tbuckley/cabot-search huggingface dataset:
Abstract 5156: RhoC decreases tight junction stabilization in breast cancer cells, revealing a potential therapeutic target
Authors: Hannah Cheriyan, Zhi-Fen Wu, Joel Yates, Sofia D. Merajver
Journal: Cancer Research (2018)

Abstract RhoC, a member of the Rho GTPase family, has been shown to have a role specifically in facilitating metastasis of breast cancer cells1, however no conclusive mechanism for how RhoC promotes metastasis currently exists. We demonstrate that CRISPR-Cas9 knockout of RhoC in SUM149 and MDA-MB231 cells results in increased epithelial morphology, cell-cell connections, and tight junction marker (ZO-1, occludin, PATJ/PALS1/CRB3) colocalization compared to wild type cells, as studied via immunofluorescent staining. These results suggest that high expression of RhoC in cancer cells destabilizes tight junctions, which could allow for the increased metastatic potential observed with RhoC-overexpressing cells in prior studies2-4. Ongoing work investigates whether these morphological and molecular changes are observed in other breast cancer cell lines, such as SUM190 and VARI-068, a low-passage PDX-derived triple negative breast cancer cell line. Furthermore, we will determine whether RhoC knockout in these cells lines actively modulates tight junction stability as measured via transepithelial electrical resistance (TEER). Taken together, these data support an important role for RhoC in tight junction modulation, thereby revealing a potential highly specific new therapeutic target in RhoC-driven metastases control. References 1. Hakem, A. et al. RhoC is dispensable for embryogenesis and tumor initiation but essential for metastasis. Genes Dev. 19, 1974-1979 (2005). 2. van Golen, K. L., Wu, Z. F., Qiao, X. T., Bao, L. W. &amp; Merajver, S. D. RhoC GTPase, a novel transforming oncogene for human mammary epithelial cells that partially recapitulates the inflammatory breast cancer phenotype. Cancer Res. 60, 5832-8 (2000). 3. van Golen, K. L., Wu, Z. F., Qiao, X. T., Bao, L. &amp; Merajver, S. D. RhoC GTPase overexpression modulates induction of angiogenic factors in breast cells. Neoplasia 2, 418-25 (2000). 4. Wu, M., Wu, Z. F., Rosenthal, D. T., Rhee, E. M. &amp; Merajver, S. D. Characterization of the roles of RHOC and RHOA GTPases in invasion, motility, and matrix adhesion in inflammatory and aggressive breast cancers. Cancer 116, 2768-2782 (2010). Citation Format: Hannah Cheriyan, Zhi-Fen Wu, Joel Yates, Sofia D. Merajver. RhoC decreases tight junction stabilization in breast cancer cells, revealing a potential therapeutic target [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 5156.
Abstract 1913: Investigation of targeting SKP2 to improve the treatment response in glioma
Authors: Jing Wang, Hong-Kai Su, Zhong-Ping Chen, Yue Qu, Hai-Ping Cai
Journal: Cancer Research (2018)

Abstract Glioma is the most frequent tumor in central nervous system (CNS), constituting about 30% of CNS tumors and 80% of malignant brain tumors. The current standard strategy for glioma treatment is surgery plus adjuvant chemotherapy and concurrent radiotherapy. However, the prognosis of glioma is still poor. It has been proved that the existence of glioma stem cells and the timely repair of DNA damages are the main causes of treatment failure. Skp2 (S-phase kinase associated protein-2), a member of F-box proteins, forms the Skp2 SCF complex with Skp1, Cullin-1, and Rbx1, serves as one of the important E3-ligases in the process of ubiquitination, and is responsible for substrate recognition. Skp2 is overexpressed in a variety of human cancers and promotes cancer progression by inducing p27 degradation. Importantly, Skp2 deficiency profoundly restricts cancer progression in multiple genetic mouse tumor models. Our group has demonstrated that Skp2 is involved in the regulation of pool size and self-renewal ability of hematopoietic stem cells, as well as breast cancer stem cells and nasopharyngeal carcinoma stem cell-like cells. However, the exact role of Skp2 in the regulation of glioma stem cells and DNA damage repair in glioma has not been elucidated yet. We proposed that targeting Skp2 could promote radio- and chemotherapy sensitivity through suppressing function of glioma stem cells. We first detected the expression of SKP2 in glioma tumor tissues and found that SKP2 was highly expressed in glioma and related to the prognosis of glioma patients. We also adopted gene knockdown methods and inhibitor pretreatment with small molecules in order to suppress the level of Skp2, and then checked the sphere formation and self-renewal ability of glioma stem cell upon radio/chemo treatments. In this way we evaluated the role of Skp2 in repressing the glioma cell proliferation and subsequently triggering apoptosis. Our project will clarify the novel mechanisms about how Skp2 is involved in the glioma radio- and chemotherapy resistance, which will provide a potential target to improve the radio/chemo therapeutic effect through targeting one single target. Citation Format: Jing Wang, Hong-Kai Su, Zhong-Ping Chen, Yue Qu, Hai-Ping Cai. Investigation of targeting SKP2 to improve the treatment response in glioma [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 1913.
Autoregulation of Cerebral Blood Flow
Authors: Alessandroagnoli, Cesarefieschi, Luigibozzao, Noèbattistini, Massimilianoprencipe
Journal: Circulation (1968)

Autoregulation of cerebral blood flow (constant perfusion despite variations in blood pressure) was studied in 15 control subjects and in 24 patients with cerebral vascular lesions. Thirteen patients were studied within the first 2 days of an episode of cerebral ischemia (acute group); 11 were studied from 15 days to several months after an ischemic episode (chronic group). Measurements of regional cerebral blood flow (rCBF) were made by recording extracranially in four to six locations the clearance of 85Kr dissolved in saline and injected into the internal carotid artery. Blood flow values were calculated with a digital computer, using a compartmental analysis of the clearance curves. After measuring rCBF in the resting state, the blood pressure was increased by 30 to 40 mm Hg by the intravenous infusion of angiotensin amide (Hypertensin, Ciba). While the blood pressure was kept constant at the new level, a second series of measurements was made. Autoregulation was present in all normal subjects: no...
Abstract 3770: Characterization of novel dual A2A/A2B adenosine receptor antagonists for cancer immunotherapy
Authors: Michal Galezowski, Paulina Wegrzyn, Aneta Bobowska, Claude Commandeur, Katarzyna Dziedzic, Marcin Nowogrodzki, Alicja Obara, Joanna Szeremeta-Spisak, Anna Dzielak, Iwona Lozinska, Marcelina Dudek, Anita Janiga, Jacek Reus, Marek Wronowski, Mateusz Swirski, Adam Radzimierski, Magdalena Ziembik, Joanna Mierzwicka, Katarzyna Wojcik-Jaszczynska, Elzbieta Gocek, Karolina Grycuk, Aniela Golas, Olga Pierzchala, Julian Zachmann, Mateusz Nowak
Journal: Cancer Research (2018)

Abstract Adenosine is the key immunometabolite responsible for immune tolerance in tumors. It is present in normal tissue in low concentrations, having various physiological functions. In the tumor, its concentration increases rapidly, as a result of overexpression of enzymes producing adenosine, additionally enhanced by hypoxia and inflammation. Adenosine inhibits the biological functions of T lymphocytes infiltrating the cancer tissue by binding to the A2A receptor. The affinity to A2B receptor is believed to attenuate the response of dendritic cells and other parts of innate system. Thus blocking simultaneously the effects mediated by both receptor subtypes with dual inhibitor seems to be a viable approach to a single agent cancer immunotherapy or a combination with current immunotherapeutic agents. We have discovered a novel series of potent and selective A2A/A2B inhibitors. Best compounds present subnanomolar activity in both in vitro recombinant cellular model and in primary human cells. Our antagonists dose-dependently restore the adenosine agonist-impaired functional activity of CD4+ and CD8+ human T-lymphocytes (cytokine release assays). We observe also the relieve of adenosine-related suppression in NK cells cytotoxicity. Most importantly tested compounds present improved primary pharmacological profile in comparison to A2A inhibitors currently tested in clinical trials. Further validation in in vivo models showed efficacy standalone and in combination with checkpoint inhibitors. Citation Format: Michal Galezowski, Paulina Wegrzyn, Aneta Bobowska, Claude Commandeur, Katarzyna Dziedzic, Marcin Nowogrodzki, Alicja Obara, Joanna Szeremeta-Spisak, Anna Dzielak, Iwona Lozinska, Marcelina Dudek, Anita Janiga, Jacek Reus, Marek Wronowski, Mateusz Swirski, Adam Radzimierski, Magdalena Ziembik, Joanna Mierzwicka, Katarzyna Wojcik-Jaszczynska, Elzbieta Gocek, Karolina Grycuk, Aniela Golas, Olga Pierzchala, Julian Zachmann, Mateusz Nowak. Characterization of novel dual A2A/A2B adenosine receptor antagonists for cancer immunotherapy [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 3770.
Abstract 1878: Molecular mechanisms of the cardiotoxicity of the proteasomal-targeted anticancer drugs bortezomib, carfilzomib, ixazomib, oprozomib, and delanzomib
Authors: Brian B. Hasinoff
Journal: Cancer Research (2018)

Abstract Bortezomib, carfilzomib, ixazomib, oprozomib, and delanzomib are anticancer drugs that target the proteasomal system. Bortezomib, carfilzomib, and ixazomib, which are approved for clinical use, have shown some cardiotoxicity. Carfilzomib and oprozomib are epoxyketones that form an irreversible bond with the 20S proteasome, whereas bortezomib, ixazomib, and delanzomib are boronic acids that form slowly reversible adducts. A primary neonatal rat myocyte model was used to study these cardiotoxic mechanisms. Using LDH release as a measure of damage in the myocyte model, after drug treatments of either 1, 4 and 72 hr all these drugs induced myocyte damage at low- to sub-micromolar concentrations. Oprozomib induced significantly less myocyte damage than any of the other drugs. Utilizing a fluorogenic substrate the kinetics of the slow-binding inhibition of the chymotrypsin-like proteasomal activity of human 20S proteasome were also determined in order to see if differences in the binding kinetics could explain the degree of myocyte damage. Oprozomib inhibited the 20S proteasome with a second-order binding “on” rate constant that was 60-fold slower than for ixazomib, the fastest binding drug. The first-order dissociation “off” rate constants for the three boronic acids were also determined. Delanzomib dissociated from its complex with the 20S proteasome with a half-time that was more than 20-fold slower than for ixazomib, the fastest dissociating drug. In conclusion, while all these drugs were potently toxic to myocytes at submicromolar concentrations, oprozomib was considerably less toxic than any of the other drugs. As a group the boronic acid drugs were not significantly more toxic than the epoxyketone drugs. The dissociation half-times of the boronic acid complexes were also not correlated with myocyte damage. The fact that oprozomib bound to the 20S proteasome more slowly than any of the other drugs may be the reason, in part, that it is less toxic. Support: CIHR; a Canada Research Chair in Drug Development. Citation Format: Brian B. Hasinoff. Molecular mechanisms of the cardiotoxicity of the proteasomal-targeted anticancer drugs bortezomib, carfilzomib, ixazomib, oprozomib, and delanzomib [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 1878.
Abstract 2335: Disulfiram overcomes trastuzumab resistance by targeting cancer stem-like properties and HER2/Akt signaling in HER2-positive breast cancer
Authors: Yoon-Jae Kim, Youngkwan Cho, Daeil Sung, Eunhye Oh, Tae-Min Cho, Seojin Jang, Ji Young Kim, Jae Hong Seo
Journal: Cancer Research (2018)

Abstract Although trastuzumab has shown a significant clinical benefit for HER2-positive breast cancers, responses are limited by the frequent emergence of resistance. Trastuzumab resistance is a multi-factorial phenomenon thought to arise from the presence of cancer stem cells and interactions between truncated p95HER2 and HER family members. Disulfiram (DSF), an anti-alcoholism drug, is known to elicit cytotoxicity in numerous cancer cell types in the presence of copper (Cu). We sought to investigate the effect of DSF on apoptosis, HER2/Akt signaling, cancer stem-like properties and trastuzumab resistance in HER2-positive breast cancer cells in vitro and in vivo. DSF/Cu treatment induced apoptosis, associated with a significant downregulation of HER2, truncated p95HER2, phospho-HER2, HER3, phospho-HER3 and phospho-Akt levels in both trastuzumab-sensitive and -resistant cell lines. This was accompanied by the eradication of cancer stem-like populations, concomitant with the suppression of aldehyde dehydrogenase 1 (ALDH1) activity and mammosphere-forming ability. DSF administration also caused significant tumor suppression in trastuzumab-resistant xenografts, coinciding with the downregulation of BCSC-related markers and intracellular HER2 in vivo. These findings highlight the mechanisms of action of DSF in overcoming trastuzumab resistance in HER2-positive breast cancer. Citation Format: Yoon-Jae Kim, Youngkwan Cho, Daeil Sung, Eunhye Oh, Tae-Min Cho, Seojin Jang, Ji Young Kim, Jae Hong Seo. Disulfiram overcomes trastuzumab resistance by targeting cancer stem-like properties and HER2/Akt signaling in HER2-positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2335.
Funny Current Downregulation and Sinus Node Dysfunction Associated With Atrial Tachyarrhythmia
Authors: Yung-HsinYeh, BrettBurstein, Xiao YanQi, MasaoSakabe, DenisChartier, PhilippeComtois, ZhiguoWang, Chi-TaiKuo, StanleyNattel
Journal: Circulation (2009)

Background— Sinoatrial node (SAN) dysfunction is frequently associated with atrial tachyarrhythmias (ATs). Abnormalities in SAN pacemaker function after termination of ATs can cause syncope and require pacemaker implantation, but underlying mechanisms remain poorly understood. This study examined the hypothesis that ATs impair SAN function by altering ion channel expression. Methods and Results— SAN tissues were obtained from 28 control dogs and 31 dogs with 7-day atrial tachypacing (400 bpm). Ionic currents were measured from single SAN cells with whole-cell patch-clamp techniques. Atrial tachypacing increased SAN recovery time in vivo by ≈70% (P 50% (P<0.01) and for the β-subunit minK by ≈42% (P<0.05). SAN transcript expression for th...
Abstract 9905: Myeloid Cell Derived Leucine Rich α2 Glycoprotein Attenuates Adverse Cardiac Remodeling After Myocardial Infarction
Authors: Shohei Kumagai, Hiroyuki Nakayama, Minoru Fujimoto, Hiromi Honda, Satoshi Serada, Atsushi Kasai, Masanori Obana, Yasushi Sakata, Yoshiki Sawa, Tetsuji Naka, Yasushi Fujio
Journal: Circulation (2015)

Background: Leucine rich α2 glycoprotein (LRG), a member of the leucine-rich repeat family, was isolated from human plasma. Recently, LRG has been identified as a novel serum biomarker for various inflammatory diseases. It was also reported that serum LRG concentrations was strongly correlated with B-type natriuretic peptide in patients with heart failure. However, its pathophysiological roles in hearts after myocardial infarction (MI) remain to be elucidated. Objective: To determine the functional roles of LRG in cardiac remodeling after MI. Methods and Results: Murine MI was generated by ligating the left coronary artery. The expression of LRG was increased in hearts after MI. Immunofluorescence microscopic and flow cytometric analyses revealed that LRG was mainly produced by CD11b-positive myeloid cells in post-infarct myocardium. To elucidate pathophysiological roles of LRG in heart, we generated MI in wild-type (WT) and LRG-knockout (KO) mice. At day 14 after MI, cardiac fibrosis and dysfunction were aggravated in KO mice compared to WT mice (fibrotic area/ LV area: WT: 34.1 ± 7.2%, KO: 46.5 ± 12.8% n=10-16, p&lt;0.01) (fractional shortening: WT: 34.8±7.1%, KO: 24.3±7.0%, n=6-9, p&lt;0.01). Immunohistochemical analysis demonstrated that CD31-positive vessel density decreased at border zone in KO mice compared to WT mice 14 days after MI (vessel density: WT: 2740±190/mm2, KO: 2183±293/mm2 n=10-16, p&lt;0.01). We explored the mechanism of LRG-mediated angiogenesis in post-infarct myocardium, and found that the activation of smad1/5/8, a pro-angiogenic signaling pathway, was attenuated in KO mice. Accompanied by impaired angiogenesis, cardiomyocytes apoptosis was increased in KO mice compared to WT mice at subacute phase after MI. Finally, bone marrow chimera experiments showed that bone marrow cells-derived LRG rescued adverse cardiac remodeling in KO mice, accompanied by restoration of capillary density. Conclusion: LRG was mainly produced by heart-infiltrated myeloid cells, and suppressed adverse cardiac remodeling after MI through enhanced angiogenesis. In this study, LRG was defined as a novel cardioprotective factor. Thus, LRG could be not only a serum biomarker but also a therapeutic target in cardiovascular diseases.
Effect of Nitroglycerin on the Coronary Circulation in Patients with Coronary Artery Disease or Increased Left Ventricular Work
Authors: Richardgorlin, Normanbrachfeld, Colinmacleod, Pierrebopp
Journal: Circulation (1959)

Except for the electrocardiogram objective evaluation of the functional state of the coronary circulation in man is often difficult. The nature of the coronary circulation in the presence of known coronary insufficiency has not been evaluated. In this report, 17 patients were studied of whom 14 had angina pectoris. Observations were made of coronary blood  and hemodynamics both at rest and following administration of nitroglycerin. The authors conclude that resting coronary  is normal, but cannot increase further with dilators. They consider this phenomenon a consequence of prior exhaustion of the dilator capacity of the arterioles in compensation for the atherosclerotic obstruction of the coronary tree. The fixed flow concept is suggested as an objective means of detecting coronary insufficiency. Nitrites probably relieve pain in some manner other than general coronary dilatation.
Abstract LB-313: CXCR2 inhibitor Reparixin enhances local tumor control and reduces distant metastases in mouse tumor radiotherapy
Authors: Chia-lun Chang, Yi-Hsin Liang, Szu-yuan Wu
Journal: Cancer Research (2018)

Abstract Inadequately irradiated primary tumor of primary Lewis lung carcinoma (LLC-LM) in vivo is a mechanism of radiation-enhanced LLC-LM cells in pulmonary metastasis. We observed a CXCL1/GRO alpha, is a member of the CXC family of chemokines is elevated after radiation therapy. CXCL1 protein is function with to bind the G-protein coupled receptor chemokine (C-X-C motif) receptor 2 (CXCR2) to recruit neutrophils. Reparixin is an inhibitor of CXCR2, and demonstrates activity against malignant behavior of human cancer cells xenografts. The effect of Reparixin on the radiotherapy of LLC-LM primary tumor and the effects on distant metastases have not been studied. The right thighs of C57BL/6 mice (n = 40) were injected s.c. with 1 x 10(6) LLC-LM cells. Animals were randomized to one of four groups: no irradiation, 10 Gy in one fraction, Reparixin (0.1mg/kg/day, for 5days) plus 10 Gy in one fraction, or Reparixin( 0.1mg/kg/day, for 5days) only . Tumors were clinically irradiated in each treatment group. All of the mice were killed within 21 days after the completion of radiation therapy. Examination of their lungs revealed &amp;gt;13 (range, 13-22) surface metastases in the 10 Gy treated mice with 3 (range, 2-7) in the no irradiation mice, in Reparixin plus 10 Gy treated mice with 6(range, 4-13), in Reparixin treated mice with 2 (range, 2-6). The lung weights had increased from 0.22 g (range, 0.21-0.24 g) in the no irradiation mice to 0.43 g (range 0.37-0.61) in the 10 Gy treated mice, in Reparixin plus 10 Gy treated mice with 0.31(range, 0.26-0.41), in Reparixin treated mice with 0.23 (range, 0.2-0.25 g). In the surface metastases and lung weight, Reparixin plus irradiation treatment were statistically significant with P &amp;lt; 0.001 when compare with irradiation alone. Other hand, the tumor growth curve also demonstrated that the Reparixin enhanced the tumor control of irradiation of LLC-LM tumor. In this model, the use of inadequately radiation to eradicate a primary LLC-LM tumor results in the growth of previously dormant lung metastases and suggests that combining CXCR2 inhibitor with radiation therapy may enhance local tumor control and reduce distant metastases. Citation Format: Chia-lun Chang, Yi-Hsin Liang, Szu-yuan Wu. CXCR2 inhibitor Reparixin enhances local tumor control and reduces distant metastases in mouse tumor radiotherapy [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-313.
lncRNA-MIAT Regulates Microvascular Dysfunction by Functioning as a Competing Endogenous RNA
Authors: BiaoYan, JinYao, Jing-YuLiu, Xiu-MiaoLi, Xiao-QunWang, Yu-JieLi, Zhi-FuTao, Yu-ChenSong, QiChen, QinJiang
Journal: Circulation Research (2015)

Rationale:Pathological angiogenesis is a critical component of diseases, such as ocular disorders, cancers, and atherosclerosis. It is usually caused by the abnormal activity of biological processes, such as cell proliferation, cell motility, immune, or inflammation response. Long noncoding RNAs (lncRNAs) have emerged as critical regulators of these biological processes. However, the role of lncRNA in diabetes mellitus–induced microvascular dysfunction is largely unknown. Objective:To elucidate whether lncRNA-myocardial infarction–associated transcript (MIAT) is involved in diabetes mellitus–induced microvascular dysfunction. Methods and Results:Using quantitative polymerase chain reaction, we demonstrated increased expression of lncRNA-MIAT in diabetic retinas and endothelial cells cultured in high glucose medium. Visual electrophysiology examination, TUNEL staining, retinal trypsin digestion, vascular permeability assay, and in vitro studies revealed that MIAT knockdown obviously ameliorated diabetes me...
Abstract 18307: The Pediatric Heart Network Digital Normal ECG Database: Measurements of Left Ventricular Hypertrophy Vary by Sex and Race
Authors: Elizabeth V Saarel, Suzanne Granger, Kaltman R John, LuAnn L Minich, Martin Tristani-Firouzi, Jeffrey Kim, Kathleen E Ash, Sabrina Tsao, Charles I Berul, Elizabeth A Stephenson, David Gamboa, Felicia Trachtenberg, Peter Fischbach, Victoria L Vetter, Richard Czosek, Tiffanie R Johnson, Jack C Salerno, Nicole Cain, Robert H Pass, Ilana Zeltser, Eric S Silver, Joshua R Kovach, Mark E Alexander
Journal: Circulation (2017)

Introduction: The ECG is a useful cardiac diagnostic and screening tool, but current utility is limited by absence of reliable normal reference values across all age, sex, and race categories. Hypo...
c-Rel is required for the development of thymic Foxp3+ CD4 regulatory T cells
Authors: Iwao Isomura, Stephanie Palmer, Raelene J. Grumont, Karen Bunting, Gerard Hoyne, Nancy Wilkinson, Ashish Banerjee, Anna Proietto, Raffi Gugasyan, Li Wu, Alice McNally, Raymond J. Steptoe, Ranjeny Thomas, M. Frances Shannon, Steve Gerondakis
Journal: The Journal of Experimental Medicine (2010)