tbuckley/cabot-search huggingface dataset:
Abstract 15696: Cytochrome B5 Reductase 3 Sensitizes Soluble Guanylate Cyclase to Nitric Oxide
Authors: Anh T Nguyen, Mizanur M Rahaman, Stephanie M Mutchler, Megan Miller, Josef T Prchal, Victor Gordeuk, Emil Martin, Adam C Straub
Journal: Circulation (2015)

Impaired soluble guanylyl cyclase (sGC)-dependent nitric oxide (NO) signaling has been linked to numerous cardiovascular diseases (CVD) such as hypertension, myocardial infarction and atherosclerosis. Despite emerging evidence indicating the importance of sGC function within the cardiovascular system, the basic mechanisms that regulate sGC activity remain incompletely understood. Herein, we provide in vitro and in vivo evidence that cytochrome b5 reductase 3 (Cyb5R3) is an sGC heme iron reductase and regulates downstream cGMP signaling. Of major significance, we also demonstrate that a Cyb5R3 T116S polymorphism with allele frequency of 0.23 in African Americans associates with increase blood pressure and is incapable of reducing sGC. Proximity ligation assay (PLA) experiments show that endogenous Cyb5R3 and oxidized sGC associate. Knockdown of Cyb5R3 results in reduced cGMP production and downstream signaling in rat aortic smooth muscle cells (SMC). Overexpression of Cyb5R3 not only rescues cGMP production but also increases baseline cGMP, whereas T116S mutant does not. Finally, inhibition of Cyb5R3 in mice significantly increases systemic blood pressure. Our studies are the first to identify an sGC heme iron reductase, provide evidence for Cyb5R3 as a key biological regulator of sGC activity and vascular tone in SMC, and link a human polymorphism of Cyb5R3 to increased blood pressure; all of which may lead to the development of novel therapeutics targeting Cyb5R3 for the treatment of CVD. Importantly, the co-expression of Cyb5R3 and sGC in multiple cells types suggests that this regulation of sGC activity may have broad applications for multiple physiological and pathophysiological processes. Results: Conclusions:
Pivotal Role of mTORC2 and Involvement of Ribosomal Protein S6 in Cardioprotective Signaling
Authors: ToshiyukiYano, MarcellaFerlito, AngelAponte, AtsushiKuno, TetsujiMiura, ElizabethMurphy, CharlesSteenbergen
Journal: Circulation Research (2014)

Rationale:There is tight coupling between Akt activation and suppression of cell death. Full Akt activation requires mammalian target of rapamycin complex 2 (mTORC2), but the regulation of mTORC2 is unclear. Objective:To gain new insights into mechanisms of mTORC2/Akt signaling. Methods and Results:The role of mTORC2 in cardioprotection was examined. In perfused mouse hearts, ischemic preconditioning increased mTORC2 activity, leading to phosphorylation of Akt on Ser473. The protective effect of ischemic preconditioning was lost by pretreatment with dual mTORC inhibitors but not with rapamycin, an mTORC1 inhibitor, which indicates the fundamental role of mTORC2 activation in cardioprotection. Next, the regulation and downstream targets of mTORC2/Akt signaling were explored. We have found that ischemic preconditioning and other Akt activators (insulin and opioids) result in phosphorylation of ribosomal protein S6 (Rps6) at Ser235/236 in mouse hearts and neonatal rat ventricular myocytes. Rps6 interacts wit...
Initial Effects of the Left Ventricular Repair by Plication May Not Last Long in a Rat Ischemic Cardiomyopathy Model
Authors: Takeshi Nishina, Kazunobu Nishimura, Sadatoshi Yuasa, Senri Miwa, Takuya Nomoto, Yutaka Sakakibara, Nobuhiro Handa, Ichiro Hamanaka, Yoshihiko Saito, Masashi Komeda
Journal: Circulation (2001)

Background Long term effects of left ventricle (LV) repair surgery (LVR) for ischemic cardiomyopathy are not well understood. Methods and Results Sixty-nine rats developed ischemic cardiomyopathy with large akinetic LV area 4 weeks after the left anterior descending artery was ligated. In a second surgery 4 weeks later, 33 rats underwent LVR by plication of the akinetic LV area (LVR group), and 36 underwent rethoracotomy alone (sham group). No medication was used in either group. All rats survived the second surgery. LV end-diastolic dimension as measured by echocardiography, LV fractional shortening, and the maximal end-systolic pressure-volume relationship (E max ) as calculated from the data by catheter-tipped manometer and echocardiography improved in the LVR group after the second surgery, but LV end-diastolic dimension and E max gradually deteriorated as time passed. LV end-diastolic pressure improved 1 week after LVR but rose significantly 4 weeks after LVR. Brain natriuretic peptide mRNA was lower in the LVR group than in the sham group 1 week after LVR but not 4 weeks postoperatively. Conclusions Initial improvement in LV function and neurohormonal status after LVR did not last for 4 weeks in this rat model when untreated medically. The mechanism of deterioration should be elucidated to improve long-term results of LVR.
Abstract 18178: Cardiotonic Steroid Lactone Ring Hydrolysis by Paraoxonases Attenuates Na/K ATPase Mediated Signaling
Authors: David J Kennedy, Bruce S Levison, Jiang Liu, Malory Weber, Brendan Agatisa-Boyle, Mir Lim, Joseph I Shapiro, Diana Shih, Aldons J Lusis, Stanley L Hazen, W. H. Wilson Tang
Journal: Circulation (2015)

Introduction: Cardiotonic steroids (CTS) such as marinobufagenin and telocinobufagin (TCB) are significantly elevated in chronic kidney disease (CKD) and heart failure and can directly lead to inflammation and cardiac fibrosis upon binding and signaling through the Na+/K+-ATPase. The 17β-lactone ring of CTS is critical for Na+/K+-ATPase binding. Paraoxonases are a family of hydrolytic enzymes which exhibit lactonase activity, although their physiologic substrate(s) are unclear. Decreased serum PON activity and increased levels of CTS are associated with increased oxidant stress and adverse clinical outcomes in the setting of HF and CKD, yet whether decreased PON activity is mechanistically linked to increased CTS levels is unclear. Hypothesis: We tested the hypothesis that PONs are capable of CTS hydrolysis and that hydrolysis of CTS to their open-ring form renders them inactive. Methods/Results: First we measured the ability of recombinant PONs to hydrolyze the lactone ring of active TCB to form open-ring TCB (ORT). Recombinant PON-1 (58.0±2.0 U/mg), PON-2 (0.49±0.01 U/mg) and PON-3 (10.8±0.6 U/mg) had specific lactonase activity for TCB as measured with a continuous pH sensitive colormetric assay. Further, plasma from PON-1 KO mice had a markedly diminished ability to open the 17β-lactone ring of TCB to form resulting ORT aldehyde as measured by a Purpald reagent assay, whereas plasma from PON1-overexpressing mice had increased production of ORT compared to wild type controls. Data from 86-Rubidium uptake experiments in LLC-PK1 cells demonstrated ORT had significantly reduced inhibition of Na+/K+-ATPase compared to TCB (0.25nM of TCB vs. 5000 nM of ORT, p&lt;0.01). In both HK2 and human cardiac fibroblast cells, TCB but not ORT increased collagen-1 mRNA production in a dose dependent manner (1 to 100 nM, p&lt;0.01). Finally, in plasma from CKD patients (n=22) both marinobufagenin (r2=0.58; p&lt;0.01) and TCB (r2=0.31; p&lt;0.01) levels were inversely proportional to lactonase activity, suggesting higher lactonase activity is associated with lower levels of CTS. Conclusion: These studies suggest CTS may be a novel physiologic substrate for PON and represent a previously unknown counter-regulatory mechanism of CTS in the setting of CKD and heart failure.
The Impact of a Rigorous Quality Program on 3D Echocardiography Data Quality in an International Multisite Randomized Trial
Authors: Anna Lisa Crowley, Eric Yow, Dawn Rabineau, Casey Norris, Jennifer White, Melissa A. Daubert, Eric J. Velazquez, Huiman Barnhart, Mitchell W. Krucoff, Sunil V. Rao, Pamela S. Douglas
Journal: JACC. Cardiovascular imaging (2018)
Abstract 153: A genome-wide CRISPR screen in hESC uncovers JNK pathway mediated inhibition of human definitive endoderm formation
Authors: Qing Li, Danwei Huangfu
Journal: Cancer Research (2018)

Abstract Human embryonic stem cells (hESCs) are uniquely suitable for interrogating human development and birth defects with high-throughput genetic manipulation. Using CRISPR/Cas, we have conducted a forward genetic screen for genes that regulate the formation of human definitive endoderm (DE), the first step towards the generation of cells in respiratory and gastrointestinal organs. Our screen identified both known and unknown regulators of endoderm differentiation, including a previously unrecognized inhibitory mechanism mediated by the JNK/JUN pathway. JNK inhibitor treatment significantly improves the efficiency of hESC differentiation to endoderm, leading to more efficient creation of endoderm-derived pancreatic and lung lineage cells. The AP1 transcription factor JUN co-occupies ESC enhancers with SMAD2/3 and OCT4, and impedes the re-configuration of the SMAD2/3 chromatin-binding landscape during the ESC-to-DE transition. Thus the hESC-based CRISPR screen enables unbiased interrogation of the functional genome during human development, which can inform hESC directed differentiation for regenerative medicine and disease modeling. Citation Format: Qing Li, Danwei Huangfu. A genome-wide CRISPR screen in hESC uncovers JNK pathway mediated inhibition of human definitive endoderm formation [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 153.
Abstract 2143: IL-6 mediated signaling regulates cytotoxic effect of Burkitt lymphoma cells by combined treatment of Danusertib and BKM120
Authors: Jun Liu, Kwang-Sung Ahn, Jun-Shik Hong, Sung-Soo Yoon
Journal: Cancer Research (2018)

Abstract Even though Burkitt Lymphoma is relative has a good response to combined treatment, some part of outcome of chemotherapy is very poor. One of the obstacles is the chemoresistance due to several cytokines which are released from stromal cells. The effects of either Danusertib or BKM120 on Namalwa and BJAB, respectively, were different. On Namalwa the IC 50 of Danusertib was 24.64 µM (72 h) and BKM120 was 12.44 µM (72h). On BJAB the IC 50 of Danusertib was 6.63 µM (72h) and BKM120 was 1.42 µM (72h). But in the combined treatment, we found that BJAB showed less sensitive than Namalwa, the IC 50 on Namalwa was Danusertib 8.33 µM+ BKM120 2.08 µM (72h) and on BJAB was Danusertib 20.36 µM+ BKM120 5.09 µM (72h). To figure out the resistant pattern of these two cell lines we performed 3 steps treatment with 16 µM Danusertib and 4 µM BKM120, every step we culture 1.5×105/mL cells in 24hours first, and then treated with combined inhibitors 48 hours. We found that although Namalwa was sensitive to combined treatment at the first step, it was more easily to become resistant to combined treatment. To confirm the resistant pattern, co-culture system was used to identify what kinds of cytokines are involving in the chemoresistance of Burkitt lymphoma. We found that IL-6 was induced with stromal cell including inflammatory cytokines when cells were co-cultured with stromal cells. Also, IL-6 mediated signaling pathway such as JAK/STATIL-6 and AKT pathway, was activated by IL-6 and sIL-6. We suggest that IL-6 mediated signaling could mediate signaling regulates cytotoxic effect of Burkitt lymphoma cells by combined treatment of Danusertib and BKM120 as well as inflammatory effects may regulate the response of chemotherapeutic treatment. Citation Format: Jun Liu, Kwang-Sung Ahn, Jun-Shik Hong, Sung-Soo Yoon. IL-6 mediated signaling regulates cytotoxic effect of Burkitt lymphoma cells by combined treatment of Danusertib and BKM120 [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 2143.
Abstract 18606: Diastolic Dysfunction in the Ischemic Pig Heart is Partially Restored by Dobutamine-Ivabradine Combination, but Not by Omecamtiv Mecarbil, Due to Increasing Lusitropy and Filling Time
Authors: LeifRonning, Jens PBakkehaug, LarsRodland, Anders BKildal, TrulsMyrmel, Ole JHow
Journal: Circulation (2016)

Introduction: Acute diastolic failure in post-ischemic cardiogenic shock is associated with a grave prognosis. We assessed the impact of two novel inotropic strategies on the diastolic properties in a clinically relevant swine model of post-ischemic acute heart failure. Hypothesis: Dobutamine-ivabradine and omecamtiv mecarbil treatments exert different lusitropic effects on early diastole in acute heart failure. Methods: Anesthetized pigs were subjected to left ventricular ischemia through the injection of polystyrene microspheres into the coronary main stem (n=12). The animals were then randomized to receive omecamtiv (OM) (bolus 0.75 mg/kg plus 0.5 mg/kg/h) (n=6) or a combination of dobutamine (5 μg/kg/min) and ivabradine (0.29 ±0.16 mg/kg) (D+I) (n=6). Results: Ischemia reduces stroke volume, despite an increase in left atrial pressure. This decrease in stroke volume is associated with impaired early relaxation, systolic dilatation and an increase in late diastolic stiffness. Both treatments reversed s...
DNA nanotriangle-scaffolded activatable aptamer probe with ultralow background and robust stability for cancer theranostics
Authors: Yanli Lei, Zhenzhen Qiao, Jinlu Tang, Xiaoxiao He, Hui Shi, Xiaosheng Ye, Lv'an Yan, Dinggeng He, Kemin Wang
Journal: Theranostics (2018)

Activatable aptamers have emerged as promising molecular tools for cancer theranostics, but reported monovalent activatable aptamer probes remain problematic due to their unsatisfactory affinity and poor stability.To address this problem, we designed a novel theranostic strategy of DNA nanotriangle-scaffolded multivalent split activatable aptamer probe (NTri-SAAP), which combines advantages of programmable self-assembly, multivalent effect and target-activatable architecture.Methods: NTri-SAAP was assembled by conjugating multiple split activatable aptamer probes (SAAPs) on a planar DNA nanotriangle scaffold (NTri).Leukemia CCRF-CEM cell line was used as the model to investigate its detection, imaging and therapeutic effect both in vitro and in vivo.Binding affinity and stability were evaluated using flow cytometry and nuclease resistance assays.Results: In the free state, NTri-SAAP was stable with quenched signals and loaded doxorubicin, while upon binding to target cells, it underwent a conformation change with fluorescence activation and drug release after internalization.Compared to monovalent SAAP, NTri-SAAP displayed greatly-improved target binding affinity, ultralow nonspecific background and robust stability in harsh conditions, thus affording contrast-enhanced tumor imaging within an extended time window of 8 h.Additionally, NTri-SAAP increased doxorubicin loading capacity by ~5 times, which further realized a high anti-tumor efficacy in vivo with 81.95% inhibition but no obvious body weight loss.Conclusion: These results strongly suggest that the biocompatible NTri-SAAP strategy would provide a promising platform for precise and high-quality theranostics.
Abstract 2014: CAMSAP3, a tubulin minus-end binding protein, attenuates epithelial-to-mesenchymal transition and alters microtubule dynamic in non-small cell lung cancer
Authors: Varisa Pongrakhananon, Onsurang Wattanathamsan, Masatoshi Takeichi
Journal: Cancer Research (2018)

Abstract Cancer metastasis become the major cause of mortality in cancer patients, which the cancer migration exerts this aggressiveness. Epithelial to mesenchymal transition (EMT) plays an important role on cell movement and survival of the cancer cells during metastasizes. The establishment of front-rare polarization is involved with the alteration of cytoskeleton and cell-cell interaction, contributing to the notable morphological transformation from cobble stone-like epithelial to fibroblast-like mesenchymal feature. Microtubule dynamic has gained attention as a modulator behind these phenotypic changes and the EMT-related signal trafficking. Tubulin behavior has been shown to be governed by microtubule-binding proteins including a family of Calmodulin-regulated spectrin-associated proteins (CAMSAPs), a tubulin minus-end binding proteins. To illustrate the role of CAMSAPs on mesenchymal transition, CAMSAP2 and 3 genes were knockout using CRISPR-Cas9 system. Wound scratching and transwell migration assays demonstrate that non-small cell lung cancer becomes more motile with an elevation of actin stress fiber and focal adhesion protein paxillin following CAMSAP3 knockout, whereas CAMSAP2 depletion shows no significant effect. The mesenchymal markers including Slug, N-Cadherin and ZEB1 were substantial up-regulated, in opposite to the epithelial marker E-cadherin. Furthermore, CAMSAP3 removal causes a decrease of tubulin dynamic and consequently sustains an active state of EMT-regulatory proteins. This study reveals the negative regulatory effect of CAMSAP3, a non-centrosomal microtubule minus-end binding protein, on mesenchymal transition and cell motility. Citation Format: Varisa Pongrakhananon, Onsurang Wattanathamsan, Masatoshi Takeichi. CAMSAP3, a tubulin minus-end binding protein, attenuates epithelial-to-mesenchymal transition and alters microtubule dynamic in non-small cell lung 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 2014.
Abstract 1104: Tumor-associated macrophages-secreted CXCL1 promotes breast cancer metastasis via activating NF-κB/SOX4 signaling
Authors: Zhiyu Wang, Neng Wang, Weiping Liu, Yifeng Zheng, Shengqi Wang
Journal: Cancer Research (2018)

Abstract Purpose: Secreted cytokines play a significant role in modulating cancer metastatic microenvironment, especially for tumor associated macrophages (TAMs). The current study aimed to determine the significance of TAMs-secreted CXCL1 in regulating cancer metastasis and its underlying mechanisms. Experimental Design: Cytokine array was utilized to screen the highest chemokine secreted from TAMs. In vivo immunohistochemistry assay and in vitro wound healing or transwell experiments were carried out to demonstrate the metastatic-promoting effects of TAMs/CXCL1. QPCR profile screening was used to identify CXCL1 targeting metastasis-related gene. In vivo luciferase imaging experiments were designed to confirm the therapeutic significance of CXCL1 silencing on breast cancer metastasis. The clinical significance of CXCL1 was analyzed by human tissue microarray and bioinformatic analysis. Results: CXCL1 was validated as the highest secreted protein released from TAMs, and TAMs-derived CXCL1 could promote breast cancer migration and invasion ability, as well as epithelial-mesenchymal transition (EMT) process. QPCR screening validated SOX4 as the most responsive gene following CXCL1 administration. Mechanistic study revealed that CXCL1 activates SOX4 transcription via NF-κB pathway. CXCL1 silencing in TAMs resulted in a significant reduction in breast cancer growth and metastatic burden. Clinical investigation suggests that high CXCL1 expression was significantly correlated with breast cancer lymph node metastasis, poor overall survival and basal-like subtype. Conclusions: TAMs/CXCL1 promotes breast cancer metastasis via NF-κB/sox4 activation, and CAV1 based therapy might become a novel strategy for breast cancer metastasis prevention. Citation Format: Zhiyu Wang, Neng Wang, Weiping Liu, Yifeng Zheng, Shengqi Wang. Tumor-associated macrophages-secreted CXCL1 promotes breast cancer metastasis via activating NF-κB/SOX4 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 1104.
The effect of socioeconomic factors on the outcome of intrahepatic cholangiocarcinoma.
Authors: Cortlandt Sellers, Johannes M Ludwig, Johannes Uhlig, Stacey Stein, Jill Lacy, Hyun S Kim
Journal: Journal of Clinical Oncology (2018)

465 Background: To investigate the impact of socioeconomic factors on overall survival (OS) for patients with intrahepatic cholangiocarcinoma (ICC) at an inner-city tertiary care hospital. Methods: Consecutive patients treated for ICC diagnosed between 2005 and 2016 in the cancer registry were studied. Patients were stratified by demographic, socioeconomic variables, and treatment course. Kaplan-Meier curves and Cox proportional hazard modeling were performed. Results: Patients were 52% male (95 pts) and 74% white (136 pts) with mean age of 65.7 yrs (SD 10.7 yrs). 82% of patients were married or had been previously married (148 pts). 11% of patients had Medicaid as their primary insurance (20 pts), 45% of patients had Medicare (78 pts) and 44% of patients had private insurance (77 pts). Patients with private insurance (66 pts, 87%) and Medicare (64 pts, 83%) were more likely to have been married than Medicaid (12 pts, 60%) (p = 0.036). Patients with Medicare (mean 72.0 yrs, SD 6.9 yrs) were older than private insurance patients (mean 60.3 yrs, SD 10.3 yrs) and Medicaid patients (mean 61.8 yrs, SD 12.4 yrs) (p &lt; 0.001). Gender and ethnicity were similarly distributed by primary insurance. Median OS stratified by primary insurance demonstrated median OS in private insurance of 13.2 mo (95% CI: 8.2–18.7 mo) vs 7.3 mo (95% CI: 3.8–10.6 mo) for Medicare (HR 1.3, p = 0.11) vs 4.7 mo (95% CI: 1.7–11.3 mo) for Medicaid (HR 1.8, p = 0.0488), (p = 0.0465). Cancer-directed treatments were utilized by 81% in private insurance vs. 67% in Medicare vs 67% in Medicaid (p = 0.18). Median OS stratified by main treatment demonstrated 43.3 mo in resection (37 pts, 21%), 17.3 mo in locoregional therapy (LRT) (22 pts, 13%), 10.0 mo in chemotherapy or radiation (79 pts, 45%), and 1.4 mo in palliative or no treatment (37 pts, 21%) (p &lt; 0.0001). Increased age was associated with decreased median OS (correlation -0.23, p = 0.0019). No differences in median OS were seen with ethnicity, gender, or marital status. Conclusions: Screening and early treatments appear to affect the OS of patients with ICC. Further investigations for preventive care for vulnerable populations to enhance survivals are warranted.
Severe Atherosclerosis and Hypoalphalipoproteinemia in the Staggerer Mouse, a Mutant of the Nuclear Receptor RORα
Authors: AnnaMamontova, SandrineSéguret-Macé, BrunoEsposito, ColetteChaniale, MurielBouly, NicoleDelhaye-Bouchaud, GéraldLuc, BartStaels, NicolasDuverger, JeanMariani, AlainTedgui
Journal: Circulation (1998)

Background—Hypoalphalipoproteinemia is the most common lipoprotein abnormality in patients with coronary artery disease, yet its causes are unknown. Methods and Results—We show that the homozygous staggerer (sg/sg) mutant mouse, which carries a deletion within the nuclear receptor RORα gene, develops severe atherosclerosis when maintained on an atherogenic diet. In addition, sg/sg mice display a profound hypoalphalipoproteinemia, which is associated with decreased plasma levels of the major HDL proteins, apolipoprotein (apo) A-I and apoA-II. This decrease in HDL levels in sg/sg mice is due to lowered apoA-I gene expression in the intestine but not in the liver. ApoA-II gene expression is unaffected. Conclusions—These results suggest that the RORα gene contributes to the plasma HDL level and susceptibility to atherosclerosis.