tbuckley/cabot-search huggingface dataset:
Abstract 4711: Modulation of NFκ-B signaling to optimize antitumor characteristics in macrophages
Authors: Esther Liu, Alyssa A. Hoover, Whitney R. Harris, Whitney Barham, Oleg Tikhomirov, Dineo Khabele, Zahra Mirafzahli, Todd D. Giorgio, Andrew J. Wilson, Fiona E. Yull
Journal: Cancer Research (2018)

Abstract While it is known that nuclear factor κ-B (NF-κB) signaling within macrophages regulates expression of downstream targets that can mediate either pro- or antitumor functions, the mechanisms that define predominant characteristics are not well understood. As macrophages are present in the tumor microenvironment of diverse tumor types, their characteristics have the potential to either support or hinder tumor growth and metastatic spread. Therefore, a method to shift the balance of tumor associated macrophages from pro- to antitumor functions could potentially target tumor cells directly and also recruit and activate other immune cells, resulting in significant therapeutic benefit. Our studies are designed to gain an understanding of how to use modulation of NF-κB signaling as the “pinch point” to generate antitumor phenotypes and determine how to achieve this modulation in a patient. We are using immortalized bone marrow-derived macrophages or ex vivo tumor-associated macrophages in cell culture approaches and inducible transgenic mice in in vivo approaches to investigate the mechanisms by which NF-κB defines macrophage characteristics. Interactions with tumor cells are also being investigated using co-culture and murine models. Our data suggests that high levels of NFκ-B activity in macrophages induce both direct tumor cell killing and immune stimulating responses. We are testing two different translational approaches. The first is liposomal muramyl tripeptide ethanolamine that acts as an immune stimulant by increasing NF-κB activity in macrophages. The second is preferential delivery of siRNA against the inhibitor of NFκ-B (IκB-alpha) to tumor-associated macrophages using polymeric nanoparticles. We hope to better understand the mechanisms by which NFκ-B regulates macrophage functions to inform development of a novel macrophage-based immunotherapy that could be effective across a wide spectrum of solid tumors and metastatic disease. Citation Format: Esther Liu, Alyssa A. Hoover, Whitney R. Harris, Whitney Barham, Oleg Tikhomirov, Dineo Khabele, Zahra Mirafzahli, Todd D. Giorgio, Andrew J. Wilson, Fiona E. Yull. Modulation of NFκ-B signaling to optimize antitumor characteristics in macrophages [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 4711.
Postconditioning Inhibits Mitochondrial Permeability Transition
Authors: LaurentArgaud, OdileGateau-Roesch, OlivierRaisky, JosephLoufouat, DominiqueRobert, MichelOvize
Journal: Circulation (2005)

Background— Brief periods of ischemia performed just at the time of reperfusion can reduce infarct size, a phenomenon called “postconditioning.” After reflow, opening of the mitochondrial permeability transition pore (mPTP) has been involved in lethal reperfusion injury. We hypothesized that postconditioning may modulate mPTP opening. Methods and Results— Anesthetized open-chest rabbits underwent 30 minutes of ischemia and 4 hours of reperfusion. Control hearts underwent no additional intervention. Postconditioning consisted of 4 episodes of 1 minute of coronary occlusion and 1 minute of reperfusion performed after 1 minute of reflow after the prolonged ischemia. Preconditioning consisted of 5 minutes of ischemia and 5 minutes of reperfusion before the 30-minute ischemia. An additional group of rabbits received 5 mg/kg IV of NIM811, a specific inhibitor of the mPTP, 1 minute before reperfusion. Infarct size was assessed by triphenyltetrazolium staining. Mitochondria were isolated from the risk region myoc...
Abstract 13271: Aortic Inflammation Continues in Patients With A History of Kawasaki Disease and Persistent Arterial Aneurysms
Authors: Kenji Suda, Nobuhiro Tahara, Akihiro Honda, Tomohisa Nakamura, Hironaga Yoshimoto, Shintaro Kishimoto, Yoshiyuki Kudo, Motofumi Iemura, Yoshihiro Fukumoto
Journal: Circulation (2015)

Introduction: Kawasaki disease (KD) is well known vasculitis that primarily affects small to middle sized arteries such as coronary arteries and/or peripheral arteries. However, little evidence showed inflammation of large vasculature such as the aorta in patients with KD. Measurements of 18F-fluorodeoxyglucose (FDG) uptake evaluated by positron emission tomography (PET) and X-ray computed tomography (CT) could be useful to identify inflammatory activity of the vessel wall. Hypothesis: We hypothesized that aortic inflammation continues long after KD. Methods: FDG-PET/CT was performed in 19 patients with a history of KD. Of 19 patients, 11 patients still had persistent coronary and/or systemic vascular aneurysms (KD-An) and the remaining 8 revealed regression of arterial aneurysms (KD-Reg). Patients suffered from KD at 2.8 ± 3.2 years old and underwent FDG-PET at 22.2 ± 8.0 years old. FDG-PET was also performed in 5 control with age 14.1 ± 2.6 years old. Vascular inflammation was measured by blood-normalized standardized uptake value, known as a target-to-background ratio (TBR). Also demographic and laboratory data were collected. Results: Aortic FDG uptake was distinctly intense in patients with a history of KD and persistent vascular aneurysms. The Aortic TBR was significantly higher in KD-An (1.50 ± 0.30) than KD-Reg (1.11 ± 0.13, p = 0.004) or controls (1.03 ± 0.25, p=0.003). Although Control was significantly younger and had significantly lower body mass index, there was no significant correlation between these values and TBR. Also there was no significant difference in laboratory data including lipid profiles and glycemic status among 3 groups. Conclusions: Vascular inflammation of the aortic wall continues long after KD with persistent arterial aneurysms.
Abstract 3066: Chemotherapy-induced GSTO1 interacts with ryanodine receptor RYR1 to trigger Ca2+-dependent breast cancer stem cell enrichment
Authors: Haiquan Lu, Gregg Semenza
Journal: Cancer Research (2018)

Abstract Breast cancer stem cells (BCSCs) play a critical role in tumor recurrence and metastasis. Exposure of breast cancer cells to chemotherapy leads to an enrichment of BCSCs. Here, we demonstrate that chemotherapy induces the expression of glutathione S-transferase omega 1 (GSTO1), which is dependent on hypoxia-inducible factor 1 (HIF-1) and HIF-2. Knockdown of GSTO1 expression abrogates carboplatin-induced BCSC enrichment, decreases tumor initiation and metastatic capacity, and delays tumor recurrence after chemotherapy. GSTO1 interacts with ryanodine receptor RYR1 and promotes calcium release from endoplasmic reticulum. Increased cytosolic calcium levels activate PYK2 → SRC → STAT3 signaling, leading to increased expression of pluripotency factors and BCSC enrichment. HIF inhibition blocks chemotherapy-induced GSTO1 expression and BCSC enrichment. Combining HIF inhibitors with chemotherapy may improve clinical outcome in breast cancer. Citation Format: Haiquan Lu, Gregg Semenza. Chemotherapy-induced GSTO1 interacts with ryanodine receptor RYR1 to trigger Ca2+-dependent breast cancer stem cell enrichment [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 3066.
Decreased Expression of Voltage- and Ca2+-Activated K+ Channels in Coronary Smooth Muscle During Aging
Authors: JureMarijic, QingXiaLi, MinSong, KazuhideNishimaru, EnricoStefani, LigiaToro
Journal: Circulation Research (2001)

Abstract—Aging is the main risk factor for coronary artery disease. One characteristic of aging coronary arteries is their enhanced contractile responses to endothelial vasoconstricting factors, which increase the risk of coronary vasospasm in older people. Because large-conductance voltage- and Ca2+-activated K+ channels (MaxiK) are key regulators of vascular tone, we explored the possibility that this class of channels is diminished with increasing age. Using site-directed antibodies recognizing the pore-forming α subunit and electrophysiological methods, we demonstrate that the number of MaxiK channels is dramatically diminished in aged coronary arteries from old F344 rats. Channel density was reduced from 52±9 channels/pF (3 months old) to 18±5 channels/pF (25 to 30 months old), which represents a 65% reduction in the older population. Pixel intensity of Western blots was also diminished by ≈50%. Moreover, the age-related decrease in the channel protein expression was also evident in humans, which sho...
Abstract MP73: Relationship of Insulin Resistance to Prevalence and Progression of Coronary Artery Calcification Beyond Metabolic Syndrome in a General Population
Authors: Masahiro Yamazoe, Takashi Hisamatsu, Katsuyuki Miura, Sayaka Kadowaki, Maryam Zaid, Aya Kadota, Akira Fujiyoshi, Robert Abbott, Hisatomi Arima, Akira Sekikawa, Hiroshi Maegawa, Minoru Horie, Hirotsugu Ueshima
Journal: Circulation (2016)

Introduction: Association between insulin resistance (IR) and prevalence of coronary artery calcification (CAC) has been inconsistent after adjustment for metabolic syndrome (MetS). In addition, relation of IR to progression of CAC has remained unclear. Recent basic science studies have reported that IR could promote atherosclerosis not only through the mechanisms that involve systemic factors such as dyslipidemia and hypertension, but also through the effect of perturbed insulin signaling at the cell level. Therefore we assessed the hypothesis that IR is associated with CAC prevalence or progression independently of MetS components in a general population. Methods: We conducted a population-based study in a random sample of men aged 40-79 years living in Kusatsu City, Shiga, Japan, without prior coronary heart disease (Shiga Epidemiological Study of Subclinical Atherosclerosis; SESSA). IR was determined by homeostasis model assessment of IR index (HOMA-IR). We measured CAC at baseline and five years later with noncontrast computed tomography. CAC prevalence was defined as baseline CAC score &gt; 0, and CAC progression as a change &gt; 2.5 between the square root transformed values of baseline and follow-up CAC scores. Multivariate logistic regression was performed to calculate adjusted odds ratios (OR) and 95% confidence intervals (95% CI) in total participants and in those without diabetes. Results: Of 1022 total participants at baseline (mean age, 64 ± 10 years), CAC prevalence was found in 658 (64.4%), and of 804 participants at follow-up (mean follow-up duration, 4.9 ± 1.3 years), CAC progression in 371 (46.1%). Even after adjustment for MetS components in addition to other confounding factors, higher HOMA-IR was independently associated with CAC prevalence (OR, 1.35; 95% CI, 1.11-1.64; P = 0.003) and CAC progression (OR, 1.44; 95% CI, 1.18-1.74; P &lt; 0.001). In participants without diabetes (N = 807 at baseline, N = 638 at follow-up), we observed similar positive associations of HOMA-IR with CAC prevalence (OR, 1.30; 95% CI 1.05-1.61; P = 0.016) and CAC progression (OR 1.31; 95% CI 1.03-1.67; P = 0.025). In contrast, fasting glucose and hemoglobin A1c were not related to CAC prevalence and progression. Conclusion: In conclusion, higher IR was associated with CAC prevalence and progression independently of MetS components in general men and also in those without diabetes. Adding measuring of IR as routine clinical examination may provide additional predictive value beyond traditional risk assessment especially among population without diabetes.
Abstract 50: Small molecule Ring1B-Bmi1 inhibitor attenuates PRC1 E3 ligase activity and targets leukemia stem cells self-renewal
Authors: Shirish Shukla, Felicia Gray, Weijiang Ying, Hyoje Cho, Qingjie Zhao, Hongzhi Miao, Hongzhi Miao, Trupta Purohit, Monica Guzman, Jolanta Grembecka, Tomasz Cierpicki
Journal: Clinical Cancer Research (2017)

Abstract Polycomb group proteins, Ring1B and Bmi1 constitute catalytic component of Poly-comb Repressive Complex 1(PRC1) and execute gene silencing through histone H2A lysine119 ubiquitination (H2AK119ub). Bmi1 is overexpressed in a wide range of human cancers and has been implicated in regulation of leukemic stem cells (LSCs) self-renewal capacity. LSCs are refractory to the conventional therapies and eventually lead to the disease relapse. Small-molecule inhibitors of the Ring1B-Bmi1 E3 ligase activity have not been reported to date, but are highly desired as potential therapeutic agents to target LSCs. In the present study, employing fragment-based screening and extensive medicinal chemistry optimization, we developed WY332 that binds to Ring1B-Bmi1 with low micromolar affinity. Extensive characterization of the WY332 demonstrated selective reduction in Ring1B-Bmi1 mediated H2AK119ub levels in vitro and in leukemic cells whereas structurally similar and less potent compound displayed similar effect at much higher concentrations. Treatment of model cell lines, TEX and M9:ENL1, enriched in leukemia initiating cells show that the reduction in H2AK119ub levels is associated with induction of cellular differentiation and altered colony-forming potential. Further, gene expression analysis of TEX cells treated with WY332 indicated reprogramming of CD34+ cells and revealed significant increase in expression of genes suppressed in LSCs. In addition, WY332 treatment led to a marked increase in CD11b expression and significantly decreased CD34 expression in TEX cells. Evaluation of WY332 in patients' derived primary AML cells further revealed reprogramming of gene expression profile and phenotypic markers associated with LSCs self-renewal property. Overall, these compounds represent the novel small-molecule inhibitors of Ring1B-Bmi1 which inhibit E3 ubiquitin ligase activity and impair leukemic stem cell self-renewal capacity. Citation Format: Shirish Shukla, Felicia Gray, Weijiang Ying, Hyoje Cho, Qingjie Zhao, Hongzhi Miao, Hongzhi Miao, Trupta Purohit, Monica Guzman, Jolanta Grembecka, Tomasz Cierpicki. Small molecule Ring1B-Bmi1 inhibitor attenuates PRC1 E3 ligase activity and targets leukemia stem cells self-renewal [abstract]. In: Proceedings of the Second AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; May 6-9, 2017; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(24_Suppl):Abstract nr 50.
Inhibition of Vascular Smooth Muscle Cell Growth Through Antisense Transcription of a Rat Insulin-Like Growth Factor I Receptor cDNA
Authors: JieDu, PatrickDelafontaine
Journal: Circulation Research (1995)

Abstract Insulin-like growth factor I (IGF I) is an autocrine/paracrine growth factor that is produced in multiple tissues and is essential for normal developmental growth. Its effects are mediated by activation of a membrane-bound tyrosine kinase receptor, IGF IR. On the basis of the partial rat IGF IR α-chain cDNA sequence previously reported, we cloned cDNA encoding the full-length rat IGF IR. The deduced amino acid sequence predicts a 1370–amino acid receptor precursor, which includes signal sequence, a 707–amino acid α-chain, a 4-Arg cleavage site, and a 629–amino acid β-chain. Overall, similarity to human IGF IR is 89% and 98% at the nucleotide and amino acid levels, respectively. Antisense IGF IR expression constructs in vectors incorporating Epstein-Barr virus replicative signals and the cytomegalovirus promoter/enhancer or the inducible human metallothionein IIa promoter/enhancer were assembled and stably transfected into cultured rat aortic smooth muscle cells. Clone CA9 (constitutively expressi...
Combined Abnormalities of Semilunar Valves
Authors: KeijiHirooka, ShujiHashimoto, NorioTanaka, NaoakiYamada, YoshikazuMasuda, AkihisaHanatani, SatoshiNakatani, YoshioYasumura, KunioMiyatake, MasakazuYamagishi
Journal: Circulation (2001)
Local Expression of C-Type Natriuretic Peptide Suppresses Inflammation, Eliminates Shear Stress–Induced Thrombosis, and Prevents Neointima Formation Through Enhanced Nitric Oxide Production in Rabbit Injured Carotid Arteries
Authors: Jian-YongQian, AkihiroHaruno, YujiroAsada, TakahiroNishida, YasushiSaito, TakehisaMatsuda, HikaruUeno
Journal: Circulation Research (2002)

We previously observed that adenovirus-mediated expression of C-type natriuretic peptide (CNP) markedly inhibits neointima formation after balloon injury in rat carotid arteries, suggesting that CNP has multiple effects over its modest inhibitory effect on cellular proliferation. We hypothesized that local expression of CNP might have antithrombotic and antiinflammatory effects. Balloon-injured rabbit carotid arteries were infected with an adenovirus expressing human CNP (AdCNP), human tissue factor pathway inhibitor (AdTFPI), or bacterial β-galactosidase (AdLacZ) or infused with saline. Seven days later, shear stress–induced thrombosis was evaluated by cyclic flow variation (CFV), reflecting recurrent cycles of thrombus formation and dislodgment. CFV was observed in all AdLacZ-infected and saline-infused arteries but not in arteries infected with AdCNP or AdTFPI even in the presence of epinephrine. Injury increased the expressions of intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion m...
Abstract 3084: Epstein Barr virus-encoded LMP1 activates the mTORC2 signaling pathway to reprogram glucose metabolism in nasopharyngeal epithelial cell
Authors: Jun Zhang, Weitao Lin, Chi-Man Tsang, Teng Fei Liu, W C. Tang, Tim Ling Yip, Wen Deng, Lin Jia, Sai-Wah Tsao
Journal: Cancer Research (2018)

Abstract Epstein-Barr virus (EBV) infection of preinvasive nasopharyngeal epithelium is believed to be an essential initiation event during nasopharyngeal carcinoma pathogenesis, but the underlying mechanisms are largely undefined. Here we demonstrate that EBV-encoded LMP1 reprograms the glucose metabolism from oxidative phosphorylation to glycolysis of nasopharyngeal epithelial (NPE) is a major process for NPC pathogenesis. RNA-seq analysis indicates that EBV infection reprograms the glucose metabolism from glycolysis and oxidative phosphorylation and enhances the metabolic associated pathways. Our study show EBV encoded LMP1 is important for this event, EBV infection and LMP1 expression enhance the extracellular acidification rate and decrease the oxygen consumption rate in NPE cells. We further show that activation of mTORC2/AKT signaling is involved in this metabolic reprogramming in EBV-infected NPE cells. Genetic or pharmacologic inhibition of the mTORC2/AKT signaling blocks the LMP1-induced glycolysis. In summary, this study provides evidences of involvement of EBV infection in metabolic reprogramming of NPE cells. Acknowledgment: This project was supported by funding from the Research Grants Council, Hong Kong: General Research Fund (17120814, 17161116, 17111516, 171110315), Area of Excellence (AoE/M-06/08), Theme-Based Research Scheme (T12-401/13-R), Collaborative Research Fund (Project reference: C7027-16G); Health and Medical Research Fund of Hong Kong (12110782, 13120872, 04151726); and CRCG, University of Hong Kong, Hong Kong. Citation Format: Jun Zhang, Weitao Lin, Chi-Man Tsang, Teng Fei Liu, W C. Tang, Tim Ling Yip, Wen Deng, Lin Jia, Sai-Wah Tsao. Epstein Barr virus-encoded LMP1 activates the mTORC2 signaling pathway to reprogram glucose metabolism in nasopharyngeal epithelial cell [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 3084.
Abstract LB-144: Molecular signatures of circulating melanoma cells for monitoring early response to immune checkpoint therapy
Authors: Xin Hong, Ryan J. Sullivan, Mark Kalinich, Tanya Kwan, Shiwei Pan, Joseph A. LiCausi, John D. Milner, Linda T. Nieman, Ben S. Wittner, Uyen Ho, Tianqi Chen, Ravi Kapur, Don Lawrence, Keith T. Flaherty, Lecia V. Sequist, Sridhar Ramaswamy, David T. Miyamoto, Michael Lawrence, Anita Giobbie-Hurder, Mehmet Toner, Kurt J. Isselbacher, Shyamala Maheswaran, Daniel A. Haber
Journal: Cancer Research (2018)

Abstract A subset of patients with metastatic melanoma have sustained remissions following treatment with immune checkpoint inhibitors. However, analyses of pretreatment tumor biopsies for markers predictive of response, including PD-L1 expression and mutational burden, are insufficiently precise to guide treatment selection and clinical radiographic evidence of response on therapy may be delayed, leading to some patients receiving potentially ineffective but toxic therapy. Here, we developed a molecular signature of melanoma Circulating Tumor Cells (CTCs) to quantify early tumor response using blood-based monitoring. A quantitative 19-gene digital RNA signature (CTC-Score) applied to microfluidically-enriched CTCs robustly distinguishes melanoma cells, within a background of blood cells in reconstituted and in patient-derived (N=42) blood specimens. In a prospective cohort of 49 patients treated with immune checkpoint inhibitors, a decrease in CTC-Score within 7 weeks of therapy correlates with marked improvement in progression-free survival (Hazard Ratio (HR): 0.17, P=0.008) and overall survival (HR: 0.12, P=0.04). Thus, digital quantitation of melanoma CTC-derived transcripts enables serial noninvasive monitoring of tumor burden, supporting the rational application of immune checkpoint inhibition therapies. Citation Format: Xin Hong, Ryan J. Sullivan, Mark Kalinich, Tanya Kwan, Shiwei Pan, Joseph A. LiCausi, John D. Milner, Linda T. Nieman, Ben S. Wittner, Uyen Ho, Tianqi Chen, Ravi Kapur, Don Lawrence, Keith T. Flaherty, Lecia V. Sequist, Sridhar Ramaswamy, David T. Miyamoto, Michael Lawrence, Anita Giobbie-Hurder, Mehmet Toner, Kurt J. Isselbacher, Shyamala Maheswaran, Daniel A. Haber. Molecular signatures of circulating melanoma cells for monitoring early response to immune checkpoint 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 LB-144.
Abstract 20339: Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes Recapitulate Clinical Phenotypes in a Multigenerational Family With Early Onset Atrial Fibrillation and Long Qt Syndrome
Authors: Chuanchau J Jou, Michael Riedel, Neil Bowles, Cammon Arrington, Steven Bleyl, Brett Kennedy, Mark Yandell, Susan Etheridge, Elizabeth Saarel, Thomas Pilcher, Shuping Lai, Chase Pribble, Brandon Bacon, Jacob Saunders, Lindsay Meyers, Angelica Lopez-Izquierdo, Scott Cho, Stacey Knight, J. Brent Muhlestein, John Carlquist, Jeffrey Anderson, Ivor Benjamin, Martin Tristani-Firouzi
Journal: Circulation (2014)

Introduction: Early-onset atrial fibrillation (AF) and Long QT Syndrome (LQTS) are associated with gain- and loss-of-function mutations in cardiac potassium channel genes, respectively. Counterintu...