tbuckley/cabot-search huggingface dataset:
Abstract 4960: Studying the impact of gut microbiome to hepatocellular cancer in an orthotopic murine model
Authors: Xiaoqiang Qi, Ming Yang, Joseph Stenberg, Guangfu Li, Kevin Staveley-O’Carroll
Journal: Cancer Research (2019)

Abstract Background and Objective: As one of the most important components of human body, gut microbiota play a vital role in human health by participating in metabolomics and maintaining immunological homeostasis. Microbiota dysbiosis is significantly associated with initiation and progression of different diseases. Due to close anatomical and functional connection between gut and liver (gut-liver axis), gut microbiota are found to impact the development of liver diseases including hepatocellular cancer (HCC) without fully understanding mechanisms. The overall objective of present study is to investigate how microbiota modulate HCC growth by regulating intrahepatic immune response. Methods: Administration of carbon tetrachloride in combination with transplant of oncogenic hepatocytes by intrasplenic injection was used to make an orthotopic mouse model of HCC. A specific antibiotics cocktail (ABX) was selected to inhibit some kinds of gut microbiota. 16s rRNA sequencing was used to characterize gut microbiota profile in mice with the different treatments. Magnetic resonance imaging (MRI) was used to monitor tumor growth. Adoptive transfer of tumor antigen-specific CD8+ T cells following the treatment was used to investigate how ABX administration impacted intrahepatic immune response. Flow cytometry and multiplex cytokine assay were used to detect the alteration of effector CD8+ T cell in phenotype, proliferation, and function. Immunohistochemistry (IHC) was used to investigate immune cell tumor-infiltration. Results: The established murine model reflects the typical features of human HCC. ABX oral administration significantly changed gut microbiota composition, particularly in abundance of P. aeruginosa and Muribaculaceae. ABX-mediated alteration of gut microbiota significantly retarded HCC progression. Interestingly, ABX treatment was found to prevent adoptively transferred tumor antigen-specific CD8+ T cell from tumor-induced immune tolerance, as higher frequency of effector CD8+ T cell was detected in ABX-treated tumor-bearing mice compared to that in control tumor-bearing mice. Correspondingly, ABX treatment resulted in the increase in expression of CD69 and enhanced production of IFN-γ in tumor antigen-specific CD8+ T cells relevant to that in control mice. Conclusion: Modulating microbiota with antibiotics is able to shape intrahepatic immune responses and therapeutically suppress tumor growth, providing a new option in HCC control. Citation Format: Xiaoqiang Qi, Ming Yang, Joseph Stenberg, Guangfu Li, Kevin Staveley-O’Carroll. Studying the impact of gut microbiome to hepatocellular cancer in an orthotopic murine model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4960.
Abstract 3034: <i>TP53</i> mutant cell lines selected for resistance to MDM2 inhibitors retain growth inhibition by MAPK pathway inhibitors but a reduced apoptotic response
Authors: Chiao-En Wu, Tsin Shue Koay, Yi-Hsuan Ho, Penny Lovat, John Lunec
Journal: Cancer Research (2019)

Abstract Emergence of resistance to molecular targeted therapy constitutes a potential limitation to clinical benefits in cancer treatment. Cross-resistance commonly happens with chemotherapeutic agents but might not with targeted agents. In the current study, TP53 wild -type cell lines with druggable MAPK pathway mutations (BRAFV600E (WM35) or NRAS Q61K (SJSA-1)) were compared with their TP53 mutant sublines (WM35-R, SN40R2) derived by selection for resistance to MDM2/p53 binding antagonists. The continued presence of the druggable MAPK pathway targets in the TP53 mutant (TP53MUT) WM35-R and SN40R2 cells was confirmed. Trametinib and vemurafenib were tested on the paired WM35/WM35-R and SJSA-1/SN40R2 cells and similar growth inhibitory effects on the paired cell lines was observed. However, apoptotic responses to trametinib and vemurafenib were greater in WM35 than WM35-R, evidenced by FACS analysis and caspase 3/7 activity, indicating that these MAPK inhibitors acted on the cells partially through p53-regulated pathways. SiRNA mediated knockdown of p53 expression in WM35 replicated the same pattern of response to trametinib and vemurafenib as seen in WM35-R, confirming that p53 plays a role in trametinib and vemurafenib induced apoptosis. In contrast, these differences in apoptotic response between WM35 and WM35-R were not seen with the SJSA-1/SN40R2 cell line pair. This is likely due to p53 suppression by overexpressed MDM2 in SJSA-1. In conclusion, the TP53MUT cells selected by resistance to MDM2 inhibitors nevertheless retained growth inhibitory but not apoptotic response to MAPK pathway inhibitors. Citation Format: Chiao-En Wu, Tsin Shue Koay, Yi-Hsuan Ho, Penny Lovat, John Lunec. TP53 mutant cell lines selected for resistance to MDM2 inhibitors retain growth inhibition by MAPK pathway inhibitors but a reduced apoptotic response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3034.
Abstract 2617: FOXC2-associated regulation of melanoma cell adhesion to the extracellular matrix and lymphatic endothelial cells
Authors: Coleman E. Johnson, Corey J. Williams, Kristian M. Hargadon
Journal: Cancer Research (2019)

Abstract The FOXC2 transcription factor has emerged as a tumor-promoting oncogene in many cancer types. We have recently investigated the impact of Foxc2 gene disruption and FOXC2 overexpression in melanoma on tumor cell adhesion to extracellular matrix (ECM) proteins and lymphatic endothelial cells. We show that melanoma-associated FOXC2 is a critical regulator of tumor cell adhesion to the ECM proteins fibrinogen and fibronectin as well as to lymphatic endothelial cells. These effects on tumor cell adhesion correlate with FOXC2-mediated regulation of the integrins ITGA5 and ITGA9. As changes in cellular adhesion frequently accompany tumor cell transformation and progression, our data suggest that FOXC2 and genes regulated by this transcription factor may play key roles in promoting melanoma invasion and metastasis. Citation Format: Coleman E. Johnson, Corey J. Williams, Kristian M. Hargadon. FOXC2-associated regulation of melanoma cell adhesion to the extracellular matrix and lymphatic endothelial cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2617.
Abstract 5274: Multi-omics integration analysis robustly predicts high grade patient survival and identified altered fatty acid metabolism in high grade bladder cancer
Authors: Venkata Rao Vantaku, Jianrong Dong, Chandrashekar R Ambati, Dimuthu Perera, Sri Ramya Donepudi, Chandra Sekhar Amara, Vasanta Putluri, Ravi Shiva Shankar, Matthew J Robertson, Danthasinghe Waduge Badrajee Piyarathna, Mariana Villanueva, Friedrich-Carl von Rundstedt, Balasubramanyam Karanam, Leomar Y Ballester, Martha K. Terris, Seth P. Lerner, Apolo B Andrea, Hugo Villanueva, Andrew Sikora, Yair Lotan, Arun Sreekumar, Cristian Coarfa, Nagireddy Putluri
Journal: Cancer Research (2019)

Abstract Cancer metabolism varies depending on tumor grade. Currently, there is an absence of integration of multi-omics data to predict Bladder cancer (BLCA) survival. We aimed to identify a metabolic signature in high-grade BLCA by integration of unbiased metabolomics, lipidomics and transcriptomics to predict patient survival and to discover novel therapeutic targets. In the current study, using a robust mass spectrometry platform, we conducted global unbiased metabolic and lipid profiling analysis. We identified 518 differential metabolites and 19 lipids of various classes using the NIST MS metabolomics compendium and lipidblast MS/MS libraries, respectively, between low-grade and high-grade BLCA then mapped them to associated genes. Pathway analysis revealed a unique set of biochemical pathways highly deregulated in high-grade BLCA. Integromics analysis identified a molecular gene signature associated with patient poor survival. Importantly, low expression of fatty acid associated enzymes in high-grade tumors was associated with low fatty acid β- oxidation and acyl carnitines in high-grade BLCA and confirmed using tissue microarray. Our key finding is that impaired fatty acid β-oxidation (FAO) by downregulation of fatty acid associate enzymes suggests a crucial role in the progression of low grade to high grade BLCA. Using a metabolic-centered multi-omics based integrative analysis provided a system-level perspective of BLCA that would facilitate the development of novel therapeutics for high-grade BLCA. Note: This abstract was not presented at the meeting. Citation Format: Venkata Rao Vantaku, Jianrong Dong, Chandrashekar R Ambati, Dimuthu Perera, Sri Ramya Donepudi, Chandra Sekhar Amara, Vasanta Putluri, Ravi Shiva Shankar, Matthew J Robertson, Danthasinghe Waduge Badrajee Piyarathna, Mariana Villanueva, Friedrich-Carl von Rundstedt, Balasubramanyam Karanam, Leomar Y Ballester, Martha K. Terris, Seth P. Lerner, Apolo B Andrea, Hugo Villanueva, Andrew Sikora, Yair Lotan, Arun Sreekumar, Cristian Coarfa, Nagireddy Putluri. Multi-omics integration analysis robustly predicts high grade patient survival and identified altered fatty acid metabolism in high grade bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5274.
Abstract 18984: Patterns and Predictors of Invasive Treatment Referral in Peripheral Artery Disease: Insights From the PORTRAIT Study
Authors: Yashashwi Pokharel, Jingyan Wang, William Hiatt, David Safley, Mark Friedell, John Spertus, Kim Smolderen
Journal: Circulation (2016)

Introduction: In patients with lifestyle limiting PAD symptoms, practice guidelines support invasive treatment after inadequate response to medical treatment, including exercise therapy and in thos...
Abstract 431: Mitochondrial Fission in the Heart is an Adaptation to Increased Energetic Demands: The Role of Physiologic Fragmentation
Authors: Michael Coronado, Giovanni Fajardo, Kim Nguyen, Mingming Zhao, Kristina Bezold Kooiker, Gwanghyun Jung, Dong-Qing Hu, Sushma Reddy, Erik Sandoval, Aleksandr Stotland, Roberta Gottlieb, Daniel Bernstein
Journal: Circulation Research (2016)

Mitochondria play a dual role in the heart, responsible for meeting energetic demands and regulating cell death. Current paradigms hold that mitochondrial fission and fragmentation are the result of pathologic stresses such as ischemia, are an indicator of poor mitochondrial health, and lead to mitophagy and cell death. However, recent studies demonstrate that inhibiting fission also results in cardiac impairment, suggesting that fission is important for maintaining normal mitochondrial function. In this study, we identify a novel role for mitochondrial fragmentation as a normal physiological adaptation to increased energetic demand. Using two models of exercise, we demonstrate that “physiologic” mitochondrial fragmentation occurs, results in enhanced mitochondrial function, and is mediated through beta 1-adrenergic receptor signaling. Similar to pathologic fragmentation, physiologic fragmentation is induced by activation of Drp1; however, unlike pathologic fragmentation, membrane potential is maintained and regulators of mitophagy are downregulated. To confirm the role of fragmentation as a physiological adaptation to exercise, we inhibited the pro-fission mediator Drp1 in mice using the peptide inhibitor P110 and had mice undergo exercise. Mice treated with P110 had significantly decreased exercise capacity, decreased fragmentation and inactive Drp1 vs controls. To further confirm these findings, we generated cardiac-specific Drp1 KO mice and had them undergo exercise. Mice with cardiac specific Drp1 KO had significantly decreased exercise capacity and abnormally large mitochondria compared to controls. These findings indicate the requirement for physiological mitochondrial fragmentation to meet the energetic demands of exercise and support the still evolving conceptual framework, where fragmentation plays a role in the balance between mitochondrial maintenance of normal physiology and response to disease.
Abstract 16280: Intramyocardial Delivery of Extracellular Vesicles Released From Induced Pluripotent Stem Cells Induces Cardiac Repair After Myocardial Infarction
Authors: Guangming Cheng, Marta Adamiak, Yu-Ting Xuan, Anweshan Samanta, Sylwia Bobis-Wozowicz, Magdy Girgis, Ou-Li Wang, Elzbieta Karnas, Arash Davani, Sylwia Kedracka-Krok, Michal Sarna, Robert J Vincent, Yanjuan Yang, Zbigniew Madeja, Ewa Zuba-Surma, Buddhadeb Dawn
Journal: Circulation (2015)

Introduction: Induced pluripotent stem cells (iPSCs) have recently emerged as a promising therapy for cardiac repair. Whether extracellular vesicles (EVs) derived from iPSCs can confer similar benefits remains unclear. Hypothesis: We hypothesized that injection of iPSC-derived EVs would produce at least similar improvement in cardiac structure and function compared with iPSCs. Methods: Murine iPSCs were generated using standard protocol and iPSC-EVs were harvested from culture supernatants by sequential centrifugation. Wild-type (C57BL/6) mice underwent a 30-min coronary occlusion followed by reperfusion, and 48 h later received intramyocardial injection of vehicle (PBS, n=14), iPSCs (n=15) or iPSC-EVs (n=13). Echocardiography was performed 4 d prior to coronary occlusion/reperfusion (BSL) and at 48 h and 30 d after injection. Mice were sacrificed at 30 d. Results: At 48 h after injection, LVEF was significantly and similarly reduced in all groups (Fig). At 30 d after MI, mice injected with iPSC-EVs exhibited significantly greater EF (Fig) compared with vehicle-treated mice. iPSC-EV-injected hearts also showed significantly smaller LVEDV compared with vehicle-treated mice, indicating improved remodeling. Although iPSCs-injected hearts also showed somewhat improved function and structure, several mice in this group grew tumors at myocardial injection sites. Conclusions: We conclude that intramyocardial injection of iPSC-EVs after a reperfused MI improves LV function and remodeling. The use of iPSC-EVs also averts cardiac tumor formation that was noted in mice after iPSC whole cell injection. These findings support therapeutic potential of iPSC-EVs in patients after MI.
Abstract 2151: Monitoring AMP Concentration,the universal product of diverse enzymatic reactions
Authors: Said A. Goueli, Kevin Hsiao, Subhanjan Mondal
Journal: Cancer Research (2019)

Abstract Many enzymatic reactions use Adenosine triphosphate (ATP) as a substrate and produce adenosine monophosphate (AMP) as the common product of these reactions. AMP also functions as a modulator of many enzymes and a key cellular metabolite regulating energy homeostasis and signal transduction. For example, by activating AMP-Dependent protein kinase (AMPK), it maintains the energy charge ratio at optimal level during metabolic activities; and its concentration is altered during disregulated disease conditions. Thus, monitoring the activities of these enzymes is a primary goal for developing modulators for these enzymes. Here, we demonstrate the versatility of an enzyme coupled assay that quantifies the amount of AMP produced by any enzymatic reactions regardless of its substrates in a homogenous and high through-put formatted form. We successfully implemented it to enzyme reactions that use ATP as a substrate (aminoacyl tRNA synthetase and DNA ligase) by first depleting the remaining residual ATP substrate and converting AMP produced into ATP, the later can be quantified using luciferase/luciferin and generating light. We also tested this assay to measure direct activities of AMP generating enzymes that do not require ATP as substrate, including phosphodiesterases (cAMP) and E.coli DNA ligases (NAD+). In a further elaboration of the AMP-Glo platform, we coupled it to E.coli DNA ligase, enabling measurement of NAD+ and enzymes that use NAD+ like mono- and poly-ADP-ribosyltransferases. Sulfotransferases use 3'-phosphoadenosine-5'-phosphosulfate (PAPS) as the universal sulfo-group donor and phosphoadenosine-5'-phosphate (PAP) is the universal product. PAP can be quantified by converting PAP to AMP by a Golgi-resident PAP-specific phosphatase, IMPAD1. By coupling IMPAD1 to the AMP-Glo system we can measure the activities of sulfotransferases. In summary, we have developed a very strong platform to monitor AMP concentrations that is applicable to diverse enzymatic reactions. Citation Format: Said A. Goueli, Kevin Hsiao, Subhanjan Mondal. Monitoring AMP Concentration,the universal product of diverse enzymatic reactions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2151.
Abstract 14563: Improving Monitoring Outcomes and Quality of Life for Heart Failure Patients in Telehomecare Program
Authors: Valeria E Rac, Yeva Sahakyan, Nida Shahid, Aleksandra Stanimirovic, Iris Fan, Welson Ryan, Petros Pechlivanoglou, Lusine Abrahamyan, Murray Krahn
Journal: Circulation (2015)

Introduction: Introduced in 2007 by the Ontario Telemedicine Network, the Telehomecare program provides monitoring of patient’s parameters and coaching sessions. There is an inconclusive data on the association of participation and patient-level outcomes. Hypothesis: We hypothesized that blood pressure (BP), daily weight fluctuation and quality of life would improve among heart failure patients participating in the Telehomecare. Methods: We applied a time series study design to analyze patients’ blood pressure and weight, transmitted via telemonitoring devices on a daily basis. Longitudinal surveys were conducted on a small sample of prospectively enrolled patients (n=22) to assess quality of life using EQ-5D and SF-12 over the three-month period. Daily weight gain was defined as an increase of ≥2 lbs between two consecutive measurements. The data for the period of July 2012 to March 2015 was analysed by repeated measures with generalized linear mixed model procedures in SAS. Results: Overall 1354 patients with heart failure (52% women) were enrolled with average age of 76.3±11.1. During the first month of enrolment, one third of the patients (n=433) had elevated BP with a monthly average systolic BP of 150.3±9.6 mm Hg and diastolic BP of 76.7±12.8, in comparison with adequately controlled (n=921) patients, who had an average systolic BP of 118.8±13.5 mm Hg and diastolic BP of 66.4±9.6 mm Hg. Over the seven month period, we found significant reduction in systolic (by 11.0 mm Hg; 95% CI 9.3-12.7) and diastolic BP (by 6.0 mm Hg; 95% CI 4.9-7.3) among patients who had elevated values at baseline, adjusted for age and gender. During the first month of enrolment, weight gain of ≥2 lbs was registered for 8% of days. The likelihood of daily weight gain slightly declined over the seven month period (OR 0.86. 95% CI 0.75-0.98). Physical and mental component scores of SF-12 and EQ 5D’s index score did not improve significantly except for EQ 5D visual analogue scale scores. Conclusion: In conclusion, changes observed in the patient monitoring parameters over time pointed out that hypertensive patients might benefit the most from the Telehomecare. The survey evaluations failed to detect any significant impact of the Telehomecare on the patients’ quality of life.
Abstract 4072: A combinational therapy of oncolytic virus and nature killer cells for melanoma treatment
Authors: Lin Chen, Xianju Chen, Xiankui Tan, Meng Li, Fang Hu, Haiyan Zhang, Xiaoyuan Wang
Journal: Cancer Research (2019)

Abstract Immunotherapy has obtained substantial impact on the clinical treatment of melanoma which is largely resistant to current therapies as chemotherapy and radiotherapy. Oncolytic virotherapy of melanoma is an appealing approach for inducing not only tumor cell death but also antitumor immunity. Furthermore, NK cells, a lineage of innate lymphocytes, not relying on peptides presented in an HLA class I context, have gained more and more attention as anti-melanoma effector cells. However, the combination of oncolytic adenovirus and NK cells has not yet been explored in melanoma. In this study, the combinational efficacies of oncolytic virus H101 and NK cells was tested in vitro. The combination of H101 and NK cells resulted more efficient killing of tumor cells (HT29, A549 and HepG2) compared to the monotherapies, and displayed no significant cytolytic effect of normal cells (HUVEC and MRC-5). In addition, we present a patient with right maxillary sinus malignant melanoma who was treated with the combination of H101 and adoptive NK cells. We observed intratumoral injections of H101 without dose-limiting toxicity. H101 injections stimulated self-immunity response with transient whole body fever. Furthermore, NK injections caused tumor temperature rise although contralateral cheek temperature was normal and body temperature was normal. Data are consistent with the hypothesis that virus-infected cancer cells attracted NK accumulation within tumor. The homing NK cells attacked targeted cancer cells, causing local temperature rise. Two courses of combination therapy in conjunction mediated the significant durable regression of melanoma, which had been ongoing for &amp;gt;22 months, and it represents a new immunotherapy approach for the treatment of these patients. Citation Format: Lin Chen, Xianju Chen, Xiankui Tan, Meng Li, Fang Hu, Haiyan Zhang, Xiaoyuan Wang. A combinational therapy of oncolytic virus and nature killer cells for melanoma treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4072.
STAT3 Ser-727 phosphorylation by CDK1 inhibits STAT3 function during cell cycle progression
Authors: Steven Pelech, Xiaoqing Shi, Hong Zhang
Journal: Cancer Research (2005)

5401  Using the Kinetworks(TM) KPSS 1.3 Phospho-Site Screening Service from Kinexus, we uncovered a 2- to 3-fold enhancement of the phosphorylation of the transcription factor STAT3 at Ser-727 in M-phase arrested HeLa cells exposed for 24 hours to various microtubule disruptors including nocodazole, taxol, vinblastine and colchicine. STAT3 Ser-727 phosphorylation was also increased during normal cell cycle progression through M phase, and this could be blocked with olomoucine, which is a cyclin-dependent kinase (CDK) inhibitor. CDK1 was shown to directly phosphorylate recombinant STAT3 at Ser-727 in vitro. In studies with STAT3 phosphorylation mutants transfected into HEK cells, the Ser-727 to Glu mutant exhibited reduced phosphorylation at the Tyr-705 activation site for transcription. Likewise, the Tyr-705 to Glu mutant had lower levels of Ser-727 phosphorylation. STAT3 Ser-727 to Ala mutants exhibited increased transcriptional activity with the STAT3 promoter in luciferase reporter assays and electrophoretic mobility shift assays that monitor DNA binding. DNA synthesis as measured by BrdU incorporation was increased in HEK cells transfected with the STAT3 Ser-727 to Ala mutant. The Kinetworks(TM) KCCP Cell Cycle Protein Screening Service revealed that the STAT3 Ser-727 to Ala mutant also enhanced the level of production of cyclin E and the p21 CDK inhibitor in HEK cells. STAT3 phosphorylation during M phase by CDK1 has not been previously described. We conclude that CDK1 and possibly CDK2 may phosphorylate STAT3 and inhibit its transcriptional activity during M phase and prior to S phase, respectively. [This work was supported by a Canada Institute for Health Research grant to SP].