy. Upon increasing the buffering capacity of the assay, the total area of cell death decreased (p &amp;lt; 10-6). There was not sufficient heat generation nor transmembrane potential to account for the observed cell death. A pH-threshold was identified, where a pH &amp;gt; 10.8 or &amp;lt; 4.4 was found to cause cell necrosis in the three different buffer conditions studied. By varying the number of electrodes, their spacing, and length of ablation, it was possible to shape the zone of cell death observed to an arbitrary geometry. Conclusions: The mechanism of EChT-induced cancer cell death is through the spread of acidic and basic species generated by hydrolysis of water upon electron transfer at the electrodes. The diffusion of these species leads to cell death in a predictable, pH dependent manner. These results suggest that an electrochemical ablation device could treat complex HCC tumor geometries with appropriate electrode placement and charge delivery. Citation Format: Nicholas Perkons, Elliot Stein, Chike Nwaezeapu, Joseph Wildenberg, Daniel Ackerman, Gregory Nadolski, Stephen Hunt, Terence Gade. Electrochemical treatment produces pH changes in the tumor microenvironment that are toxic to cancer cells [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 195.
Letter by Sharma et al Regarding Article, “Impact of the Presence and Extent of Incomplete Angiographic Revascularization After Percutaneous Coronary Intervention in Acute Coronary Syndromes: The Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) Trial”
Authors: AbhishekSharma, RobertFrankel, GeraldHollander
Journal: Circulation (2012)
Abstract 3486: Metabolomics in estrogen receptor or triple-negative breast cancer
Authors: Jennifer J. Hu, Cristiane Takita, Eunkyung Lee, Jean Wright
Journal: Cancer Research (2018)

Abstract Breast cancer is the most frequently diagnosed cancer in women. Metabolic syndrome and obesity may contribute to triple-negative breast cancer (TNBC) and there are obesity-related alterations in metabolites. Therefore, we pilot-tested metabolomics in ER-negative or TNBC using urine samples from 60 breast cancer cases. In total, 475 metabolites were quantified in different super-pathways: 147 in amino acid, 38 in carbohydrate, 27 in cofactors and vitamins, 12 in energy, 50 in lipid, 31 in nucleotide, 17 in peptide, and 153 in xenobiotics. Our data in 13 ER- and 47 ER+ showed that urinary beta-alanine is higher (3.35+3.73 vs. 1.82+2.26) in ER- breast cancer patients. Our data also show, the first time, that the urinary beta-alanine was higher in TNBC (3.60+4.33; N=8) compared to other subtypes (1.93+2.32; N=52). Beta-alanine is a nonessential amino acid that has previously been shown to be metabolized into carnosine, which functions as an intracellular buffer. In breast cancer cells, beta-alanine reduces both tumor cell migration and proliferation without acting in a cytotoxic fashion. It also significantly increased breast cancer cell sensitivity to doxorubicin. Our data on xanthine are also consistent with the previous study on breast tumor that slightly higher level was observed in ER- patient (1.41+1.35 vs. 1.16+0.88). The level of xanthine was significantly higher in TNBC compared to other subtypes (1.67+1.69 vs. 1.14+0.84). More importantly, our pilot data also showed that urinary mannose levels were significantly higher in ER- tumor (2.21+1.90 vs. 0.90+1.21 p=0.032) and TNBC (2.19+1.77 vs. 1.03+1.38, p=0.037), which is consistent with a previous study that reported that serum mannose levels can differentiate patients with metastatic and localized breast cancer. Metabolic drugs for cancer, such as glutaminase inhibitors, are currently under development and being tested in clinical trials. Therefore, if our data are validated, metabolomics of ER- or TNBC will contribute to innovative discoveries that will impact breast cancer prevention and precision medicine targeting metabolomic pathways. Citation Format: Jennifer J. Hu, Cristiane Takita, Eunkyung Lee, Jean Wright. Metabolomics in estrogen receptor or triple-negative breast 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 3486.
Abstract 15114: Temporal Trends and Outcomes of Patients Undergoing Percutaneous Coronary Intervention for Cardiogenic Shock in the Setting of Acute Myocardial Infarction in the United States
Authors: Udhay Krishnan, Josef Brejt, Joshua S Marcus, Parag Goyal, Rajesh Swaminathan, Dimitriy Feldman, S. Chiu Wong, Robert Minutello, Geoffrey Bergman, Harsimran Singh, Luke Kim
Journal: Circulation (2016)

Background: Multiple studies have reported a decline in mortality for patients with cardiogenic shock after acute myocardial infarction (CS-AMI), a finding which has been attributed to the increasing use of revascularization over the past decade. However, other recent studies that have focused specifically on patients with CS-AMI treated with early percutaneous coronary intervention (PCI) have paradoxically found no improvement in risk-adjusted mortality. Hypothesis: To reconcile these discordances, we hypothesize that the clinical complexity of the PCI-population has changed over time, in ways not precisely adjusted for in previous studies. The objective of this study was to elucidate changes in the clinical characteristics of the CS-AMI population treated with PCI, and clarify its impact on mortality trends. Methods: We conducted a retrospective analysis of the 2005-2012 Nationwide Inpatient Sample database. Patients with CS-AMI who underwent PCI within 24 hours of hospitalization were identified. Tempo...
Abstract LB-197: Transposon mutagenesis and CRISPR/Cas9 screening reveal pathways driving peripheral nerve sheath tumor development and maintenance
Authors: German L. Velez Reyes, Nicholas Koes, Gabriel Kaufmann, Esther Ryu, David A. Largaespada
Journal: Cancer Research (2018)

Abstract Malignant Peripheral Nerve Sheath tumors(MPNSTs) are highly aggressive soft tissue sarcomas derived Schwann cell tumors. Half of these tumors occur sporadically, while the rest occur in the context of Neurofibromatosis Type 1 Syndrome (NF1) developing from pre-existing plexiform neurofibromas. NF1 is characterized by loss-of-function mutations in the gene encoding neurofibromin, a negative regulator of the oncogenic Ras pathway. To better understand genetic factors that give rise to MPNSTs, we performed a Sleeping Beauty (SB) transposon screen in mice. The results implicated Wnt/β-catenin, PI3K-AKT-mTOR, growth factor receptor signaling, and other pathways. It is our goal to understand the role of these pathways in human Schwann cell transformation, tumorigenesis, and tumor maintenance. We next sought to validate SB screen gene hits in a human cellular model using CRISPR/Cas9 technology as a tool to induce loss-of-function mutations in tumor suppressor gene (TSG) and oncogene candidates. A total 103 genes were independently targeted with multiple guideRNAs in immortalized human Schwann and MPNST cell lines and effects on transformation assessed. Transformation was assessed by anchorage-independent colony formation in soft agar, transwell migration, and tumor formation in NRG mice. In these assays, more than 30 genes scored as TSG candidates. Our results revealed a role for the Wnt/β-catenin, Hippo/Yap, PI3K-AKT-mTOR, Rho, and growth factor receptor signaling pathways in human neurofibroma and MPNST development and maintenance. These are generating hypothesis driven pre-clinical treatment studies we're pursuing now. Citation Format: German L. Velez Reyes, Nicholas Koes, Gabriel Kaufmann, Esther Ryu, David A. Largaespada. Transposon mutagenesis and CRISPR/Cas9 screening reveal pathways driving peripheral nerve sheath tumor development and maintenance [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-197.
Abstract 5857: Isorhapontigenin inhibits triple-negative breast cancer via activating NRF2-mediated pathway
Authors: Yusha Zhu, Anthony Murphy, Thomas Kluz, Bo Li, Max Costa, Chuanshu Huang, Hong Sun
Journal: Cancer Research (2018)

Abstract Breast cancer is the most prevalent cancer among women worldwide, and is the second leading cause of cancer mortality among women. Triple-negative breast cancers (TNBCs; ER-/PR-/HER2-) are highly aggressive tumors with poor prognosis. Due to lack of these specific receptors, TNBCs cannot be treated with hormone therapies or anti-HER2 targeted therapies. Chemotherapy, combined with surgery and radiation therapy, is the primary strategy for treating TNBCs. Thus, discovery and evaluation of new alternative medications targeting triple-negative breast cancer is of tremendous importance for reducing breast cancer mortality. Isorhapontigenin (ISO), a new derivative of stilbene isolated from Chinese herb Gnetum Cleistostachyun, exhibits a strong inhibitory effect on human bladder cancers. However, its anticancer activity with respect to breast cancer remains unclear. In the present study, we investigated the potential anticancer effect of ISO on TNBCs. ISO treatment inhibited the proliferation and anchorage-independent growth of 4T1 cells, a murine triple-negative breast cancer cell line, in a dose-dependent manner. In addition, the results from wound healing and Transwell invasion assay indicated significantly reduced cell migration and invasion in ISO-treated cells. Moreover, we performed the whole transcriptome analysis using RNA-seq to elucidate the molecules and pathways that mediate ISO's anticancer activity. A total of 1972 differentially expressed genes were identified in ISO-treated cells. IPA analysis revealed that the top canonical pathway altered by ISO is NRF2-mediated pathway. ISO-induced NRF2 activation was further confirmed by nuclear translocation of NRF2 protein and upregulation of NRF2 downstream target genes (GSTA1, GSTM1, HMOX1, and NQO1). In summary, our study is the first to demonstrate that ISO inhibits breast cancer cell growth and invasion, in part, by activating NRF2-mediated signaling pathway. Our results provide a novel mechanism for ISO-induced anticancer effect, and strongly support ISO as a promising therapeutic agent for triple-negative breast cancers. Citation Format: Yusha Zhu, Anthony Murphy, Thomas Kluz, Bo Li, Max Costa, Chuanshu Huang, Hong Sun. Isorhapontigenin inhibits triple-negative breast cancer via activating NRF2-mediated pathway [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 5857.