tbuckley/cabot-search huggingface dataset:
Abstract 192: Preclinical evaluation of TQBWX220, a small-molecule inhibitor of IDO1
Authors: Shilan Liu, Guibai Liang, Dahai Wang, Shuhui Chen, wenyuan Qian, Chi-Chung Chan, Xiquan Zhang, Lin Yang, Xin Tian, Yong Gao, Tiantian Dong, Mei Liu, Lihua He
Journal: Cancer Research (2018)

Abstract Objective: Indoleamine-2, 3-dioxygenase-1 (IDO1) catalyzes conversion of tryptophan to kynurenine (Kyn), which triggers signaling through GCN2, mTOR and AHR and affects differentiation and proliferation of T cells. Expression of IDO1 by tumor cells or host APCs can inhibit tumor-specific effector CD8+ T cells and enhance the immunosuppressing activity of regulatory T cells. Targeting the IDO pathway via inhibition of IDO1 or blocking its downstream signaling pathways is recognized as one of the prime immunomodulation approaches to unleash antitumor immunity in the tumor microenvironment. As reported, inhibition of IDO1 pathway may also synergize with inhibitory Abs of immune checkpoint proteins, PD-1 and CTLA-4, etc. We report herein TQBWX220, a potent small-molecule inhibitor of IDO. Method: Potency of TQBWX220 was determined by corresponding IDO1 biochemical and cell assays. Antitumor efficacy of TQBWX220 was evaluated in the syngeneic CT26 xenograft colon cancer model. CT26 cells were engrafted onto the back of BALB/c mice. BID oral administration of vehicle, positive control (INCB024360, 100 mg/kg) and TQBWX220 at different doses were performed. Tumor volumes and mouse body weight were measured at time points after the start of the treatments. Other assays were carried out by using standard methods. Result: TQBWX220 displayed good IDO1 enzymatic (IDO1 IC50=22 nM) and cellular (Hela EC50=117 nM) potency. It has excellent solubility (&amp;gt;500uM pH7.4) and low inhibition on CYPs and hERG. TQBWX220 significantly inhibited tumor growth at tested doses (60% TGI at 50 mpk/PO BID and 73% TGI at 100 mpk /PO BID) (P&amp;lt;0.05) in the CT-26 syngeneic model. As a result of IDO1 inhibition, reduction of Kyn level in the tumor was also observed. Conclusion: The promising preclinical antitumor results and its favorable DMPK properties indicate that TQBWX220 has high potential in the clinic as a cancer immunotherapy in combination with checkpoint inhibitors such as anti-PD1 antibodies. Citation Format: Shilan Liu, Guibai Liang, Dahai Wang, Shuhui Chen, wenyuan Qian, Chi-Chung Chan, Xiquan Zhang, Lin Yang, Xin Tian, Yong Gao, Tiantian Dong, Mei Liu, Lihua He. Preclinical evaluation of TQBWX220, a small-molecule inhibitor of IDO1 [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 192.
Abstract 12281: Outcomes in Patients Treated With Transfemoral Aortic Valve Implantation After Admission to the Intensive Care Unit
Authors: Fadi Al-Rashid, Philipp Kahlert, Heike Hildebrandt, Friederike Selge, Polykarpos-Christos Patsalis, Daniel Wendt, Matthias Thielmann, Heinz Jakob, Gerd Heusch, Raimund Erbel, Rolf Alexander Janosi
Journal: Circulation (2015)

Introduction: Transcatheter aortic valve implantation (TAVI) has become established as a treatment option for patients with severe symptomatic aortic valve stenosis. Postoperative treatment of these old patients presents a new challenge for intensive care specialists. Although numerous studies have addressed perioperative anesthetic management, little is known about risk factors that lead to a longer intensive care unit (ICU) stay. Hypothesis: We retrospectively analyzed data focusing on the risk factors and indications for a prolonged ICU stay and their outcomes. We also compared predictive value of the SAPS II and EuroSCORE risk evaluation scales. Methods: From 2006 to 2012 a total of 214 consecutive patients (age: 80 ± 6 years) were admitted to the ICU after transfemoral TAVI. Results: Total 30-day mortality was 7%. Non-survivors differed from survivors in the rates of catecholamine therapy on ICU admission (93 vs. 29%; p&lt;0.001), stroke (20 vs. 1%; p&lt;0.001), and sepsis (27 vs. 2%; p&lt;0.001). Acute kidney injury (83 vs. 56%; p &lt; 0.001) and catecholamine therapy (88 vs. 61%; p &lt; 0.001) significantly influenced 2-year survival. Mean SAPS II score was higher in non-survivors (38.1 ± 7.0 vs. 29.9 ± 6.2; p &lt; 0.001), giving a predicted mortality of 23.1 ± 11.7% and 10.5 ± 8.2%, respectively, whereas the logistic EuroSCORE was not able to discriminate between the groups (p = 0.555) (figure 1). Among the biochemical parameters, the maximum values of creatinine (2.46±1.24 vs. 1.77±1.16 mg/dL; p &lt;0.05), procalcitonin (1.44 ± 1.84 vs. 0.51 ± 1.65 ng/mL; p &lt; 0.05), and troponin I (4.46 ± 4.19 vs. 2.02 ± 2.25 ng/mL; p &lt; 0.001) during ICU admission were significantly higher in non-survivors. Conclusions: The SAPS II score was superior to the EuroSCORE in predicting ICU mortality and could be used for post-interventional risk stratification while distinct TAVI risk scores are lacking. Creatinine, procalcitonin, and troponin are strong predictors of 30-day and 2-year mortality after TAVI.
Coronary Flow Velocity Pattern Immediately After Percutaneous Coronary Intervention as a Predictor of Complications and In-Hospital Survival After Acute Myocardial Infarction
Authors: AtsushiYamamuro, TakashiAkasaka, KoichiTamita, KenjiYamabe, MinakoKatayama, TsutomuTakagi, ShigefumiMorioka
Journal: Circulation (2002)

Background— Recently, it was reported that the degree of microvascular injury and left ventricular functional recovery during the chronic period can be predicted after treatment of the infarct-related artery based on the coronary flow velocity (CFV) pattern assessed using a Doppler guidewire. The aim of this prospective study was to examine whether the CFV pattern may predict complications and in-hospital survival after acute myocardial infarction (AMI). Methods and Results— The study population consisted of 169 consecutive patients with a first anterior AMI successfully treated with percutaneous coronary intervention (PCI). We examined the CFV pattern immediately after PCI using a Doppler guidewire. In accordance with previous findings, we defined severe microvascular injury as a diastolic deceleration time ≤600 ms and the presence of systolic flow reversal. Patients were divided into two groups: those without severe microvascular injury (n=118; group 1) and those with severe microvascular injury (n=51; ...
Glibenclamide, an ATP-Sensitive K+ Channel Blocker, Inhibits Cardiac cAMP-Activated Cl− Conductance
Authors: MakotoTominaga, MinoruHorie, ShigetakeSasayama, YasunobuOkada
Journal: Circulation Research (1995)

Abstract Stimulation of the β-adrenoceptor activates a time-independent Cl− conductance that is known to be regulated via phosphorylation by cAMP-dependent protein kinase in guinea pig ventricular myocytes. Since epithelial cystic fibrosis transmembrane conductance regulator Cl− channels are known to be sensitive to an antidiabetic sulfonylurea, glibenclamide, we tested whether the drug modulates cardiac cAMP-activated Cl− conductance. Bath application of isoproterenol (1 μmol/L, n=11) or forskolin (1 μmol/L, n=17) or the intracellular application of cAMP (1 mmol/L, n=9) activated whole-cell Cl− currents recorded from single myocytes at 36°C. External glibenclamide (≥10 μmol/L, n=26) inhibited the Cl− current induced by either of the stimulants in a concentration-dependent manner. The half-maximal inhibition concentration (IC50) of glibenclamide and the Hill coefficient were 24.5 to 37.9 μmol/L and 1.6 to 2.2, respectively. During current-clamp experiments, forskolin was found to shorten the action potent...
Abstract P187: Aortic Arch Width is Associated with Increasing Age and Cardiovascular Disease Risk Factors: The Framingham Heart Study
Authors: Saadia Qazi, Philimon Gona, Rebecca M Musgrave, Caroline S Fox, Joseph M Massaro, Udo Hoffmann, Michael L Chuang, Christopher J O'Donnell
Journal: Circulation (2015)

Introduction: Aortic arch geometry changes with aging: curvature decreases and aortic arch width (AAW) increases. AAW can be easily measured using thoracic multidetector computed tomography (MDCT). In addition to greater age, increases in AAW may also occur due to other cardiovascular disease (CVD) risk factors, but the distribution and determinants of excess AAW are unknown. We hypothesized that, in addition to increasing age, standard CVD risk factors are associated with increased AAW in community-dwelling adults. Methods: 3026 (1560 men) Offspring and Third Generation cohort participants (men ≥35y; women ≥40y) underwent thoracic MDCT (2002-2005) and had complete risk factor profiles. AAW was defined as the distance between centroids of the ascending and descending aorta at the level of main pulmonary artery bifurcation. A healthy referent group free of CVD, hypertension, dyslipidemia, smoking, and diabetes was used to generate sex and 10-year age group specific upper 90th percentile (P90) cutpoints for...
Abstract 1109: S100A10 contributes to cancer stemness, invasion and metastasis of head and neck cancer cells
Authors: Nobuyukit Tanaka, Taketo Nishikawaji, Naoko Ogama
Journal: Cancer Research (2018)

Abstract Head and neck cancer is one of the most common cancers worldwide, and an innovating therapy is awaited. We attempted to identify proteins associated with cancer stem cell phenotypes, and found an EF-hand protein S100A10 is highly expressed in the stem cell population. Together with its binding partner, Annexin-A2, S100A10 regulates a spectrum of dynamic membrane-related events, such as actin cytoskeleton control, vesicle formation and intercellular interaction. Immunohistochemical analysis using clinical head and neck cancer specimens showed that elevated S100A10 expression is typically present in the invasion front of tumors, and S100A10-high cases were associated with poor prognosis. S100A10 knockdown and knockout resulted in significant reduction of cell migration and invasion in vitro. Cell movement was slowed down by S100A10 knockdown. Accordingly, in vivo tumor formation was impaired by S100A10 depletion. Cell cycle progression was delayed by the depletion, suggesting its potential role in proliferation controls. These results suggest that S100A10 has a significant role in head and neck cancer cell proliferation and invasion. Citation Format: Nobuyukit Tanaka, Taketo Nishikawaji, Naoko Ogama. S100A10 contributes to cancer stemness, invasion and metastasis of head and neck 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 1109.
Abstract 46: A Randomized Trial of Moderate and Intensive Exercise on Fatty Liver and Cardiometabolic Risk Factors in Obese Adults
Authors: HuijieZhang, XuejunLi, ZhiMinMa, LingLingPan, ZhengChen, zhufengHuang, ChengKunHan, ShiChen, XiongJieZhuang, MingzhuLin, ZhiBinLi, JiangHe, ShuYuYang, XiaoyingLi
Journal: Circulation (2015)

Corresponding authors: Shu-yu Yang, Xiamen Diabetes Institute, Department of Endocrinology and Metabolism, The First Hospital of Xiamen, Xiamen University, 55 Zhenhai Road, Xiamen 361003, China ( xmyangshuyu@126.com). Jiang He, MD, PhD, Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, 1440 Canal St, Ste 2000, New Orleans, LA 70112 (jhe@tulane.edu). Xiao-Ying Li, MD, PhD, Department of Endocrinology and Metabolism, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, 197 Rui-Jin 2nd Road, Shanghai 200025 (lixy@sibs.ac.cn). Introduction: Nonalcoholic fatty liver disease (NAFLD) and its cardiovascular complications are common public health problems. Hypothesis: Although the benefit of exercise on NAFLD and cardiometabolic risk factors is documented, the effects of intensive and moderate exercise on these outcomes have not been thoroughly investigated.. Methods: We conducted a randomized controlled trial among 220 individuals aged 40-65 years with a w...
Abstract 5632: Targeted immunotherapy with SV-BR-1-GM: Mechanism of action and companion diagnostic development
Authors: Markus D. Lacher, Sanne Graeve, Charles L. Wiseman, Ying Y. Kong, William W. Kwok, William V. Williams
Journal: Cancer Research (2018)

Abstract SV-BR-1-GM is a GM-CSF-engineered whole-cell targeted immunotherapy derived from a breast cancer cell line (SV-BR-1). We are currently assessing SV-BR-1-GM in a phase I/IIa clinical trial in metastatic and locally recurrent breast cancer (ClinicalTrials.gov identifier NCT03066947). Subjects who fail to respond with tumor regression are offered participation in a “roll-over” study in which an immune checkpoint inhibitor (pembrolizumab or ipilimumab) is added to the SV-BR-1-GM regimen (ClinicalTrials.gov identifier NCT03328026). To identify patients likely to respond to SV-BR-1-GM we are co-developing a companion diagnostic. In a pilot phase I study with four evaluable patients, one subject (A002), with metastatic breast cancer, experienced systemic tumor regression including in soft tissue, lung, and brain lesions. In contrast to the three nonresponders, A002 matched with SV-BR-1-GM at both a class I (HLA-A) and a class II (HLA-DRB3) HLA allele. Strikingly, SV-BR-1-GM cells also express HLA class II “accessory” factors such as HLA-DMA and -DMB, HLA-DRA, and CD74 (encoding invariant chain and CLIP), and immunostimulators such as IL6, Il18, and KITLG, and the damage-associated molecular pattern (DAMP) protein HMGB1. SV-BR-1-GM cells do not express the T cell co-stimulatory ligands CD80 or CD86. These findings are consistent with a potential to activate previously primed but not naïve CD4+ T cells. In agreement, peptide-pulsed SV-BR-1-GM cells selectively activated peptide-HLA specific, pre-primed T cells. Given this functional data and the expression of the “immune signature”, comprised of factors including those mentioned above, we hypothesized that SV-BR-1-GM cells can act as antigen-presenting cells (APCs) and present tumor-associated antigens (TAAs) directly to HLA-matched T cells, which in turn would induce an immune response directed to the patients' tumors. To evaluate this hypothesis, we have begun developing bioassays for assessing antibody and T cell responses to SV-BR-1-GM. Here, we present data on SV-BR-1-GM's molecular makeup and development of anti-SV-BR-1-GM humoral and cellular immune responses. Our findings support SV-BR-1-GM acting as antigen-presenting cells for HLA class I and class II restricted immune responses. Citation Format: Markus D. Lacher, Sanne Graeve, Charles L. Wiseman, Ying Y. Kong, William W. Kwok, William V. Williams. Targeted immunotherapy with SV-BR-1-GM: Mechanism of action and companion diagnostic development [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 5632.
William Dewi Rees
Authors: Michael Millar-Craig
Journal: BMJ (2018)

After national service, William Dewi Rees (who was always known as “Dewi”), met his future wife, Valerie, while a medical student in London. She was a biochemist at the Hammersmith Hospital and was the initial breadwinner in the family. Dewi had always planned a career in general practice and, after a year as a trainee GP in London, worked as a rural GP in Labrador, Canada, for a year. After a brief period as a senior house officer in psychiatry, he became a partner in general practice in Llanidloes, mid Wales, in 1960. His work in remote practices, in both rural Canada and Wales, gave him …
Ca2+-Dependent Activation of Rho and Rho Kinase in Membrane Depolarization–Induced and Receptor Stimulation–Induced Vascular Smooth Muscle Contraction
Authors: SotaroSakurada, NorikoTakuwa, NaotoshiSugimoto, YuWang, MinoruSeto, YasuharuSasaki, YohTakuwa
Journal: Circulation Research (2003)

Ca2+ sensitization of vascular smooth muscle (VSM) contraction involves Rho-dependent and Rho-kinase–dependent suppression of myosin phosphatase activity. We previously demonstrated that excitatory agonists in fact induce activation of RhoA in VSM. In this study, we demonstrate a novel Ca2+-dependent mechanism for activating RhoA in rabbit aortic VSM. High KCl-induced membrane depolarization as well as noradrenalin stimulation induced similar extents of sustained contraction in rabbit VSM. Both stimuli also induced similar extents of time-dependent, sustained increases in the amount of an active GTP-bound form of RhoA. Consistent with this, the Rho kinase inhibitors HA1077 and Y27632 inhibited both contraction and the 20-kDa myosin light chain phosphorylation induced by KCl as well as noradrenalin, with similar dose-response relations. Either removal of extracellular Ca2+ or the addition of a dihydropyridine Ca2+ channel antagonist totally abolished KCl-induced Rho stimulation and contraction. The calmodu...
Stent Placement Compared With Balloon Angioplasty for Small Coronary Arteries
Authors: RenéKoning, HélèneEltchaninoff, PhilippeCommeau, KhalifeKhalife, MartineGilard, JanuszLipiecki, PierreCoste, MarcBedossa, ThierryLefèvre, PhilippeBrunel, Marie-ClaudeMorice, LucMaillard, PhilippeGuyon, JacquesPuel, AlainCribier
Journal: Circulation (2001)

Background Stenting has been demonstrated to be superior to balloon angioplasty in de novo focal lesions located in large native vessels. However, in small vessels, the benefit of stenting remains questionable. Methods and Results A total of 381 symptomatic patients with de novo focal lesion located on a small coronary segment vessel (<3 mm) were randomly assigned to either stent implantation (192 patients; 197 lesions) or standard balloon angioplasty (189 patients; 198 lesions). The primary end point was the angiographic restenosis rate at 6 months, as determined by quantitative coronary angiography. On intention-to-treat analysis, angiographic success rate and major adverse cardiac events were comparable: 97.9% and 4.6% versus 93.9% and 5.8% in the stent group and the balloon group, respectively. After the procedure, a larger acute gain was achieved with stent placement (1.35±0.45 versus 0.94±0.47 mm, P=0.0001), resulting in a larger minimal lumen diameter (2.06±0.42 versus 1.70±0.46 mm, P=0.0001). At f...
Abstract 11977: Tranilast, Transient Receptor Potential Vanilloid 2 Antagonist, Ameliorates End-Stage Heart Failure of Mice With Dilated Cardiomyopathy
Authors: YukoIwata, KazuoKomamura
Journal: Circulation (2014)

Introduction: Abnormal intracellular Ca2+ handling seems to be involved in the pathogenesis of idiopathic dilated cardiomyopathy (DCM). We have found up-regulation of the expression of transient receptor potential vanilloid 2 (TRPV2), a calcium-permeable cation channel, in the sarcolemma of myocardium of animal and human DCM. Hypothesis: We hypothesized an orally active TRPV2 antagonist, tranilast, ameliorated heart failure symptoms of DCM mice. Methods: We used 4C30 mice (created by National Institute of Biomedical Innovation, Japan), which has abnormal myocardial calcium handling, as a model of DCM. Sixteen 4C30 mice of 25 weeks old with end-stage heart failure were given no drug (control) or 20 mg/kg/day of carvediol (group C) or 400 mg/kg/day of tranilast (group T) or both of them (group B) for 2 weeks. Results: Blood pressure and heart rate were similar among the 4 groups. Echocardiography demonstrated tranilast improved fractional shortening (in %). Control: 6.2±2.5; Group C: 14.2±5.6, NS; Group T: ...
Role of Endogenous Endothelin in the Development of Graft Arteriosclerosis in Rat Cardiac Allografts
Authors: KenjiOkada, YasuhiroNishida, HiroshiMurakami, IsaoSugimoto, HiroakiKosaka, HironobuMorita, ChojiroYamashita, MasayoshiOkada
Journal: Circulation (1998)

Background—The purpose of this study was to determine whether endothelin-1 (ET-1) contributes to the development of graft arteriosclerosis and whether the orally active nonpeptide endothelin receptor antagonist bosentan, which blocks both ETA and ETB receptors, can protect against this pathologic damage. Methods and Results—Recipient male Lewis rats were divided into three groups; group 1 received heterotopic heart transplantations from Lewis donors and groups 2 and 3 received transplantations from Brown-Norway donors; group 3 recipients also received bosentan orally at the dose of 20 mg/kg per day for 120 days. All recipients were given cyclosporine and were euthanized at examination 120 days after transplantation. Plasma ET-1 levels were significantly higher in group 2 than in group 1 (6.99±0.91 and 4.15±0.83 pg/mL, respectively). Strong ET-1 immunoreactivity was seen in both the thickened neointima and the media of the coronary arteries in group 2 but not in group 1. The mean ratio of the coronary lumi...
Abstract 4304: Development of a new nucleoside triphosphate transporter (NTP) technology for rapid DNA labeling that measures cell cycle progression in live cancer cells
Authors: Nick Asbrock, Vi Chu, Kevin Su, Tomas Kraus
Journal: Cancer Research (2018)

Abstract At its core, cancer is a disease of uncontrolled cell division. Mutations in different genes cause or accelerate cancer by increasing cell division rates or inhibiting cell proliferation control mechanisms such as apoptosis and tumor suppression. Traditional DNA incorporation cell proliferation assays that label nucleic acids (BrdU, EdU) have been popular but are limited by requiring cell fixation, high cost and lengthy protocols. Here, we have developed a new NTP transporter technology that allows the incorporation of Cyanine-3 fluorescently labeled dUTP's into DNA during the S-phase of the cell cycle to measure cell proliferation in live cancer cells (U2OS). Similar cell cycle profiles were produced using this new NTP transporter technology as analyzed by FACS analysis and live cell imaging vs. BrdU based cell proliferation assays. This technology will allow new insights into cancer cell proliferation and progression. Citation Format: Nick Asbrock, Vi Chu, Kevin Su, Tomas Kraus. Development of a new nucleoside triphosphate transporter (NTP) technology for rapid DNA labeling that measures cell cycle progression in live 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 4304.
Launching Global Lung Function Initiative reference values in Belgium: tips and tricks
Authors: Eric Derom, Giuseppe Liistro, Ellie Oostveen, Eric Marchand, Lieven Bedert, Rudi Peché, Wim Janssens
Journal: European Respiratory Journal (2018)

<b>A model consisting of a motivated working group that identified the different stakeholders to convince them, through education, over the Global Lung Function Initiative reference values has appeared to be successful in implementing these in Belgium</b>http://ow.ly/Q21630kuE1N