tbuckley/cabot-search huggingface dataset:
Sustained Elevation of Serum Cortisol Level Causes Sensitization of Coronary Vasoconstricting Responses in Pigs In Vivo
Authors: TakatoshiHizume, KeikoMorikawa, AyaTakaki, KohtaroAbe, KenjiSunagawa, MutsukiAmano, KozoKaibuchi, ChiharuKubo, HiroakiShimokawa
Journal: Circulation Research (2006)

Vasospastic angina is induced by stress, for which cortisol secreted by activated hypothalamic/pituitary/adrenal axis may play an important role. However, direct evidence for this notion is still lacking. In this study, we examined whether sustained elevation of serum cortisol level sensitizes coronary vasoconstricting responses in pigs in vivo and, if so, whether Rho-kinase, which we found is a key molecule of coronary vasospasm, is involved. Oral administration of cortisol (20 mg/kg per day) increased its serum level to that seen in restraint stress in pigs. Thus, we examined coronary vasomotor responses in the following 4 groups: (1) control (without cortisol); (2) cortisol (20 mg/kg per day, PO) for 9 days; (3) cortisol plus RU38486 (a glucocorticoids receptor antagonist, 10 mg/kg per day, PO) for 9 days; and (4) cortisol for 9 days followed by 6-week withdrawal. Coronary angiography showed that intracoronary serotonin caused coronary hyperconstriction and reduction in coronary blood flow associated w...
The Electrolytes of Arterial Wall in Experimental Renal Hypertension
Authors: Louistobian, Loiswhite
Journal: Circulation Research (1956)

In rats with renal hypertension, smooth muscle cells in the wall of the aorta appear to have more water, sodium, potassium, magnesium and phosphorus per unit of cell solids than similar cells in normotensive rats. When the blood pressure of a few hypertensive rats dropped to normal as a result of a low sodium diet, the potassium and phosphorus in the arterial cells also appeared to decrease to normal levels. These studies give indications of the compositional changes in arterial smooth muscle cells that are associated with renal hypertension.
Angiotensin II Type 2 Receptor Deficiency Exacerbates Heart Failure and Reduces Survival After Acute Myocardial Infarction in Mice
Authors: YuichiroAdachi, YoshihikoSaito, IchiroKishimoto, MasakiHarada, KoichiroKuwahara, NobukiTakahashi, RikaKawakami, MichioNakanishi, YasuakiNakagawa, KeijiTanimoto, YoshitomoSaitoh, ShinjiYasuno, SatoruUsami, MasaruIwai, MasatsuguHoriuchi, KazuwaNakao
Journal: Circulation (2003)

Background— Angiotensin II plays a prominent role in the progression of heart failure after acute myocardial infarction (AMI). Although both angiotensin type 1 (AT1) and type 2 (AT2) receptors are known to be present in the heart, comparatively little is known about the latter. We therefore examined the role played by AT2 receptors in post-AMI heart failure. Methods and Results— In wild-type mice subjected to AMI by coronary artery ligation, AT2 receptor immunoreactivity is upregulated in the infarct and border areas. Among AT2 receptor-null (−/−) mice, the 7-day survival rate after AMI was significantly lower than among wild-type mice (43% versus 67%; P<0.05). All sham-operated animals of both genotypes survived through the study. Ventricular mRNA levels for brain natriuretic peptide were elevated in both genotypes 24 hours after coronary occlusion, with levels in AT2−/− significantly higher than in wild-type mice, as were their lung weights, and histological examination revealed marked pulmonary congest...
Abstract 355: Histone acetyltransferase KAT6A upregulates PI3K/AKT signaling through TRIM24 binding
Authors: Deguan Lv, Feng Jia, Yanli Hou, Youzhou Sang, Angel A. Alvarez, Weiwei Zhang, Bo Hu, Shi-Yuan Cheng, Jianwei Ge, Yanxin Li, Haizhong Feng
Journal: Cancer Research (2018)

Abstract Lysine acetyltransferase KAT6A is a chromatin regulator that contributes to histone modification and cancer, but the basis of its actions are not well understood. Here we identify a KAT6A signaling pathway that facilitates glioblastoma (GBM) where it is upregulated. KAT6A expression was associated with GBM patient survival. KAT6A silencing suppressed cell proliferation, cell migration, colony formation and tumor development in an orthotopic mouse xenograft model system. Mechanistic investigations demonstrated that KAT6A acetylates lysine 23 of histone H3 (H3K23), which recruits the nuclear receptor binding protein TRIM24 to activate PIK3CA transcription, thereby enhancing PI3K/AKT signaling and tumorigenesis. Overexpressing activated AKT or PIK3CA rescued the growth inhibition due to KAT6A silencing. Conversely, the pan-PI3K inhibitor LY294002 abrogated the growth-promoting effect of KAT6A. Overexpression of KAT6A or TRIM24, but not KAT6A acetyltransferase activity- deficient mutants or TRIM24 mutants lacking H3K23ac binding sites promoted PIK3CA expression, AKT phosphorylation and cell proliferation. Taken together, our results define an essential role of KAT6A in glioma formation, rationalizing its candidacy as a therapeutic target for GBM treatment. Citation Format: Deguan Lv, Feng Jia, Yanli Hou, Youzhou Sang, Angel A. Alvarez, Weiwei Zhang, Bo Hu, Shi-Yuan Cheng, Jianwei Ge, Yanxin Li, Haizhong Feng. Histone acetyltransferase KAT6A upregulates PI3K/AKT signaling through TRIM24 binding [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 355.
Abstract 12967: Efficacy of Combining Assessment of Right Ventricular Function and Right Atrial Remodeling as Prognostic Factor in Patients With Pulmonary Hypertension
Authors: YukoFukuda, HidekazuTanaka, YoshikiMotoji, KeikoRyo, HirokiMatsuzoe, KeikoHatazawa, YutakaHatani, KumikoDokuni, HiromiToki, HiroyukiShimoura, JunichiOoka, HiroyukiSano, TakumaSawa, YasuhideMochizuki, KazuhiroTatsumi, KensukeMatsumoto, NoriakiEmoto, Ken-ichiHirata
Journal: Circulation (2014)

Background: Since survival of patients with pulmonary hypertension (PH) is closely related to right ventricular (RV) function, assessment of RV function is important for patients with PH. Right atrial (RA) area and/or RA pressure have also been reported to serve as prognostic predictors for adverse outcomes for in PH patient. Accordingly, we tested the hypothesis that the addition of RA remodeling to RV function enhances the capability of the latter to predict long-term outcome for PH patients. Methods: We studied 82 PH patients, all of whom underwent echocardiography and right heart catheterization. RV function was calculated by averaging the three regional peak speckle-tracking longitudinal strains from RV free wall (RV-free). RA remodeling was assessed as the RA area traced planimetrically at end-systole. Pre-defined cutoffs for RV dysfunction and RA remodeling were RV-free≤19.4% and RA area of >18cm2, respectively. Long-term unfavorable outcome events were tracked for 2.0 years. Results: RA area corre...
Abstract 3273: rkmh: A MinHash toolbox for analyzing HPV coinfections
Authors: Eric T. Dawson, Sarah Wagner, David Roberson, Meredith Yeager, Joseph Boland, Erik Garrison, Mark Schiffman, Tina Raine-Bennet, Thomas Lorey, Phillip Castle, Stephen Chanock, Lisa Mirabello, Richard Durbin
Journal: Cancer Research (2018)

Abstract Human papillomaviruses are common infections transmitted by direct physical contact. Two sexually transmitted types, HPV16 and HPV18, are responsible for almost 75% of cervical cancer cases worldwide; another 10 types of &amp;gt;200 known types are considered carcinogenic. Among the four HPV16 lineages (A, B, C, and D), 100-fold differences in odds ratios for adenocarcinoma are observed. It is therefore informative to distinguish between infection with HPV16 lineages, even though they differ by as little as 2% of their genome. We present a computational toolkit, rkmh, for characterizing viral coinfections. rkmh uses kmer matching strategies to rapidly determine the most similar type or lineage reference genome for a given read. The proportion of reads matching each reference genome can then be calculated and the ratios of the infecting viruses can be estimated. To assess the performance of rkmh we first simulated 100bp paired end Illumina read sets from the PAVE database of HPV reference genomes, then also evaluated performance on a real HPV16 sample sequenced on the Ion Torrent Proton platform (typical read length 250bp), and a set of 3,660 Oxford Nanopore minION reads generated from two HPV16 reference strains (typical read length over 6500bp). We demonstrate that rkmh can adequately classify HPV infections at the type and lineage level. We discuss further applications of the tool in metagenomics. rkmh is freely available at https://github.com/edawson/rkmh. Citation Format: Eric T. Dawson, Sarah Wagner, David Roberson, Meredith Yeager, Joseph Boland, Erik Garrison, Mark Schiffman, Tina Raine-Bennet, Thomas Lorey, Phillip Castle, Stephen Chanock, Lisa Mirabello, Richard Durbin. rkmh: A MinHash toolbox for analyzing HPV coinfections [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 3273.
Abstract 19169: The Her2 Inhibitor Lapatinib Aggravates Doxorubicin-induced Cardiotoxicity via Inos Signaling
Authors: Wan-Tseng Hsu, Ching-Ying Huang, Chris Y.T. Yen, Ann-Lii Cheng, Patrick C.H. Hsieh
Journal: Circulation (2017)

Introduction: Lapatinib (LAP) is a crucial alternative to trastuzumab when drug resistance arises during treatment of metastatic human epidermal growth factor receptor 2 (HER2)-positive breast canc...
Abstract 4790: YH25448, an irreversible 3rd generation EGFR TKI, exhibits superior anticancer effects with potent brain BBB penetration in NSCLC
Authors: Jiyeon Yun, Min Hee Hong, Seok-Young Kim, Chae Won Park, So-Young Kim, Mi Ran Yun, Han Na Kang, Kyoung-Ho Pyo, Jong Sung Koh, Ho-Juhn Song, Young- Sung Lee, Se-Woong Oh, Soongyu Choi, Byoung-Chul Cho
Journal: Cancer Research (2018)

Abstract EGFR mutated lung cancer shows approximately 10-15% of non-small cell lung cancer (NSCLC). Although the best therapeutic EGFR tyrosine kinase inhibitors (TKIs) targeting mutant EGFR, such as gefitinib and erlotinib, are used in the first line treatment of patients with advanced EGFR mutated NSCLC, the acquired resistance to the drugs usually appears in 10-12 months of therapy by the occurrence of a second EGFR mutation T790M. YH25448, a highly mutant-selective and irreversible 3rd generation EGFR TKI potently penetrating blood-brain barrier (BBB) penetration, targets both activating EGFR mutations Del19, L858R and T790M mutation while sparing wild type. In NSCLC cell lines and primary cancer cells from patients harboring EGFR mutations, YH25448 showed more potent inhibition of cancer cell growth and significantly increased tumor cell apoptosis compared to osimertinibs, which is one of 3rd generation EGFR TKIs. In vivo mouse model implanted with H1975 cells, YH25448 treatment at the once-daily showed a dramatic dose-dependent tumor regression in both subcutaneous and intracranial lesions with no abnormal signs such as skin keratosis shown in osimertinib-treated mice. Plasma half life of YH25448 was 5.9-6.8 hr and tumor to plasma AUC0-last ratio was 3.0-5.1 in tumor bearing mice. YH25448 also showed excellent penetration of the BBB, achieving CSF concentrations exceeding the IC50 value for pEGFR inhibition in the tumor-bearing mice. Taken together, these findings suggest important role for the further development of YH25448 as a novel therapeutic for the treatment of EGFR mutant-positive NSCLC patients with brain metastases. Citation Format: Jiyeon Yun, Min Hee Hong, Seok-Young Kim, Chae Won Park, So-Young Kim, Mi Ran Yun, Han Na Kang, Kyoung-Ho Pyo, Jong Sung Koh, Ho-Juhn Song, Young- Sung Lee, Se-Woong Oh, Soongyu Choi, Byoung-Chul Cho. YH25448, an irreversible 3rd generation EGFR TKI, exhibits superior anticancer effects with potent brain BBB penetration in NSCLC [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 4790.
Abstract 2716: Development of 4-1BB agonists: Ligand fusion shows greater anti-tumor activity than antibodies <i>in vivo</i>
Authors: Eric Tam, Galina Craig, Sara Ghassemifar, Alexander Koshkaryev, Sara Movassaghian, Cormac Cosgrove, James Sampson, Daryl Drummond, Andreas Raue
Journal: Cancer Research (2018)

Abstract Members of the tumor necrosis factor (TNF) superfamily of costimulatory receptors have emerged as promising targets for modulation of tumor infiltrating lymphocytes. Among these, 4-1BB (CD137) has a prominent role in promoting survival and expansion of cytotoxic CD8 T cells as well as activation of CD4 T cells, NK cells, and antigen presenting cells. The clinical relevance of 4-1BB agonism is currently being evaluated for two antibodies: urelumab (IgG4) and utomilumab (IgG2). However, it has been established that for the trimeric TNF receptor family, the homotrimeric ligands are superior activators compared to bivalent agonistic antibodies. Here we describe a prototype 4-1BB agonist consisting of three human 4-1BB ligands linked together as a single polypeptide chain and fused to the C-terminus of human IgG1 Fc (STIM-41BBL). Compared to a clinically relevant human 4-1BB antibody, STIM-41BBL shows increased activation of 4-1BB in a NF-kappa B reporter cell line. STIM-4-1BBL also shows augmented cytokine release compared to the antibody in CD8 T cells. Furthermore, we have developed a mouse STIM-41BBL and like the human counterpart, the ligand fusion induced greater cytokine release than an agonistic mouse 4-1BB antibody (IgG2a) in CD8 T cells. We have also introduced mutations (D265A/N297A) to the mouse 4-1BB antibody to make it effectorless in order to better approximate the clinical 4-1BB antibodies. Subsequently, we demonstrate that the murine STIM-41BBL had greater anti-tumor activity than the 4-1BB antibody in a MC38 tumor model. These results support the continued development of a 4-1BB ligand based therapeutic and suggests the greater potential of a STIM-41BBL fusion to a targeting antibody for more precise activation of immune system. Citation Format: Eric Tam, Galina Craig, Sara Ghassemifar, Alexander Koshkaryev, Sara Movassaghian, Cormac Cosgrove, James Sampson, Daryl Drummond, Andreas Raue. Development of 4-1BB agonists: Ligand fusion shows greater anti-tumor activity than antibodies in vivo [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 2716.
In Vivo Suppression of MicroRNA-24 Prevents the Transition Toward Decompensated Hypertrophy in Aortic-Constricted Mice
Authors: Rong-ChangLi, JinTao, Yun-BoGuo, Hao-DiWu, Rui-FengLiu, YanBai, Zhi-ZhenLv, Guan-ZhengLuo, Lin-LinLi, MengWang, Hua-QianYang, WeiGao, Qi-DeHan, You-YiZhang, Xiu-JieWang, MingXu, Shi-QiangWang
Journal: Circulation Research (2013)

Rationale:During the transition from compensated hypertrophy to heart failure, the signaling between L-type Ca2+ channels in the cell membrane/T-tubules and ryanodine receptors in the sarcoplasmic reticulum becomes defective, partially because of the decreased expression of a T-tubule–sarcoplasmic reticulum anchoring protein, junctophilin-2. MicroRNA (miR)-24, a junctophilin-2 suppressing miR, is upregulated in hypertrophied and failing cardiomyocytes. Objective:To test whether miR-24 suppression can protect the structural and functional integrity of L-type Ca2+ channel–ryanodine receptor signaling in hypertrophied cardiomyocytes. Methods and Results:In vivo silencing of miR-24 by a specific antagomir in an aorta-constricted mouse model effectively prevented the degradation of heart contraction, but not ventricular hypertrophy. Electrophysiology and confocal imaging studies showed that antagomir treatment prevented the decreases in L-type Ca2+ channel–ryanodine receptor signaling fidelity/efficiency and w...
Abstract 769: Zeb-1 contributes to the development of chemotherapeutic resistance in mantle cell lymphoma
Authors: Sudjit Luanpitpong, Jirarat Poohadsuan, Montira Janan, Kanjana Thumanu, Yon Rojanasakul, Surapol Issaragrisil
Journal: Cancer Research (2018)

Abstract Despite progress overall in improving cancer treatments, the complete response of mantle cell lymphoma (MCL) is still limited due to the inevitable development of drug resistance. Understanding how MCL cells acquire resistance at the molecular level may be a key innovation to targeted therapy. We established a series of bortezomib (BTZ)-resistant MCL cells and performed gene/protein profiling along with metabolic fingerprinting using synchrotron-based Fourier-transform infrared spectroscopy. Zeb-1, an epithelial-mesenchymal transition-inducing transcription factor better known for promoting metastasis in solid carcinomas, was found to be aberrantly expressed in the resistant MCL cells in accordance with an excessive production of lipids. Ectopic expression of Zeb-1 in parental MCL cells rendered the cells to acquire apoptosis resistance to BTZ. Here we demonstrated, for the first time, two possible encompassing mechanisms for Zeb-1-mediated BTZ resistance: (i) Zeb-1 induces cancer stem cells, as evaluated by tumor spheres and aldehyde dehydrogenase activity; and (ii) Zeb-1 induces lipid reprograming that may interfere with cell growth and drug response. Together, our results unveil a novel role of Zeb-1 in MCL aggressiveness. These findings have a clinical significance insight to the development of chemotherapeutic resistance of MCL. Citation Format: Sudjit Luanpitpong, Jirarat Poohadsuan, Montira Janan, Kanjana Thumanu, Yon Rojanasakul, Surapol Issaragrisil. Zeb-1 contributes to the development of chemotherapeutic resistance in mantle cell lymphoma [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 769.
Sulfhydryl Redox State Affects Susceptibility to Ischemia and Sarcoplasmic Reticulum Ca2+ Release in Rat Heart
Authors: RiccardoZucchi, GongyuanYu, PaolaGalbani, MarioMariani, GiovanniRonca, SimonettaRonca-Testoni
Journal: Circulation Research (1998)

Abstract—We investigated the effect of sulfhydryl and disulfide reagents on ischemic preconditioning and on sarcoplasmic reticulum Ca2+ release. Isolated working rat hearts were subjected to ischemic preconditioning (three 3-minute periods of global ischemia) or to control aerobic perfusion, which was followed by 30 minutes of global ischemia and 120 minutes of retrograde reperfusion. Necrosis was evaluated on the basis of lactate dehydrogenase release and triphenyltetrazolium chloride staining. In parallel experiments, sarcoplasmic reticulum Ca2+ release and [3H]-ryanodine binding were determined before the sustained ischemia. Ischemic preconditioning was associated with protection versus ischemic injury, decreased Ca2+ release and reduced [3H]-ryanodine binding. The disulfide reducing agent dithiothreitol (1 mmol/L) removed the protection provided by ischemic preconditioning, if added to the perfusion buffer either before or after the preconditioning procedure. In preconditioned hearts, dithiothreitol i...
Abstract 4413: DNA methylation of miR-7 is a mechanism involved in platinum response throughMAFGoverexpression in cancer cells
Authors: Olga Vera, Julia Jimenez, Carlos Rodriguez-Antolin, Olga Pernia, Carmen Rodriguez, Javier Soto, Rocio Rosas, Isabel Esteban-Rodriguez, Rosario Perona, Javier de Castro, Inmaculada Ibáñez-de-Cáceres
Journal: Cancer Research (2018)

Abstract One of the major limitations associated with platinum use is the resistance that almost invariably develops in different tumor types. In the current study, we sought to identify epigenetically regulated microRNAs as novel biomarkers of platinum resistance in lung and ovarian cancers, the ones with highest ratios of associated chemo-resistance. Experimental procedures: We combined transcriptomic data from microRNA and mRNA under the influence of an epigenetic reactivation treatment in a panel of four paired cisplatin -sensitive and -resistant cell lines, followed by real-time expression and epigenetic validations for accurate candidate selection in 19 human cancer cell lines. To identify specific candidate genes under miRNA regulation, we assembled “in silico” miRNAs and mRNAs sequences by using ten different algorithms followed by qRT-PCR validation. Functional assays of site-directed mutagenesis and luciferase activity, miRNAs precursor overexpression, silencing by antago-miR and cell viability were performed to confirm their specificity in gene regulation. Results were further explored in 187 primary samples obtained from ovarian tumors and controls. Results: We identified 4 candidates, miR-7, miR-132, miR-335 and miR-148a, which deregulation seems to be a common event in the development of resistance to cisplatin in both tumor types. miR-7 presented specific methylation in resistant cell lines, and was associated with poorer prognosis in ovarian cancer patients. Our experimental results strongly support the direct regulation of MAFG through miR-7 and their involvement in the development of CDDP resistance in human tumor cells. Conclusion: The basal methylation status of miR-7 before treatment may be a potential clinical epigenetic biomarker, predictor of the chemotherapy outcome to CDDP in ovarian cancer patients. To the best of our knowledge, this is the first report linking the regulation of MAFG by miRNA-7 and its role in chemotherapy response to CDDP. Furthermore, this data highlights the possible role of MAFG as a novel therapeutic target for platinum resistant tumors. Citation Format: Olga Vera, Julia Jimenez, Carlos Rodriguez-Antolin, Olga Pernia, Carmen Rodriguez, Javier Soto, Rocio Rosas, Isabel Esteban-Rodriguez, Rosario Perona, Javier de Castro, Inmaculada Ibáñez-de-Cáceres. DNA methylation of miR-7 is a mechanism involved in platinum response through MAFG overexpression in cancer cells [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 4413.
The Perlecan Fragment LG3 Is a Novel Regulator of Obliterative Remodeling Associated With Allograft Vascular Rejection
Authors: MathildeSoulez, Eve-AnniePilon, MélanieDieudé, HéloïseCardinal, NathalieBrassard, ShijieQi, Shyh-JongWu, YvesDurocher, FrançoisMadore, ClaudePerreault, Marie-JoséeHébert
Journal: Circulation Research (2012)

Rationale:Endothelial apoptosis is increased in association with acute and chronic vascular rejection (VR) of solid allografts. Apoptotic endothelial cells (EC) release LG3, a C-terminal fragment of perlecan of potential importance in vascular remodeling and neointima formation. Objective:Our 2 goals were to determine whether circulating levels of LG3 are increased in association with acute VR of renal allografts and to evaluate the impact of LG3 on vascular remodeling. Methods and Results:We conducted a case-control study to compare serum LG3 levels in human renal transplant patients with acute VR, tubulo-interstitial rejection (ATIR) and normal graft function. Aorta transplantation between fully MHC-mismatched mice in association with intravenous LG3 injection was used to characterize the impact of LG3 on vascular remodeling. Scratch assays evaluated the promigratory activity of LG3 on vascular smooth muscle cells (VSMC) in vitro. Serum LG3 levels were significantly elevated in human renal transplant pa...