tbuckley/cabot-search huggingface dataset:
Abstract 5878: Effect of cannabinoid WIN 55,212-2 on prostate cancer cell proliferation, migration, invasion, and tumor growth
Authors: Domenica Roberto, Laurence H. Klotz, Vasundara Venkateswaran
Journal: Cancer Research (2018)

Abstract Introduction and Objective: Prostate cancer (PCa) is the most commonly diagnosed cancer in men and the second leading cause of cancer related death in Canada. A large body of evidence supports a possible role for cannabinoids in certain aspects of human health and disease, acting as palliative agents and more importantly, as inhibitors of cancer cell proliferation, migration, invasion, and the angiogenesis of tumours. WIN 55,212-2 (WIN) is a highly potent synthetic cannabinoid, binding to the cannabinoid receptors 1 and 2. This study aims to determine the anti-cancer effect of WIN using preclinical models of prostate cancer. Methodology: Human PCa cells (DU145, PC3) were treated with WIN at concentrations ranging from 1μM to 20μM and growth of cells (using the MTS assay) was assessed at various times following treatment. Wound-healing assays were conducted to investigate the migratory potential of cells following exposure to treatment, and trans-well invasion assays were performed to explore the influence of WIN on cell invasion. In vivo evaluation using PC3 xenografts was performed using swiss athymic mice. Treatment was administered thrice weekly and tumor volume assessed for a total of three weeks. Results: Treatment with 10μM WIN resulted in a significant reduction in the proliferation of DU145 and PC3 cells after 24 h compared to control (p&amp;lt;0.05). Cell migration and invasion studies revealed a significant reduction in cell motility at 15μM WIN (p&amp;lt;0.05) and a significant reduction in cell invasion at a concentration as low as 1μM (p&amp;lt;0.05). Treatment with 5mg/kg WIN (ip) revealed significant differences in tumor volume compared to controls that received the vehicle (p&amp;lt;0.05). There were no significant alterations in body weight in both groups. Conclusion: WIN 55,212-2 is a highly potent cannabinoid, having significant influences on cell proliferation, migration, and invasion, with reduction in the growth of tumors in prostate cancer xenografts. We are the first to demonstrate the use of WIN in PC3 xenografts and provide evidence for its use as a novel therapeutic option in patients with prostate cancer. Funding/Conflicts of Interest: None Citation Format: Domenica Roberto, Laurence H. Klotz, Vasundara Venkateswaran. Effect of cannabinoid WIN 55,212-2 on prostate cancer cell proliferation, migration, invasion, and tumor growth [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 5878.
Abstract 15584: Mitotimer Protein Reveals Remarkable Macro and Micro Heterogeneity in the Heart; A Novel Tool for Determining Mitochondrial Turnover in the Heart
Authors: Aleksandr Stotland, Jennifer Ramil, Roberta A Gottlieb
Journal: Circulation (2015)

In order to study mitochondrial turnover at the level of a single mitochondrion, our laboratory has developed the MitoTimer protein. Timer is a mutant of DsRed fluorescent protein developed by Terskikh et al. The Timer protein transitions from green fluorescence to a more stable red conformation as it matures over a span of 48 h. Furthermore, the protein is very stable under physiological conditions, insensitive to variations in ionic strength, and changes in pH between 7.0 and 8.0. Notably, Timer maturation from green to red is significantly slowed in deoxygenated buffer, suggesting that molecular oxygen plays a part in fluorophore maturation. We created a construct that fused the Timer protein cDNA with the inner mitochondrial membrane signal sequence and placed it under the control of the cardiac-restricted α-myosin heavy chain promoter. This construct was used to create the α-MHC MitoTimer mice. Surprisingly, initial analysis of the hearts from these mice demonstrated a high degree of heterogeneity in the ratio of red-to-green fluorescence of MitoTimer in cardiac tissue, revealing regions of high and low oxygen tension. Further, individual mitochondria within cardiomyocytes display a higher red-to-green fluorescence relative to fluorescence of the other mitochondria in the cell, implying a block in import of newly synthesized MitoTimer caused by the lack of a high membrane potential, indicative of older, dysfunctional mitochondria. These mitochondria can be isolated and sorted from the heart by flow cytometry for further analysis. Initial studies suggest that these mice represent an elegant tool for the investigation of mitochondrial turnover in the heart.
Abstract 4315: Colorectal cancer epigenomic landscape
Authors: Elias Orouji, Ayush Raman, Ming Tang, Mayura Dhamdhere, Kunal Rai
Journal: Cancer Research (2018)

Abstract Cancer cells utilize genetic and epigenetic aberrations for their excessive growth. Although we have sufficient understanding of the genomic alterations in colorectal cancer, we have incomplete knowledge of epigenomic aberrations and their impact on tumor growth. In order to comprehensively define the epigenetic patterns specific to colorectal cancer, we generated profiles for 6 histone modification marks, including H3K4me1 (enhancer), H3K27Ac (active enhancer), H3K9me3 (heterochromatin), H3K27me3 (polycomb repression), H3K79me2 (transcription) and H3K4me3 (promoter), using a high-throughput ChIP-Seq methodology developed in house applicable to frozen tumors. Chromatin state transitions specifically pointed to drastic changes in enhancer patterns, consistent with some prior studies. Furthermore, using similarity network fusion (SNF) we identified the best singular mark and are currently developing a tool to identify combinatorial chromatin states that could most efficiently distinguish and eventually predict CRC from normal colon. In a more detailed investigation into patterns of active enhancers using normal colon, adenomas and colorectal cancers, we identified specific changes in enhancers from normal tissue to these neoplastic lesions. Importantly, we noted gains of enhancers in a large number of genomic loci in colon cancer compared to adjacent normal tissues. These enhancers are enriched in important signaling components including Notch, Wnt, and stem cell regulators. We specifically noted changes in enhancer regions in the proximity of ASCL2 (intestinal cancer stem cell gene), SALL4 (early pluripotency marker) as well as FZD10 and CTNNB1 (Wnt signaling). A preliminary Cas9-based deletion study suggested these enhancers to be functional in regulating gene expression, and currently its effect on cell proliferation and other cancer properties is being investigated. Further, we reasoned that blocking aberrantly gained enhancers using BRD inhibitor in combination with pathway inhibitors could be a useful strategy in this cancer. Our data supported this hypothesis, and we are currently performing a systematic study to identify most effective combinations. In summary, we have identified aberrant enhancer gains as a major feature of colorectal cancer and propose this to be utilized as a therapeutic approach. Citation Format: Elias Orouji, Ayush Raman, Ming Tang, Mayura Dhamdhere, Kunal Rai. Colorectal cancer epigenomic landscape [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 4315.
Abstract 188: Regulation of breast cancer progression by stromal DDR1
Authors: Xiujie Sun
Journal: Cancer Research (2018)

Abstract Adipose stromal cells (ASC) constitute a significant component of breast stroma. Emerging evidence demonstrates a functional interaction between ASC and breast cancer (BC) cells. Here, we report that stromal discoidin domain receptor 1 (DDR1) is important for ASC-BC communication. Using a DDR1 knockout mouse model, we find that syngeneic mammary tumors grow more slowly in KO mice than wild-type littermate controls. In vitro, loss of DDR1 in stromal vascular fraction (SVF) impairs its ability to stimulate migration and invasion of tumor cells. Furthermore, we show that DDR1-dependent IL-6 production in SVF is responsible for the SVF effect on tumor cells. These results uncover a previously unrecognized role of stromal DDR1 in BC progression and a potential therapeutic target for BC treatment. Citation Format: Xiujie Sun. Regulation of breast cancer progression by stromal DDR1 [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 188.
Left Main Revascularization With PCI or CABG in Patients With Chronic Kidney Disease
Authors: Gennaro Giustino, Roxana Mehran, Patrick W. Serruys, Joseph F. Sabik, Milan Milojevic, Charles A. Simonton, John D. Puskas, David E. Kandzari, Marie-Claude Morice, David P. Taggart, Anthony H. Gershlick, Philippe Généreux, Zixuan Zhang, Thomas McAndrew, Björn Redfors, Michael Ragosta, Irving L. Kron, Ovidiu Dressler, Martin B. Leon, Stuart J. Pocock, Ori Ben-Yehuda, Arie Pieter Kappetein, Gregg W. Stone
Journal: Journal of the American College of Cardiology (2018)
Abstract 4473: Tumorigenesis by deregulation of CRAD-controlled cytoskeleton dynamics
Authors: Youn-Sang Jung, Wenqi Wang, Sohee Jun, Jie Zhang, Mrianl Srivastava, Moon Jong Kim, Esther M. Lien, Joan Shang, Pierre D. McCrea, Songlin Zhang, Junjie Chen, Jae-Il Park
Journal: Cancer Research (2018)

Abstract Epithelial cell behavior and homeostasis are mainly modulated by the cytoskeleton and cell adhesion. However, much concerning epithelial cell deregulation in cancer remains unknown. We identified Cancer-related Regulator of Actin Dynamics (CRAD) as frequently mutated or transcriptionally downregulated in colorectal cancer. We found that CRAD is a capping protein inhibitor and stabilizes the cadherin-catenin-actin (CCA) complex. CRAD inactivation disrupts the CCA complex via inhibiting actin polymerization, liberating β-catenin and aberrantly activating Wnt pathway. In mice, CRAD knockout induces the loss of epithelial cell integrity and hyperactivates Wnt signaling, resulting in intestinal adenoma development. With APC mutation, CRAD knockout induces and accelerates mucinous and invasive adenoma development in the colorectum. These results define CRAD as a new tumor suppressor, of which inactivation deregulates the cytoskeleton and hyperactivates Wnt signaling, initiating mucinous intestinal tumorigenesis. Our study reveals the unexpected roles of an actin cytoskeletal regulator in maintaining epithelial cell integrity. Citation Format: Youn-Sang Jung, Wenqi Wang, Sohee Jun, Jie Zhang, Mrianl Srivastava, Moon Jong Kim, Esther M. Lien, Joan Shang, Pierre D. McCrea, Songlin Zhang, Junjie Chen, Jae-Il Park. Tumorigenesis by deregulation of CRAD-controlled cytoskeleton dynamics [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 4473.
Abstract 3319: Epigenetic upregulation of E3 ubiquitin ligase CBLC enhances EGFR dysregulation and signaling
Authors: Shiao-Ya Hong, Yu-Rung Kao, Te-Chang Lee, Cheng-Wen Wu
Journal: Cancer Research (2018)

Abstract CBLC (CBL proto-oncogene c) belongs to the CBL protein family which has E3 ubiquitin ligase activity towards activated receptor tyrosine kinases. CBLC expression is physiologically restricted to normal epithelial cells but frequently upregulated in non-small cell lung cancer (NSCLC). Compared to its family members, very little is known about the functions of CBLC in tumorigenesis. Here, we demonstrated that CBLC is an epigenetically demethylated target and its expression can be upregulated after treatment with a DNA methylation inhibitor, 5'-azacytidine in NSCLC cells. CBLC depletion significantly inhibited cell viability and clonogenicity in vitro and reduced the tumor growth in a xenograft model. In addition, CBLC silencing further sensitized EGFR-mutated NSCLC cells to tyrosine kinase inhibitors treatment. On the other hand, after ligand stimulation, ectopic expression of CBLC enhanced the activation of EGFR and its downstream ERK1/2 signaling via competing with CBL for EGFR binding. By analyzing the ubiquitin linkages on activated EGFR (aEGFR), we found that CBLC ubiquitinated and positively regulated aEGFR stability through the conjugation of polyubiquitin by K6 and K11 linkages. The CBLC-mediated polyubiquitination promoted aEGFR preferentially recycling back to the plasma membrane or trafficking to the cell nucleus. In summary, we demonstrate a novel mechanism by which aEGFR escape lysosomal degradation in a CBLC/ubiquitin-dependent manner to sustain its activation. Our work identifies CBLC as a potential diagnostic biomarker and also points to its utilization as a novel therapeutic target for NSCLC therapy. Citation Format: Shiao-Ya Hong, Yu-Rung Kao, Te-Chang Lee, Cheng-Wen Wu. Epigenetic upregulation of E3 ubiquitin ligase CBLC enhances EGFR dysregulation and signaling [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 3319.
Abstract 1665: AZ304, a novel dual BRAF inhibitor, exerts antitumor activity in colorectal cancers independent of BRAF status
Authors: Rui Ma, Ling Xu, Xiaofang Che, Xiujuan Qu, Lisa Drew, Minhui Shen, Tony Cheung, Yunpeng Liu
Journal: Cancer Research (2018)

Abstract Background: BRAF mutation is associated with poor clinical outcome of malignant tumors and mediates resistance to chemotherapy and targeted therapy. We aimed to determine whether wild type and V600E mutant BRAF colorectal cancers exhibit distinct sensitivities to dual BRAF inhibitor, AZ304. Methods: We measured kinase activity by AlphaScreen assay. MTT assays, colony-formation assays, and Western blot were performed to evaluate the in vitro anti-tumor effects of AZ304. In vivo efficacy was investigated by xenograft study and Immunohistochemistry. Results: AZ304 exhibited potent inhibitory activity against both wild type and V600E mutant forms of the serine/threonine-protein kinase BRAF with enzyme IC50values of 79nM and 38nM, respectively. By suppressing the ERK phosphorylation, AZ304 led to effective cell proliferation inhibition against a panel of human cancer cell lines with different BRAF and RAS generic status. In selected colorectal cancer cell lines, AZ304 significantly inhibited cell growth in vitro and in vivo, regardless of BRAF genetic status. Additionally, combination with the EGFR inhibitor Cetuximab enhanced the potency of AZ304 independent of BRAF mutational status. Conclusions: The BRAF inhibitor, AZ304, had a broad spectrum of antitumor activities and the combination with Cetuximab significantly enhanced AZ304 potency against colorectal cancers in vitro and in vivo. Citation Format: Rui Ma, Ling Xu, Xiaofang Che, Xiujuan Qu, Lisa Drew, Minhui Shen, Tony Cheung, Yunpeng Liu. AZ304, a novel dual BRAF inhibitor, exerts antitumor activity in colorectal cancers independent of BRAF status [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 1665.
Low-Dose Aspirin for Primary Prevention of Cardiovascular Events in Patients With Type 2 Diabetes Mellitus
Authors: Yoshihiko Saito, Sadanori Okada, Hisao Ogawa, Hirofumi Soejima, Mio Sakuma, Masafumi Nakayama, Naofumi Doi, Hideaki Jinnouchi, Masako Waki, Izuru Masuda, Takeshi Morimoto
Journal: Circulation (2016)

The long-term efficacy and safety of low-dose aspirin for primary prevention of cardiovascular events in patients with type 2 diabetes mellitus are still inconclusive.The JPAD trial (Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes) was a randomized, open-label, standard care-controlled trial examining whether low-dose aspirin affected cardiovascular events in 2539 Japanese patients with type 2 diabetes mellitus and without preexisting cardiovascular disease. Patients were randomly allocated to receive aspirin (81 or 100 mg daily; aspirin group) or no aspirin (no-aspirin group) in the JPAD trial. After that trial ended in 2008, we followed up with the patients until 2015, with no attempt to change the previously assigned therapy. Primary end points were cardiovascular events, including sudden death, fatal or nonfatal coronary artery disease, fatal or nonfatal stroke, and peripheral vascular disease. For the safety analysis, hemorrhagic events, consisting of gastrointestinal bleeding, hemorrhagic stroke, and bleeding from any other sites, were also analyzed. The primary analysis was conducted for cardiovascular events among patients who retained their original allocation (a per-protocol cohort). Analyses on an intention-to-treat cohort were conducted for hemorrhagic events and statistical sensitivity.The median follow-up period was 10.3 years; 1621 patients (64%) were followed up throughout the study; and 2160 patients (85%) retained their original allocation. Low-dose aspirin did not reduce cardiovascular events in the per-protocol cohort (hazard ratio, 1.14; 95% confidence interval, 0.91-1.42). Multivariable Cox proportional hazard model adjusted for age, sex, glycemic control, kidney function, smoking status, hypertension, and dyslipidemia showed similar results (hazard ratio, 1.04; 95% confidence interval, 0.83-1.30), with no heterogeneity of efficacy in subgroup analyses stratified by each of these factors (all interaction P>0.05). Sensitivity analyses on the intention-to-treat cohort yielded consistent results (hazard ratio, 1.01; 95% confidence interval, 0.82-1.25). Gastrointestinal bleeding occurred in 25 patients (2%) in the aspirin group and 12 (0.9%) in the no-aspirin group (P=0.03), and the incidence of hemorrhagic stroke was not different between groups.Low-dose aspirin did not affect the risk for cardiovascular events but increased risk for gastrointestinal bleeding in patients with type 2 diabetes mellitus in a primary prevention setting.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00110448.
The Intermediary Metabolism of Cholesterol
Authors: Konradbloch
Journal: Circulation (1950)

Animal tissues synthesize cholesterol from metabolities of small molecular size, principally cholesterol. This synthetic process is known to take place in the liver but may also occur in other organs. In all tissues, with the exception of brain and nerve, cholesterol is continually regenerated. Cholesterol is the parent substance which the animal organism uses to produce bile acids, progesterone and possibly also other steroid hormones. The catabolism of cholesterol leads to the formation of several saturated, metabolically inert sterols, cholestenone presumably being the common intermediate.
Abstract 4492: Aggressive breast cancer cells reduce CCL5 and Nodal expression in response to a human adipose-derived stromal cell microenvironment
Authors: Daniel Berrebi, Abhishek Yadav, Eric Lundstrom, Nicole Werwie, Dominic Muttillo, Richard E. Seftor, Elisabeth A. Seftor, Linda Vona-Davis
Journal: Cancer Research (2018)

Abstract Clinical studies indicate that obesity is correlated with poor outcomes in breast cancer patients. Obese individuals have a high proportion of adipose tissue, which is abundant in stem and progenitor cells. Human adipose-derived stromal cells (hADSCs) secrete several cytokines including CCL5, an inflammatory chemokine shown to increase tumor metastatic ability in vitro. We previously identified that CCL5 is secreted into the microenvironment when hADSCs are co-cultured with breast tumor cells. When the clinical relevance of CCL5 was assessed using cBioPortal, an open-source genomics database, we found that CCL5 mRNA overexpression was correlated with increased overall survival in breast cancer patients, which counters what we and others have observed in vitro. In this study, we compared the expression of CCL5 and Nodal, a potent embryonic morphogen re-expressed by aggressive cancer cells, in either hADSC or MDA-MB-231 breast cancer cells in response to three-dimensional collagen matrices conditioned by hADSCs or breast cancer cells. After preconditioning a three-dimensional collagen matrix with either hADSCs or MDA-MB-231 cells (and following removal of the cells), the denuded three-dimensional matrices were reseeded with the opposite cell type. We found that the expression of both CCL5 and Nodal was significantly reduced in the breast cancer cells plated on the hADSC-preconditioned matrix. However, hADSCs did not express Nodal or alter CCL5 protein expression when grown on a MDA-MB-231-preconditioned matrix. MDA-MB-231 cells plated onto a hADSC-preconditioned matrix appeared more mesenchymal and stem-like, while the adipose stem cells placed into a tumor-preconditioned matrix were induced into a more aggressive cancer cell phenotype by engaging in vasculogenic mimicry. Furthermore, we found there was no change in cell proliferation of any cells grown under these different conditions. These observations suggest a relationship between hADSCs and the breast tumor microenvironment where human adipose-derived stem cells appear to inhibit the expression of CCL5 and Nodal by the aggressive tumor cells without altering tumor cell proliferation. Citation Format: Daniel Berrebi, Abhishek Yadav, Eric Lundstrom, Nicole Werwie, Dominic Muttillo, Richard E. Seftor, Elisabeth A. Seftor, Linda Vona-Davis. Aggressive breast cancer cells reduce CCL5 and Nodal expression in response to a human adipose-derived stromal cell microenvironment [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 4492.
Abstract 20761: Predictors of Incident HFrEF and HFpEF in a Large Multiracial Cohort of Preclinical Diastolic Dysfunction
Authors: Lili Zhang, Jared J Liebelt, Nidhi Madan, Jian Shan, Cynthia C Taub
Journal: Circulation (2016)

Introduction: Preclinical diastolic dysfunction (PDD) is defined as left ventricular diastolic dysfunction and normal left ventricular ejection fraction (LVEF) without symptoms. PDD is a known risk...
Abstract SY26-03: Dual targeting of senescence and tumor immunity for cancer therapy
Authors: Andrea Alimonti
Journal: Cancer Research (2018)

Abstract Senescence induction in cancer works as a potent weapon to eradicate tumorigenesis. Therapies that enhance senescence not only promote a stable cell growth arrest but also work as a strong stimulus for the activation of the tumor immune response. However, cancer cells bypass senescence by either acquiring new genetic alterations or by disrupting the tumor immune response. Here, I will discuss the identification of oncogenic pathways that bypass Pten-loss-induced cellular senescence, thereby promoting prostate cancer progression and metastasis. Next, I will present evidence demonstrating that both tumor-infiltrating myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) control senescence induction in chemotherapy-treated prostate cancers and that immunotherapies that interfere with either MDSCs' recruitment or the polarization of TAMs promote senescence in advanced PTEN-deficient prostate cancer. Citation Format: Andrea Alimonti. Dual targeting of senescence and tumor immunity for cancer therapy [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 SY26-03.