tbuckley/cabot-search huggingface dataset:
Abstract 5425: Investigating the effects of p53 activation and HDAC inhibition on genes associated with poor prognosis prostate cancer
Authors: Gemma M. Gregg, Fiammetta Falcone, Andrea Lees, Gerard Quinn, Peter Gallagher, Richard Kennedy, Ian I. Mills, Simon S. McDade
Journal: Cancer Research (2018)

Abstract Background Prostate cancer (PCa) is now the most commonly diagnosed malignancy in men worldwide. SOC combines radiotherapy with ADT, however recurrence rate remains unacceptably high and many men present with late stage aggressive and metastatic disease, with poor prognosis and limited treatment options. Despite tumor suppressor p53 being mutated in approximately 50% of human tumors, it has been reported that p53 alteration occurs in only 12% of primary prostate tumors. Emerging data links epigenetic-mediated gene silencing as a major differentiator between aggressive and indolent disease that is associated with up-regulation of key cell cycle regulator FOXM1, which is known to be suppressed by p53. HDAC inhibitors (HDACi) are an emerging class of epigenetic modifying anti-cancer agents, which we hypothesises will enhance p53 activity, cell death and alter patterns of gene expression to targeting p53 dependent and independent vulnerabilities in PCa. Methods We used basally p53 deficient/proficient PCa models (PC3/LNCaP) and novel C4-2B and LNCap p53 CRISPR-Cas9 knockout models to investigate the combination effects of Nutlin 3A or radiation (IR) with class 1 HDACi Entinostat by Annexin V/PI Flow Cytometry and Western Blot. Transcriptional effects were evaluated by RT-PCR and RNA-seq analysis. TCGA mutational and RNA-seq data were used to link p53 mutation with altered gene expression and outcome. Results We have demonstrated that there is a synergistic induction of cell death when we combine N3A/IR with Entinostat that is p53-dependent. In addition, we see that p53 acts as a barrier to genes associated with poor prognosis including FOXM1 which is phenocopied by single-agent Entinostat independent of WT-p53. This suppression may potentially be downstream of p21 via the DREAM complex. Importantly p53 mutation in TCGA primary PCa patients is associated with poor outcome and elevated FOXM1 expression. Conclusion and Future Work Results to date suggest that Entinostat enhances p53 dependent cell death but also has p53 dependent and independent mechanisms to suppress genes associated with poor prognosis PCa. The mechanism looks to be dependent of p21 and may involve DREAM complex. Citation Format: Gemma M. Gregg, Fiammetta Falcone, Andrea Lees, Gerard Quinn, Peter Gallagher, Richard Kennedy, Ian I. Mills, Simon S. McDade. Investigating the effects of p53 activation and HDAC inhibition on genes associated with poor prognosis prostate 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 5425.
Overview of Oncology and Hematology Drug Approvals at US Food and Drug Administration Between 2008 and 2016
Authors: Jiaxi Zhou, Jonathon Vallejo, Paul Kluetz, Richard Pazdur, Tamy Kim, Patricia Keegan, Ann Farrell, Julia A Beaver, Rajeshwari Sridhara
Journal: JNCI Journal of the National Cancer Institute (2018)

BackgroundWe previously conducted an overview of oncology products reviewed by the Office of Oncology Drug Products in the Center for Drug Evaluation and Research at the US Food and Drug Administration for marketing approval and the regulatory actions taken during July 2005 to December 2007. There is a need to understand if the changes in the laws, regulations, and the organization that occurred after 2007 had any impact on the regulatory drug approvals. We present a detailed overview of hematology and oncology products reviewed by Office of Oncology Drug Products and Office of Hematology and Oncology Drug Products.
Techniques, Evaluation, and Consequences of Linear Block at the Left Atrial Roof in Paroxysmal Atrial Fibrillation
Authors: MélèzeHocini, PierreJaïs, PrashanthanSanders, YoshihideTakahashi, MartinRotter, ThomasRostock, Li-FernHsu, FrédéricSacher, SylvainReuter, JacquesClémenty, MichelHaïssaguerre
Journal: Circulation (2005)

Background— There are no reports describing the technique, electrophysiological evaluation, and clinical consequences of complete linear block at roofline joining the superior pulmonary veins (PVs) in patients with paroxysmal atrial fibrillation (AF). Methods and Results— Ninety patients with drug-refractory paroxysmal AF undergoing radiofrequency ablation were prospectively randomized into 2 ablation strategies: (1) PV isolation (n=45) or (2) PV isolation in combination with linear ablation joining the 2 superior PVs (roofline; n=45). In both groups, the cavotricuspid isthmus, fragmented peri-PV-ostial electrograms, and spontaneous non-PV foci were ablated. Roofline ablation was performed at the most cranial part of the left atrium (LA) with complete conduction block demonstrated during LA appendage pacing by the online mapping of continuous double potential and an activation detour propagating around the PVs to activate caudocranially the posterior wall of the LA. The effect of ablation at the LA roof w...
Angiotensin II Activates RhoA in Cardiac Myocytes
Authors: HirokiAoki, SeigoIzumo, JunichiSadoshima
Journal: Circulation Research (1998)

Abstract—The organization of actin into striated fibers (myofibrils) is one of the major features of cardiac hypertrophy. However, its signal transduction mechanism is not well understood. Although Rho-family small G proteins have been implicated in actin organization in many cell types, it is not fully elucidated whether Rho mediates the organization of actin fibers by hypertrophic stimuli in cardiac myocytes. Therefore, we examined (1) whether Rho is activated by the hypertrophic stimulus, angiotensin II (Ang II), and (2) whether Rho mediates the Ang II–induced organization of actin fibers in cultured neonatal rat cardiac myocytes. Treatment of myocytes with Ang II caused a rapid formation of both striated (mature myofibrils) and nonstriated (premyofibrils) actin fibers within 30 minutes, as determined by phalloidin stainings of the polymerized actin and troponin T stainings. Immunoblot analyses and immunostainings have indicated that cardiac myocytes express RhoA, but RhoB is undetectable. In the contr...
Abstract 11232: Assessment of Diffuse Myocardial Fibrosis With Native T1 Values on Cardiovascular Magnetic Resonance and Its Relationship With Myocardial Function in Asymptomatic Aortic Stenosis Patients
Authors: Seung-PyoLee, WhalLee, Eun-AhPark, Hyung-KwanKim, Yong-JinKim, Dae-WonSohn
Journal: Circulation (2014)

Introduction: Aortic stenosis (AS) typically provokes diffuse myocardial fibrosis (DMF). Methods to evaluate DMF using cardiovascular magnetic resonance (CMR) are yet to be made easier and validated for wide clinical use. Hypothesis: To test whether T1 mapping, without the use of gadolinium contrast, may be useful for assessment of DMF and whether it correlates with subclinical myocardial dysfunction in asymptomatic AS patients. Methods: 80 asymptomatic patients with moderate or severe AS and normal LVEF and 15 sex-matched control subjects were prospectively enrolled. Patients underwent 2D-echocardiography, speckle tracking imaging and CMR in a 3.0T scanner including mapping of T1 relaxation time with modified Look-Locker Inversion-recovery (MOLLI) sequence. Patients were divided into three groups according to the native T1 value. Results: Native T1 values correlated well with the degree of DMF on intraoperative myocardial biopsy specimens (r=0.777, p-value<0.001) and differed significantly between AS and...
Rad As a Novel Regulator of Excitation–Contraction Coupling and β-Adrenergic Signaling in Heart
Authors: GangWang, XiaojunZhu, WenjunXie, PeidongHan, KaitaoLi, ZhongcuiSun, YanruWang, ChunleiChen, RuishengSong, ChunmeiCao, JifengZhang, CaihongWu, JieLiu, HepingCheng
Journal: Circulation Research (2010)

Rationale: Rad (Ras associated with diabetes) GTPase, a monomeric small G protein, binds to Cavβ subunit of the L-type Ca2+ channel (LCC) and thereby regulates LCC trafficking and activity. Emerging evidence suggests that Rad is an important player in cardiac arrhythmogenesis and hypertrophic remodeling. However, whether and how Rad involves in the regulation of excitation–contraction (EC) coupling is unknown. Objective: This study aimed to investigate possible role of Rad in cardiac EC coupling and β-adrenergic receptor (βAR) inotropic mechanism. Methods and Results: Adenoviral overexpression of Rad by 3-fold in rat cardiomyocytes suppressed LCC current (ICa), [Ca2+]i transients, and contractility by 60%, 42%, and 38%, respectively, whereas the “gain” function of EC coupling was significantly increased, due perhaps to reduced “redundancy” of LCC in triggering sarcoplasmic reticulum release. Conversely, ≈70% Rad knockdown by RNA interference increased ICa (50%), [Ca2+]i transients (52%) and contractility ...
Abstract 4389: HEXIM1 is a negative regulator ofH. pylori-induced BIRC3 enhancer RNA
Authors: Donald R. Sheppard
Journal: Cancer Research (2018)

Abstract The bacterium Helicobacter pylori inhabits the human stomach and is responsible for a number of pathologies, including being strongly associated with the development of gastric adenocarcinoma. H. pylori inhibits apoptosis in gastric cells, but the mechanism is poorly understood. We investigated how H. pylori inhibits apoptosis using cultured G27-strain H. pylori to stimulate cancer cell lines, and apoptosis was induced with Raptinal. We found that H. pylori induces the transcription of the apoptosis-inhibiting protein cIAP2, and this induction is sufficient to inhibit apoptosis in stimulated cells. We found an enhancer region upstream of the gene that codes for cIAP2 (BIRC3). H. pylori induces expression of RNA from this enhancer, and RNAi treatment targeting this eRNA inhibited induction of the BIRC3 mRNA. Chromatin immunoprecipitation revealed that positive transcription elongation factor b (P-TEFb) is recruited to the enhancer following H. pylori stimulation, and RNA polymerase II is activated. We found that the negative regulator of transcription HEXIM1 inhibits P-TEFb recruitment and eRNA production. HEXIM1 also inhibits BIRC3 mRNA transcription, cIAP2 protein induction and H. pylori's anti-apoptotic effect. Together, these findings indicate that H. pylori inhibits apoptosis induction in cultured cells, and this inhibition is mediated by the induction of BIRC3/cIAP2. H. pylori stimulates the production of RNA from the enhancer region of BIRC3, which is required for the induction of the gene, and the eRNA production is regulated by HEXIM1 and P-TEFb. Citation Format: Donald R. Sheppard. HEXIM1 is a negative regulator of H. pylori-induced BIRC3 enhancer RNA [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 4389.
Diastolic Murmurs in Apparently Normal Children
Authors: Jeromeliebman, Santoshsood
Journal: Circulation (1968)

Diastolic murmurs have always been considered abnormal, but this report presents nine apparently normal children with high-frequency, early, diamond-shaped diastolic murmurs confirmed by intracavitary phonocardiography to arise within the left ventricle. Each child (aged 5 to 15 years) was referred for evaluation of a systolic murmur at the lower left sternal border, but an additional finding at the initial examination was a grade I to III/VI high-pitched diastolic murmur, thought to be decrescendo, at the third and fourth intercostal space at the left sternal edge. The murmurs were best heard when the patient was supine. Cardiac x-rays, including four views with barium, were all clearly normal, as were eight of the nine electrocardiograms and the Frank and McFee vectorcardiograms. Multiple parameters of right and left heart catheterizations were normal in all.
Exercise Training Augments Flow-Dependent Dilation in Rat Skeletal Muscle Arterioles
Authors: AkosKoller, AnHuang, DongSun, GaborKaley
Journal: Circulation Research (1995)

Abstract We aimed to test the hypothesis that as a consequence of short-term daily exercise, flow (shear stress)–dependent dilation and its mediation by the endothelium are altered in skeletal muscle arterioles. After initial familiarization with the protocol, rats ran on a treadmill once a day (with gradually increasing intensity up to 40 minutes and 28 m/min) for ≈3 weeks (EX group); a control group remained sedentary (SED group). The active (internal) diameters of isolated gracilis muscle arterioles of SED and EX rats at 80 mm Hg were significantly different (55.2±2.1 and 49.3±2.0 μm, P<.05), and their passive diameters (in Ca2+-free solution) were 105.3±3.1 and 111.2±2.4 μm (not significantly different), respectively. Increases in flow of the perfusion solution from 0 to 12 μL/min elicited a significantly greater increase in diameter of EX arterioles (by 83.5% at maximum flow). This enhanced sensitivity maintained a lower shear stress in EX arterioles (15 to 20 dyne/cm2) compared with SED arterioles (...
Intrarenal Distribution of Blood Flow in Man
Authors: Jugorotakeuchi, Isaoishikawa, Tohruinasaka, Shuichirosakai, Akirashinoda, Akiratakada, Noboruhamada
Journal: Circulation (1970)

To measure blood flow through fast and slow pathways of the kidney separately, a new method of analyzing dye-dilution curves was devised. Twenty-five patients with hypertension or renal disease were selected for study. Indocyanine green was injected into one renal artery and dye-dilution curves were recorded in blood from the ipsilateral renal vein, using a densitometer. Recirculation effect was eliminated by the curve obtained from the contralateral renal vein. For analyzing the dyedilution curves, a new mathematical model and an iterative least squares method of fitting the curve using a digital computer were employed. Basic assumption for the model was that the transit time of each molecule of the dye through fast and slow pathways was a random variable and followed a log-normal distribution. The fast flow measured by the new method was significantly decreased in 11 patients with azotemia compared with that in 14 without azotemia, while changes in slow flow were not significant. Consequently, the ratio...
CD28 blockade controls T cell activation to prevent graft-versus-host disease in primates
Authors: Benjamin K. Watkins, Victor Tkachev, Scott N. Furlan, Daniel J. Hunt, Kayla Betz, Alison Yu, Melanie Brown, Nicolas Poirier, Hengqi Betty Zheng, Agne Taraseviciute, Lucrezia Colonna, Caroline Mary, Gilles Blancho, Jean-Paul Soulillou, Angela Panoskaltsis-Mortari, Prachi Sharma, Anapatricia Garcia, Elizabeth Strobert, Kelly Hamby, Aneesah Garrett, Taylor Deane, Bruce R. Blazar, Bernard Vanhove, Leslie S. Kean
Journal: Journal of Clinical Investigation (2018)

Controlling graft-versus-host disease (GVHD) remains a major unmet need in stem cell transplantation, and new, targeted therapies are being actively developed. CD28-CD80/86 costimulation blockade represents a promising strategy, but targeting CD80/CD86 with CTLA4-Ig may be associated with undesired blockade of coinhibitory pathways. In contrast, targeted blockade of CD28 exclusively inhibits T cell costimulation and may more potently prevent GVHD. Here, we investigated FR104, an antagonistic CD28-specific pegylated-Fab′, in the nonhuman primate (NHP) GVHD model and completed a multiparameter interrogation comparing it with CTLA4-Ig, with and without sirolimus, including clinical, histopathologic, flow cytometric, and transcriptomic analyses. We document that FR104 monoprophylaxis and combined prophylaxis with FR104/sirolimus led to enhanced control of effector T cell proliferation and activation compared with the use of CTLA4-Ig or CTLA4-Ig/sirolimus. Importantly, FR104/sirolimus did not lead to a beneficial impact on Treg reconstitution or homeostasis, consistent with control of conventional T cell activation and IL-2 production needed to support Tregs. While FR104/sirolimus had a salutary effect on GVHD-free survival, overall survival was not improved, due to death in the absence of GVHD in several FR104/sirolimus recipients in the setting of sepsis and a paralyzed INF-γ response. These results therefore suggest that effectively deploying CD28 in the clinic will require close scrutiny of both the benefits and risks of extensively abrogating conventional T cell activation after transplant.
Role of Rho-Associated Kinase in Neointima Formation After Vascular Injury
Authors: ReiShibata, HisashiKai, YukihikoSeki, SeiyaKato, MinoruMorimatsu, KozoKaibuchi, TsutomuImaizumi
Journal: Circulation (2001)

Background—The Rho/Rho-associated kinase (Rho-kinase) system is implicated in various cellular functions, including migration, proliferation, and apoptosis. Because a possible role of the system is suggested in neointima formation after vascular injury, we sought to examine whether a new specific Rho-kinase inhibitor, Y27632, prevents neointima formation of the balloon-injured rat carotid artery, and if so, to investigate the effects of Y27632 on migration, proliferation, and apoptosis of smooth muscle cells (SMCs) in the injured artery. Methods and Results—Y27632 was administered intraperitoneally from 1 day before to 14 days after vascular injury. Treatment with Y27632 inhibited phenylephrine-induced Rho-kinase activation in the carotid artery on the basis of immunoblotting against the phosphorylated myosin-binding subunit of myosin phosphatase. Y27632 markedly prevented neointima formation at days 7 and 14. In controls, BrdU+ proliferating and TUNEL+ apoptotic SMCs were transiently and coincidentally i...
Abstract 11928: An Interaction Between The Time Delay And Pharmacologic Pre-treatment. Effect On Myocardial Perfusion And Infarct Size
Authors: Marek Prech, Ewa Bartela, Magdalena Janus, Aleksander Araszkiewicz, Igor Jeremicz, Aleksandra Kutrowska, Malgorzata Pyda
Journal: Circulation (2015)

Introduction: Primary percutaneous coronary intervention (PCI) is the preferred method of reperfusion in STEMI patients. However, optimal adjunctive pharmacotherapy is still under investigation. Hypothesis: To assess the effect of triple pharmacologic therapy on myocardial perfusion and infarct size in relation to different time delays. Methods: We studied 309 consecutive STEMI patients admitted within 12 hours from symptom onset with: (1) chest pain persisting for &gt;30min, (2) ST-segment elevation &gt;1mm in ≥ 2 contiguous leads, (4) pre-treatment with 600mg of clopidogrel, 300mg of aspirin and 5000U of intravenous heparin. Group I (n=90) comprised patients transferred immediately to cathlab, group II (n=219) consisted of patients transferred via local hospitals (staged transfer). Results of TIMI flow prior to PCI and post-PCI, ST-segment resolution, troponin T level and MBG were analyzed in relation to time delay to intervention. Results: The median time interval between the onset of symptoms and pharmacologic pre-treatment was comparable in both groups, but the delay between pharmacologic pre-treatment and angiography was twice longer in cases of staged transfer. Despite a longer delay to intervention, higher rates of pre-angiography total ST-segment resolution (STSR) and TIMI flow 3 at initial angiography were observed in those patients. Differences in the rate of total STSR, TIMI flow 3 and MBG were no longer observed post PCI. Similarly, the peak troponin level was comparable in both groups - table. Conclusions: 1. Pre-hospital treatment with a combination of antiplatelet and antithrombotic agents improves myocardial perfusion. 2. Longer transfer delay paradoxically allows for the amplification of pharmacologic pre-treatment before mechanical reperfusion.
Abstract 59: 14-3-3zeta overexpressing breast cancer cells promote fibroblast senescence and CAF-like phenotype
Authors: Hongzhong Li, Yi Xiao, Xiangliang Yuan, Wenling Kuo, Ping Li, Dihua Yu
Journal: Cancer Research (2018)

Abstract 14-3-3ζ overexpression in breast cancer is associated with accelerated cancer progression and poor clinical outcome in patients. Our previous study revealed that 14-3-3ζ overexpression promotes epithelial mesenchymal transition (EMT) of breast cancer cells, which facilitates progression of ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC). However, the impact of 14-3-3ζ overexpressing breast cancer cells on tumor microenvironment (TME) and the underlying mechanisms have not been explored. We found dramatically increased cancer associated fibroblast (CAF) signatures in patients' matched IDC lesions compared to their DCIS lesions, suggesting that activated fibroblasts may be involved in DCIS to IDC transition. Global gene expression profiling uncovered increased expression of pro-inflammatory cytokines/chemokines, including IL6 and IL8, in 14-3-3ζ AND ErbB2 co-overexpressed 10A.ErbB2.1433ζ cells compared to ErbB2 overexpressed 10A.ErbB2 cells. This finding was further confirmed by ELISA and validated in other breast cancer cell lines. We tested whether increased pro-inflammatory cytokines in the conditional medium (CM) from 14-3-3ζ overexpressed cancer cells promotes CAF-like phenotype. Indeed, CM from 14-3-3ζ overexpressed cancer cells significantly increased SMA+ activated fibroblast cells compared to controls. Additionally, up-regulation of β-galactosidase and reduced cell proliferation, hallmarks of senescence cells, were detected in fibroblast cells cultured in CM from 14-3-3ζ overexpressed cancer cells. Next, we explored potential mechanism of how 14-3-3ζ overexpression in cancer cells leads to up-regulation of pro-inflammatory cytokines/chemokines. Since NF-kappaB is one of the master upstream regulator of IL-6 and IL-8, we next investigated the NF-kappaB signaling activation in 14-3-3ζ overexpressed vs control cancer cells. 14-3-3ζ overexpressing cancer cells had hyperactive canonical NF-kappaB responses, including accelerated IκBα degradation, p65 phosphorylation, as well as nuclear translocation compared to 14-3-3ζ low cancer cells. Prolonged NF-kappaB signaling activation upon pro-inflammatory cytokine stimulation was also detected in 14-3-3ζ overexpressing cancer cells. These results suggest that 14-3-3ζ overexpressing cancer cells may promote fibroblast cell senescence and CAF-like phenotype by creating by a chronic inflammatory microenvironment, which ultimately enhances DCIS to IDC transition. Citation Format: Hongzhong Li, Yi Xiao, Xiangliang Yuan, Wenling Kuo, Ping Li, Dihua Yu. 14-3-3zeta overexpressing breast cancer cells promote fibroblast senescence and CAF-like phenotype [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 59.