tbuckley/cabot-search huggingface dataset:
Abstract 12534: Clinical Impact of Gap Angle Ratio in Patient With Ostial Lesion of Right Coronary Artery Undergoing Percutaneous Coronary Intervention
Authors: Koichi Ohashi, Daisuke Abe, Hitoshi Hirano, Tatsuro Sassa, Akira Takayama, Masakazu Kaneko, Tomohiko Harunari, Yoshiaki Yui, Norihiro Kuroki, Takao Yuba, Kou Suzuki
Journal: Circulation (2016)

Background: However in drug-eluting stent (DES) era, ostial lesion of right coronary artery (RCA) is associated with high incidence of in-stent restenosis (ISR). And the issue of DES implantation in ostial lesion of RCA has not been adequately evaluated. Objective: The purpose of this study is to investigate the incidence of ISR and the predictive value in patients with ostial lesion of RCA who underwent percutaneous coronary intervention (PCI). Methods: A cohort of 56 patients (73.4±9.9 years-old, 70% male) who underwent PCI for ostial lesion of RCA was retrospectively analyzed in Tokyo Metropolitan Bokutoh hospital from November 2001 to October 2015. We investigated the angle between greater curvature of aortic wall and RCA take-off at diastolic and systolic phase in left anterior oblique (LAO) position view. Clinical outcome was defined as ISR at follow up coronary angiography. We performed receiver operating characteristic analysis for ISR. Results: Incidence of ISR was 41.1% (n=23) in entire patients. Area under the curve of Gap (angle difference between maximum and minimum) / minimum Angle Ratio (GAR-min) for ISR was 0.723 and the cut off value was 0.306 (specificity 0.818, sensitivity 0.696). We divided patients into 2 group; Low GAR group (&lt;0.306: n=35); High GAR group (≥0.306: n=21). There were no significant differences between 2 groups in baseline characteristics. ISR was significantly lower incidence in Low GAR compared with High GAR (22.9% vs. 71.4%, p&lt;0.001). GAR&gt;0.306 was an independent predictor of ISR after adjustment of multiple cofounders (OR: 8.54, 95% CI: 2.18-33.1, p=0.002). Conclusion: These data suggest that High GAR (≥0.306) may predict ISR in patient undergoing PCI to ostial lesion of RCA.
Alternative to pethidine could halve rate of epidurals
Authors: Jacqui Wise
Journal: BMJ (2018)

Using remifentanil instead of pethidine to relieve pain during labour could halve the number of women needing an epidural, a randomised controlled trial has shown.1

About a third of women receiving pethidine for labour pain subsequently require an epidural, which increases the risk of instrumental vaginal delivery. Remifentanil is a potent synthetic opioid with a very rapid onset and ultrashort duration of action, but it is rarely used in UK practice.

The authors of the study, published in the Lancet , are calling for a change in national clinical guidelines to incorporate the more routine use of remifentanil.

The …
Antihypertensive Effects of the Putative T-Type Calcium Channel Antagonist Mibefradil Are Mediated by the L-Type Calcium Channel Cav1.2
Authors: SvenMoosmang, NicoleHaider, BirgitBrüderl, AndreaWelling, FranzHofmann
Journal: Circulation Research (2006)

The role of T-type Ca2+ channels for cardiovascular physiology, in particular blood pressure regulation, is controversial. Selective blockade of T-type Ca2+ channels in resistance arteries has been proposed to explain the effect of the antihypertensive drug mibefradil. In the present study, we used a third generation, time- and tissue-specific conditional knockout model of the L-type Ca2+ channel Cav1.2 (Cav1.2SMAKO mice) to genetically dissect the effects of mibefradil on T- and L-type Ca2+ channels. Myogenic tone and phenylephrine-induced contraction in hindlimb perfusion experiments were sensitive to mibefradil in control mice, whereas the drug showed no effect in Cav1.2-deficient animals. Mean arterial blood pressure in awake, freely moving control mice was reduced by 38±2.5 mm Hg at a dose of 1.25 mg/kg bodyweight mibefradil, but not changed in Cav1.2SMAKO mice. These results demonstrate that the effect of the putative T-type Ca2+ channel-selective blocker mibefradil on blood pressure and small vesse...
Nitric Oxide–Independent Dilation of Conductance Coronary Arteries to Acetylcholine in Conscious Dogs
Authors: ZhiMing, RobertParent, MichelLavallée
Journal: Circulation Research (1997)

Abstract NO and prostacyclin formation cannot entirely account for receptor-operated endothelium-dependent dilation of coronary vessels, since vasodilator responses are not completely suppressed by inhibitors of these agents. Therefore, we considered that another factor, such as an endothelium-derived hyperpolarizing factor described in vitro, may participate in NO- and prostacyclin-independent coronary dilator responses. In conscious instrumented dogs, intracoronary acetylcholine (ACh, 30.0 ng · kg−1 · min−1) increased the external epicardial coronary diameter (CD) by 0.18±0.03 mm (from 3.44±0.11 mm) when increases in coronary blood flow (CBF) were prevented and increased the CD by 0.20±0.05 when CBF was allowed to increase. After the administration of intracoronary Nω-nitro-l-arginine methyl ester (L-NAME), CBF responses to ACh were abolished, but CD responses (0.23±0.05 from 3.22±0.09 mm) were maintained. Blockade of NO formation was confirmed by reduced CD baselines and blunted flow-dependent CD respo...
Abstract 320: Ultrafast Cooling Induced by Total Liquid Ventilation Limits Early Oxidative Stress and Blood Brain Barrier Disruption After Cardiac Arrest
Authors: MatthiasKohlhauer, IsabelleRemy-Jouet, FannyLidouren, Jean-DamienRicard, RaymondRobert, MarianaBarretto, PhilippeMicheau, HervéWalti, PierreCarli, BenoitVivien, VincentRichard, PaulMulder, BijanGhaleh, AlainBerdeaux, RenaudTissier
Journal: Circulation (2014)

Introduction: We previously demonstrated that total liquid ventilation (TLV) with perfluorocarbons can afford ultra-fast cooling and improve outcome after non-shockable cardiac arrest in rabbits. Hypothesis: We determined whether this protection could be linked to an early inhibition of reperfusion injury after cardiac arrest, including oxidative stress and blood brain barrier (BBB) disruption. Methods: Anesthetized rabbits were randomly submitted to 13 min of asphyxia followed by cardiopulmonary resuscitation. Then, they randomly underwent normothermic life support (Control group) or hypothermia induced by either i.v. cold saline (30 ml/kg; CONV group) or TLV (TLV group). In a first set of experiments, reactive oxygen species (ROS) were measured by electron paramagnetic resonance spectroscopy using CMH as spin probe on tissues sampled 30 min after cardiac arrest. In a second set of experiments, BBB integrity was assessed by the administration of Evans blue dye (EBD) 30 min after resuscitation. Brains wer...
Phased Chest and Abdominal Compression-Decompression Versus Conventional Cardiopulmonary Resuscitation in Out-of-Hospital Cardiac Arrest
Authors: Hans-RichardArntz, RahulAgrawal, HansRichter, StefanSchmidt, TanjaRescheleit, MarliesMenges, HubertBurbach, JoachimSchröder, Heinz-PeterSchultheiss
Journal: Circulation (2001)

Background Several methods have been developed to improve the efficacy of mechanical resuscitation, because organ perfusion achieved with conventional manual resuscitation is often insufficient. In animal studies, phased chest and abdominal compression-decompression resuscitation by use of the Lifestick device has resulted in a better outcome compared with that of conventional resuscitation. In end-of-life patients, an increased coronary perfusion pressure was achieved. The aim of the present study was to determine the feasibility, safety, and efficacy of the Lifestick compared with conventional resuscitation in patients with sudden nontraumatic out-of-hospital cardiac arrest. Methods and Results The crews of 4 mobile intensive care units, staffed by an emergency physician and a paramedic, were trained to use the device. Fifty patients were randomized by sealed envelopes to either Lifestick (n=24) or conventional (n=26) resuscitation. No differences were found regarding demographic and logistical conditio...
An Alternative Transcript of the Rat Renin Gene Can Result in a Truncated Prorenin That Is Transported Into Adrenal Mitochondria
Authors: SusanneClausmeyer, RaphaelaStürzebecher, JörgPeters
Journal: Circulation Research (1999)

Abstract—Characterization of the local renin-angiotensin system in the rat adrenal zona glomerulosa indicated a dual targeting of renin both to the secretory pathway and mitochondria. To investigate the transport of renin into mitochondria, we constructed a series of amino-terminal deletion variants of preprorenin. One of these variants, lacking the complete signal sequence for the endoplasmic reticulum and 10 amino acids of the profragment, was transported efficiently into isolated mitochondria. The transport was further shown to be dependent on mitochondrial membrane potential and ATP synthesis. Analysis of adrenal RNA revealed the existence of 2 renin transcripts. While one of the transcripts corresponds to the known full-length transcript, the other one lacks exon 1; instead, exon 2 is preceded by a domain of 80 nucleotides originating from intron 1. This domain, as well as the following region of intron 1 being excised, shows all essential sequence elements defining an additional, so-far-unknown exon...
Abstract 1805: Development of a selective androgen receptor degrader (SARD) for treatment of castration-resistant prostate cancer
Authors: ZhongKe Yao, Suzanne Wardell, Ivan Spasojevic, John Norris, John Katzenellenbogen, Donald McDonnell, Jatinder S. Josan
Journal: Cancer Research (2018)

Abstract Current treatments for prostate cancer are centered on blocking androgen-signaling axis, which is the target of several clinical androgen receptor (AR) antagonists such as enzalutamide. Recent studies have shown that a single AR mutation (F876L) converts enzalutamide from an antagonist to an agonist—a fate shared by earlier antagonists as well such as bicalutamide and flutamide. While hormonal therapy is often successful in the initial stages of the disease, prostatic tumors inevitably become resistant to these therapeutics. Remarkably though, several mechanistic studies suggest that the androgen receptor signaling remains active even in these hormonal refractory cancers, which suggests that AR remains a viable target in the castration-resistant prostate cancers (CRPC). Thus, novel therapeutics that target and degrade AR could provide unique druggable opportunities for complete and more sustained AR inhibition in prostate cancers. Based on an AR-gelsolin interaction in a mammalian two-hybrid luciferase assay, we conducted a screen of an in-house library of 170,000 compounds, re-assayed and validated the top 2K hits. The top 500 hits were then characterized in a battery of assays such as AR-driven gene expression, inhibition of cell proliferation in WT and mutant cell lines, ChIP-seq, transcriptional and conformational profiling, and AR degradation studies. We have identified a selective androgen receptor degrader (SARD) series that shows efficacy against both WT and AR mutants. Further structure-activity relationship (SAR) studies revealed analogs with IC50 equivalent or superior to enzalutamide. In vivo studies are currently under way to evaluate the efficacy of the optimized lead in mouse tumor xenografts. These preclinical findings highlight the utility of SARDs as an effective therapeutic prostate tumor strategy in the context of AR mutations and overexpression that bestow resistance to the second-generation AR antagonists. Citation Format: ZhongKe Yao, Suzanne Wardell, Ivan Spasojevic, John Norris, John Katzenellenbogen, Donald McDonnell, Jatinder S. Josan. Development of a selective androgen receptor degrader (SARD) for treatment of castration-resistant 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 1805.
Hypoxia-Induced Apelin Expression Regulates Endothelial Cell Proliferation and Regenerative Angiogenesis
Authors: MélanieEyries, GéraldineSiegfried, MarianaCiumas, KevinMontagne, MoniqueAgrapart, FranckLebrin, FlorentSoubrier
Journal: Circulation Research (2008)

Apelin has been identified as the endogenous ligand of the human orphan G protein–coupled receptor APJ. This peptide exerts a variety of cardiovascular effects and particularly acts as an activator of angiogenesis. Importantly, hypoxia has been reported to regulate apelin expression but the molecular mechanism underlying hypoxia-induced apelin expression and the relationship with the physiological response of the apelin/APJ system are still not established. Here, we demonstrate that apelin expression is induced by hypoxia in cultured endothelial and vascular smooth muscle cells as well as in lung from mice exposed to acute hypoxia. Transient transfection experiments show that hypoxia-inducible transcriptional activation of apelin requires an intact hypoxia-responsive element (+813/+826) located within the first intron of the human apelin gene. Chromatin immunoprecipitation assay reveals that hypoxia-inducible factor-1α binds to the endogenous hypoxia-responsive element site of the apelin gene. Moreover, o...
Abstract 2785: Potency-matched dual cytokine antibody fusion proteins in combination with PD-L1 blockade
Authors: Roberto De Luca, Dario Neri
Journal: Cancer Research (2018)

Abstract Among the different pharmacological approaches for cancer treatment, antibody-cytokine fusion proteins (also called “immunocytokines”) represent an emerging class of biopharmaceutical products, capable of boosting the immune system to attack tumor cells. These products promote the selective accumulation of pro-inflammatory molecules at the site of disease, mediated by the antibody fragment. These fusion proteins have been designed to reduce the systemic toxicity of traditional cytokines, currently approved for certain malignancies. Immunocytokine products based on interleukin-2 (IL2), interleukin-12 (IL12) or tumor necrosis factor (TNF) have been extensively studied in mouse model of cancer and in patients. When used as single agents, immunocytokines are often not able to cure mice and patients. However it as been shown by our group that the combination of IL2- and TNF- based products was capable to completely eradicate tumors in mouse models and to induce complete responses in patients. The development of combination products at the industrial level leads to a duplication of activities and costs. On the other hand, the opportunity to develop products with two payloads fused into a single molecular entity may facilitate development. This approach is limited by the fact that different cytokines often show different maximal tolerated doses (MTDs), and their relative potency need to be tuned. For example, TNF is administered at a dose, which is ten times lower compered to the one of IL2. We have recently described a novel class of immunocytokine products, termed “potency-matched dual cytokine antibody fusion proteins” consisting of a tumor-targeting antibody (for example F8, specific to the alternatively spliced EDA domain of fibronectin), simultaneously fused to both IL2 and TNF. To match biological activity of the two payloads a single-point mutation was inserted in the TNF sequence and the resulting product, named IL2-F8-TNFmut was able to selectively localize to lesions with an excellent tumor-to-organ ratios and it was found to completely eradicate soft-tissue sarcomas in immunocompetent mice, which did not respond to standard chemotherapy. We now report that complete responses were observed in a variety of mouse models of cancer and that the therapeutic efficacy of IL2-F8-TNFmut was further improved when used in combination with an anti-PD-L1 antibody. Potency-matched dual cytokine antibody fusion proteins may find clinical applications for various types of malignancies, used either as single agents or in combination with immune-checkpoint inhibitors. Citation Format: Roberto De Luca, Dario Neri. Potency-matched dual cytokine antibody fusion proteins in combination with PD-L1 blockade [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 2785.
Abstract 13090: Autonomic Dysfunction Exacerbates New-Onset Heart Failure in Patients with Hypertension after the 2011 Great East Japan Earthquake
Authors: Shinya Yamada, Hitoshi Suzuki, Tomofumi Misaka, Hiroyuki Mizukami, Koichi Sugimoto, Shu-ichi Saitoh, Fumio Suzuki, Yasuchika Takeishi
Journal: Circulation (2014)

Introduction: We and others have reported that the occurrence of heart failure (HF) increased after the Great East Japan Earthquake on March 11, 2011, but the association of hypertension with HF remains unclear. In Minamisoma City, located approximately 20 km north of the Fukushima Daiichi Nuclear Power Plant, we hypothesized that autonomic dysfunction due to chronic stressful conditions may be associated with new-onset HF in patients with essential hypertension. Methods: We studied 110 outpatients (63 males, mean age 73 years) with essential hypertension in Minamisoma Municipal General Hospital. Holter monitoring was performed between July, 2011 and March, 2012 to evaluate standard deviation of all R-R intervals (SDNN) and standard deviation of the 5-min mean R-R intervals (SDANN). During the follow-up period (20.8 ± 4.5 months) under anti-hypertensive therapy, there were 7 hospitalizations due to new-onset HF and 1 sudden cardiac death. With the exception of sudden cardiac death, study subjects were divided into two groups based on whether new-onset HF occurred (n=7, HF) or not (n=102, no HF). We compared systolic and diastolic blood pressures, SDNN and SDANN between two groups. Results: Although there were no differences in systolic and diastolic blood pressures, SDNN and SDANN were significantly lower in HF than in no HF (SDNN: 92.5 ± 30.0 ms vs. 139.2 ± 44.9 ms; SDANN: 83.4 ± 27.8 ms vs. 127.6 ± 43.8 ms, P&lt;0.01, respectively). Based on the receiver operating characteristic analyses for new-onset HF, cut-off values of SDNN and SDANN were defined as &lt; 94.0 ms and &lt; 77.5 ms, respectively. Kaplan-Meier analyses demonstrated that event-free rates from new-onset HF were lower in patients with low SDNN and in those with low SDANN (P&lt;0.01, respectively) as shown in Figure. Conclusions: These results suggest that autonomic dysfunction plays an important role in new-onset HF after catastrophic disasters in patients with hypertension.
Complete Prevention of Cerebral Accidents in Malignant Hypertension
Authors: Andrérobert
Journal: Circulation Research (1956)

Ligation of the common carotid arteries was found to prevent the development of cerebral lesions (edema, hemorrhage, softening) in animals rendered hypertensive by daily injections of desoxycorticosterone acetate. The protection was complete when both carotids were ligated, and limited to the homolateral side in the case of unilateral ligation.
Effect of HnRNPAB on epithelial-mesenchymal transition and metastasis of hepatocellular carcinoma by transcriptionally activating snail.
Authors: Dai Zhi, Zhengjun Zhou, Jia Fan
Journal: Journal of Clinical Oncology (2014)

e22004 Background: Expression of heterogeneous nuclear ribonucleoprotein AB (hnRNPAB)is dysregulated in tumorigenesis and tumor progression. However, little is known about the role of hnRNPAB in hepatocellular carcinoma (HCC). Methods: We examined hnRNPAB mRNA and protein levels in HCC cell lines with various metastatic potentials and in two independent cohorts of HCC patients (n=417). The role of hnRNPAB in the regulation of HCC metastasis was investigated in vitro and in vivo. Using qRT-PCR, western blotting, immunofluorescence, and tissue microarrays (TMA), correlations between hnRNPAB and epithelial-mesenchymal transition (EMT) markers were detected in HCC cells. Additionally, Chip-PCR and luciferase reporter assays were used to assess hnRNPAB-dependent regulation of Snail mRNA transcription. Results: HnRNPAB was overexpressed in highly metastatic HCC cell lines and in patients with recurrent HCC. Overexpression of hnRNPAB promoted EMT and HCC metastasis in vitro and in vivo. Knockdown of Snail expression significantly attenuated hnRNPAB-enhanced cell invasion and lung metastasis. HnRNPAB transactivated Snail expression in a DNA binding domain-dependent manner, thereby inhibiting E-cadherin transcription. Additionally, nucleotides (nt) -1180 to -694 of the Snail promoter region are indispensable for the transcriptional response of hnRNPAB. Overexpression of hnRNPAB in HCC samples correlated with significantly higher Snail levels, shorter overall survival, and higher tumor recurrence. HnRNPAB overexpression, alone or in combination with Snail, was an independent and significant risk factor for recurrence and survival after curative resection. Conclusions: HnRNPAB promotes HCC metastasis through EMT induction via transactivation of Snail. HnRNPAB overexpression may serve as a novel prognostic biomarker and a potential therapeutic target for HCC.
Thrombin Regulates Insulin-Like Growth Factor-1 Receptor Transcription in Vascular Smooth Muscle
Authors: JieDu, MarijkeBrink, TaoPeng, BiancaMottironi, PatrickDelafontaine
Journal: Circulation Research (2001)

Abstract—We have previously demonstrated that thrombin upregulation of insulin-like growth factor-1 receptor (IGF-1R) is essential for thrombin-induced mitogenic signaling. To characterize the mechanisms involved, we studied transcription of the IGF-1R gene in rat aortic smooth muscle cells. Thrombin markedly increased IGF-1R mRNA levels, peaking at 3 hours (112±7% above control). This effect was mimicked by the hexapeptide SFFLRN (that functions as a tethered ligand) and was blocked by the thrombin inhibitor hirudin. Nuclear run-on assays indicated that thrombin stimulated IGF-1R gene transcription by 2.1-fold, and this was confirmed with the use of actinomycin D. Thrombin-mediated upregulation of IGF-1R mRNA and protein levels was protein kinase C independent but was completely inhibited by the protein tyrosine kinase inhibitor genistein and by the antioxidants N-acetyl-l-cysteine and pyrrolidinedithiocarbamate, suggesting the involvement of reactive oxygen species. The thrombin-induced increase in IGF-...
A Highly Sensitive A-Kinase Activity Reporter for Imaging Neuromodulatory Events in Awake Mice
Authors: Lei Ma, Bart C. Jongbloets, Wei-Hong Xiong, Joshua B. Melander, Maozhen Qin, Tess J. Lameyer, Madeleine F. Harrison, Boris V. Zemelman, Tianyi Mao, Haining Zhong
Journal: Neuron (2018)