tbuckley/cabot-search huggingface dataset:
Abstract LB-018: ARQ 531, a novel and reversible inhibitor of Bruton's tyrosine kinase, displays favorable oral bioavailability and exposure in patients with B-cell malignancies
Authors: Terence Hall, Yi Yu, Sudharshan Eathiraj, Deborah Stephens, Ian Flinn, Jennifer Woyach, Brian Schwartz, Ronald E. Savage
Journal: Cancer Research (2018)

Abstract Background: ARQ 531 is a novel, ATP competitive reversible inhibitor Bruton's tyrosine kinase (BTK). BTK is a key regulator of the B cell receptor (BCR) signaling pathway that mediates signaling from the cell surface to the cytoplasm and into the nucleus. ARQ 531 is not metabolized by any of the major drug metabolizing CYP450 enzymes. Here we report pharmacokinetic profile of ARQ 531 in a phase I study evaluating safety, pharmacokinetics and pharmacodynamics activity and clinical activity of ARQ 531 in selected subjects with relapsed/refractory B-cell malignancies. Preclinical studies in rats, dogs and monkeys are also described. Methods: Oral and intravenous single dose pharmacokinetic studies of ARQ 531 were conducted in rats, dogs, and monkeys to determine oral bioavailability and drug exposure. In a standard ‘3+3' dose-escalation study design, ARQ 531 was given orally once per day beginning at 5 mg/dose and escalating for 4 weeks [NCT03162536]. Plasma samples were collected to determine ARQ 531 concentrations and whole blood / PBMCx to quantify pBTK inhibition. Plasma samples from each species were analyzed by liquid chromatography-mass spectrometry/ mass spectrometry (LC-MS/MS). Results: Consistent with preclinical studies, patients enrolled in the phase I study showed favorable exposures, the steady state peak to trough ratio was generally 3:1 or lower. ARQ 531 had an elimination half-life at steady state of ~24 hr and Cmax occurred 2 to 3 hours after dosing. Pharmacodynamic changes included suppression of BTK phosphorylation. No drug related AEs or DLTs have been observed thus far in the study. Conclusions: ARQ 531 demonstrates a favorable PK profile in humans supporting once daily dosing. Sufficient plasma levels are attained and high levels of pBTK inhibition in peripheral blood can be achieved following oral dosing. Additional dose and schedule evaluations continue, and updated clinical and biomarker results will be presented. Citation Format: Terence Hall, Yi Yu, Sudharshan Eathiraj, Deborah Stephens, Ian Flinn, Jennifer Woyach, Brian Schwartz, Ronald E. Savage. ARQ 531, a novel and reversible inhibitor of Bruton's tyrosine kinase, displays favorable oral bioavailability and exposure in patients with B-cell malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-018.
Transplantation of Blood-Derived Progenitor Cells After Recanalization of Chronic Coronary Artery Occlusion
Authors: SandraErbs, AxelLinke, VolkerAdams, KarstenLenk, HolgerThiele, Klaus-WernerDiederich, FrankEmmrich, RegineKluge, KaiKendziorra, OsamaSabri, GerhardSchuler, RainerHambrecht
Journal: Circulation Research (2005)

Transplantation of blood-derived circulating progenitor cells (CPC) has been shown to improve myocardial regeneration after myocardial infarction. It remains unclear whether CPC transplantation exerts beneficial effects also in patients with chronic myocardial ischemia. We initiated a randomized, double-blind, placebo-controlled study evaluating the impact of intracoronary infusion of CPCs on coronary vasomotion and left ventricular (LV) function in patients after recanalization of chronic coronary total occlusion (CTO). After recanalization of CTO, 26 patients (age, 63±2 years; LV ejection fraction, 53±2%) were randomly assigned to the treatment (intracoronary transplantation of CPCs) or control group. Coronary flow reserve in response to adenosine (2.4 mg/min) was measured in the target vessel at the beginning of the study and after 3 months. LV function and infarct size were assessed by MRI and metabolism by 18F deoxyglucose positron emission tomography. CPC application resulted in an increase in coron...
Stenosis of a Branch of the Pulmonary Artery
Authors: Fredericeldridge, Arthurselzer, Herberthultgren
Journal: Circulation (1957)

Three patients have been demonstrated by cardiac catheterization to have stenosis of a main branch of the pulmonary artery. Two exhibited continuous ductus-like murmurs at the chest wall over the site of stenosis. Demonstration of a pressure gradient throughout the cardiac cycle at the site of stenosis in these 2 patients and the experimental production in the dog of a continuous murmur at the site of partial constriction of a pulmonary artery prove that the murmur is due to the stenosis. This anomaly should be added to the differential diagnosis of continuous murmurs over the chest.
Abstract 16609: Obstructive Sleep Apnea and 4q25 Genotype are Associated With Atrial Fibrillation Independent of Traditional Risk Factors
Authors: Neel Patel, Quinn Wells, Raghu Upender, Ken Monahan
Journal: Circulation (2016)

Introduction: Obstructive sleep apnea (OSA) and common single nucleotide polymorphisms (SNPs) at the 4q25 locus are associated with increased risk of atrial fibrillation (AF). Whether these associa...
Abstract 5488: Serine racemase is a new therapeutic target for colon cancer
Authors: Kenji Ohshima, Satoshi Nojima, Naoki Wada, Yumiko Hori, Shinichiro Tahara, Masako Kurashige, Keisuke Kawasaki, Junichiro Ikeda, Eiichi Morii
Journal: Cancer Research (2018)

Abstract Cancer cells have an altered metabolic state to meet the requirements of rapid proliferation, and altered amino acid metabolism is known to be significant for cancer cell growth. Amino acids consist of L- and D-amino acids, and humans are known to metabolize L-amino acids. D-amino acids have been considered not to exist in human body except in intestinal flora. Recently, D-serine was reported to be synthesized and catabolized by serine racemase (SRR) and D-amino acid oxidase, respectively, and it has an important function as co-activator of the N-methyl-D-aspartate receptor in the human brain. However, whether D-amino acids function in other human organs has not been elucidated. Moreover, the role of enzymes metabolizing D-amino acids in the context of cancer metabolism has not been studied. Here, we present a novel role for SRR in colon cancer. First, we analyzed SRR expression levels in colon adenoma, colon adenocarcinoma, and normal colon mucosa in ONCOMINE datasets. We found that SRR expression levels were significantly elevated in colon adenoma and colon adenocarcinoma compared to normal colon mucosa in several datasets, including that of the Cancer Genome Atlas (TCGA). To determine whether SRR has a functional role in colon cancer cells, we disrupted its expression using the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated 9 (Cas9) system in two colon cancer cell lines, HCT116 and DLD-1, using two distinct targets of short guide RNAs and examined the effects on cell proliferation. We found that SRR knockout resulted in reduced cell proliferation in both HCT116 and DLD-1 cells, which was recovered by exogenous SRR expression. In addition, a positive correlation was found between SRR expression levels and cell proliferation rate in four colon cancer cell lines, HCT116, DLD-1, WiDr, and Lovo. Moreover, phenazine methosulfate and L-aspartic acid β-hydroxamate, which have been previously reported to inhibit SRR, suppressed in vitro colon cancer cell proliferation. In conclusion, SRR is highly expressed in colon adenoma and colon adenocarcinoma compared to normal colon mucosa, and it enhances colon cancer cell proliferation. SRR is expected to be a potential new target for the development of novel therapies for colon cancer. Citation Format: Kenji Ohshima, Satoshi Nojima, Naoki Wada, Yumiko Hori, Shinichiro Tahara, Masako Kurashige, Keisuke Kawasaki, Junichiro Ikeda, Eiichi Morii. Serine racemase is a new therapeutic target for colon 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 5488.
Abstract 4042: Metformin-induced caveolin-1 expression promotes T-DM1 drug efficacy in breast cancer cells
Authors: Wan-Chen Wei, Yuan-Chiang Chung, Ling-Yi Kao, Hsiang-Ling Chiu, Yi-Che Wu, Wei-Ting Chao
Journal: Cancer Research (2018)

Abstract Trastuzumab emtansine (T-DM1, Kadcyla) is an antibody-drug conjugate (ADC) that was recently approved by the Federal Drug Administration (FDA) of the USA for the treatment of HER-2-positive metastatic breast cancer. The drug sensitivity of ADCs depends in the main on the internalization efficiency of the drug. Endocytic protein caveolin-1 was shown to promote T-DM1 internalization and enhance drug sensitivity. Whether caveolin-1 can be overexpressed to improve T-DM1 efficacy is interesting and has the potential for clinical application. In this study, the first-line diabetes drug metformin was investigated in terms of induction of caveolin-1 expression for increased efficacy of subsequent T-DM1 application. HER-2-positive BT-474 cells were pretreated with metformin, followed by combined therapy with metformin and T-DM1. The T-DM1 internalization and drug efficacy were determined, and the protein expressions for signal transduction were also monitored by Western blot to ascertain the molecular mechanism. Caveolin-1 shRNA was applied to suppress endogenous cellular caveolin-1 expression, and the ability of metformin to promote T-DM1 efficacy was investigated. The results showed that in BT-474 cells pretreated with metformin, cellular caveolin-1 overexpression was induced, which then promoted drug efficacy by enhancing T-DM1 internalization. As cellular caveolin-1 was suppressed by shRNA, the effect of metformin-enhanced T-DM1 cytotoxicity was decreased. This study demonstrated that metformin can be applied prior to T-DM1 treatment to improve the clinical efficacy of T-DM1 by enhancing caveolin-1-mediated endocytosis. Citation Format: Wan-Chen Wei, Yuan-Chiang Chung, Ling-Yi Kao, Hsiang-Ling Chiu, Yi-Che Wu, Wei-Ting Chao. Metformin-induced caveolin-1 expression promotes T-DM1 drug efficacy in breast 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 4042.
Abstract LB-296: Discovery and development of MEDI7247, a novel Pyrrolobenzodiazepine (PBD)-based antibody drug conjugate targeting ASCT2, for treating hematological and solid cancers
Authors: Nabendu Pore, M Jack Borrok, Marlon Rebellato, MaryJane Hinrichs, Kevin P. Schifferli, Noel R. Monks, Ravinder Tammali, Ronald Herbst, Steven R. Coats, David A. Tice
Journal: Cancer Research (2018)

Abstract The sodium dependent neutral amino acid transporter, ASCT2/SLC1A5 is frequently overexpressed in cancer to sustain “glutamine addiction” of cancer cells and to meet their increased demand for energy and nutrients. High expression of ASCT2 is often associated with poor disease prognosis. Immuno-histochemistry (IHC) data from 600+ tumor samples suggest ASCT2 expression in hematologic and solid cancers, including MM, AML, and DLBCL (≥ 95% positive in respective tumor samples), as well as squamous cell carcinoma of the head and neck (SCCHN), non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), prostate, pancreatic, and colorectal cancer (66% to 95% positivity in respective tumors). Broad expression across various cancers and restricted expression in normal tissues warrant ASCT2 as an attractive candidate for an antibody drug conjugate. MEDI7247 is a novel investigational antibody-drug conjugate (ADC) comprising an anti-ASCT2 human monoclonal antibody site-specifically conjugated to pyrrolobenzodiazepine (PBD) dimer via a protease-cleavable linker, with a drug to antibody ratio (DAR) of 2. MEDI7247 specifically binds to cell surface ASCT2 while exhibiting no affinity to the other members of the family, including ASCT1. Following binding, MEDI7247 is internalized and trafficked to the lysosomes to subsequently release the PBD warhead. PBD enters the nucleus where it induces DNA damage and results in tumor cell death. MEDI7247 shows potent in vitro cytotoxicity in several human cancer cell lines expressing variable levels of ASCT2. Dose dependent in vivo efficacy of MEDI7247 was determined in solid tumor xenografts and disseminated hematological malignancy models. MEDI7247 is cross-reactive with cynomolgous monkey ASCT2 and shows similar binding and killing with cyno ASCT2 expressing cells. MEDI7247 demonstrated acceptable safety profile in toxicity studies with non-human primates to support first in human trials. Based on its combined efficacy and safety, MEDI7247 is in clinical development for the treatment of ASCT2 positive cancers. Citation Format: Nabendu Pore, M Jack Borrok, Marlon Rebellato, MaryJane Hinrichs, Kevin P. Schifferli, Noel R. Monks, Ravinder Tammali, Ronald Herbst, Steven R. Coats, David A. Tice. Discovery and development of MEDI7247, a novel Pyrrolobenzodiazepine (PBD)-based antibody drug conjugate targeting ASCT2, for treating hematological and solid cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-296.
The Bispecific SDF1-GPVI Fusion Protein Preserves Myocardial Function After Transient Ischemia in Mice
Authors: MelanieZiegler, MargittaElvers, YvonneBaumer, ChristophLeder, CarmenOchmann, TanjaSchönberger, TobiasJürgens, TobiasGeisler, BurkhardSchlosshauer, OlegLunov, StefanEngelhardt, ThomasSimmet, MeinradGawaz
Journal: Circulation (2012)

BackgroundCXCR4-positive bone marrow cells (BMCs) are critically involved in cardiac repair mechanisms contributing to preserved cardiac function. Stromal cell–derived factor-1 (SDF-1) is the most prominent BMC homing factor known to augment BMC engraftment, which is a limiting step of stem cell–based therapy. After myocardial infarction, SDF-1 expression is rapidly upregulated and promotes myocardial repair. Methods and ResultsWe have established a bifunctional protein consisting of an SDF-1 domain and a glycoprotein VI (GPVI) domain with high binding affinity to the SDF-1 receptor CXCR4 and extracellular matrix proteins that become exposed after tissue injury. SDF1-GPVI triggers chemotaxis of CXCR4-positive cells, preserves cell survival, enhances endothelial differentiation of BMCs in vitro, and reveals proangiogenic effects in ovo. In a mouse model of myocardial infarction, administration of the bifunctional protein leads to enhanced recruitment of BMCs, increases capillary density, reduces infarct si...
Measurement of Bronchial Blood Flow in Tetralogy of Fallot
Authors: Takashinakamura, Ryokatori, Kozuimiyazawa, Junshioda, Kinjiishikawa
Journal: Circulation (1967)

Bronchial blood flow was measured in nine patients with tetralogy of Fallot and in two of these cases after radical operation also. The study was made of simultaneous recording of dye-dilution curves from the left atrium and the ear following dye injection into the aortic root. A method of calculating the bronchial blood flow was devised by combining the dye-dilution method with the Fick principle. The bronchial blood flow was increased in all cases. The mean value was 0.46±0.31 L/min, with a range from 0.14 to 1.27 L/min; this is equivalent to 15.3% of the pulmonary artery flow on the average. This study showed no definite relationships among pulmonary artery blood flow, pulmonary artery pressure, arterial oxygen saturation, severity of disease, and patient's age. The postoperative measurement revealed no significant change in bronchial blood flow though its ratios to the pulmonary artery or aortic blood flows were considerably decreased.
US dietary guidelines: is saturated fat a nutrient of concern?
Authors: Zoe Harcombe
Journal: British Journal of Sports Medicine (2018)

US public health dietary advice was announced by the Select Committee on Nutrition and Human needs in 1977 and was followed by UK public health dietary advice issued by the National Advisory Committee on Nutritional Education in 1983. Dietary recommendations in both cases focused on reducing dietary fat intake; specifically to (i) reduce overall fat consumption to 30% of total energy intake and (ii) reduce saturated fat consumption to 10% of total energy intake. The recommendations were an attempt to address the incidence of coronary heart disease. These guidelines have been reiterated in the Dietary Guidelines for Americans since the first edition in 1980. The most recent edition has positioned the total fat guideline with the use of ‘Acceptable Macronutrient Distribution Ranges’. The range given for total fat is 20%–35% and the AMDR for saturated fat is given as &lt;10%—both as a percentage of daily calorie intake. In February 2018, the Center for Nutrition Policy and Promotion announced ‘The US Departments of Agriculture and Health and Human Services currently are asking for public comments on topics and supporting scientific questions to inform our development of the 2020–2025 Dietary Guidelines for Americans’. Public comments were invited on a number of nutritional topics. The question asked about saturated fats was: ‘What is the relationship between saturated fat consumption (types and amounts) during adulthood and risk of cardiovascular disease?’ This article is a response to that question.
Abstract 5778: Preclinical evaluation of TQB3616, a highly potent and selective small-molecule CDK4/6 inhibitor
Authors: Xu Zhaobing, Hu Lihong, Liu Yingchun, Charles Z. Ding, Xiaoyu Zhu, Chen Chen, Yusong Zhu, Jiahu Wu, Dongdong Wu, Shuhui Chen, Xiquan Zhang, Ling Yang, Xin Tian
Journal: Cancer Research (2018)

Abstract Objective: The G1 restriction point is critical for regulating the cell cycle and is controlled by the retinoblastoma protein (Rb) pathway (CDK4/6-cyclin D1-Rb-p16/ink4a). Selective CDK4/6 inhibitors, such as palbociclib and ribociclib have been approved by US FDA in combination with letrozole to treat patients with HR+/Her2- breast cancer, and selective CDK4/6 inhibitor LY2835219 is in Phase 3 trials for the same and related indications. Here, we disclose TQB3616 for the first time, a novel selective, potent, oral inhibitor of CDK4/6. Method: The anti-proliferative activity of TQB3616 was evaluated in a panel of 18 Rb-proficient cell lines in a 72-hour viability assay. Daily oral administration was used to evaluate in vivo antitumor activity of TQB3616 in the MCF-7 cell-derived xenograft (CDX) breast cancer model. Effect on CDK4/6-cyclin D1-Rb signaling was assessed by western blot analysis of downstream effector protein p-Rb. In vivo antitumor activity of TQB3616 was also tested in a patient-derived xenograft (PDX) lung cancer model LU-01-0393. Result: TQB3616 displayed potent anti-proliferative activity in 8 of 18 Rb-proficient cancer cell lines (&amp;gt;50% inhibition at 0.3 µM). Inhibition of p-Rb in the tumor samples was verified by western blot analysis. TQB3616 showed in vivo antitumor activity in the MCF-7 CDX model with TGI of 60% @7.5 mpk and 93% @15 mpk, better than palbociclib (TGI = 52% @20 mpk, 80% @40 mpk) and LY2835219 (TGI = 45% @7.5 mpk, 76% @15 mpk). TQB3616 also showed good in vivo antitumor activity in the LU-01-0393 lung cancer PDX model with 65% of TGI @35 mpk. Conclusion: TQB3616 is a potent and selective CDK4/6 inhibitor and shows excellent antitumor activity in preclinical tumor models. These results warrant TQB3616 going to the clinic for exploration of its potential for treating HR+/Her2-/Rb+ breast cancer as well as other Rb+ cancer types. Citation Format: Xu Zhaobing, Hu Lihong, Liu Yingchun, Charles Z. Ding, Xiaoyu Zhu, Chen Chen, Yusong Zhu, Jiahu Wu, Dongdong Wu, Shuhui Chen, Xiquan Zhang, Ling Yang, Xin Tian. Preclinical evaluation of TQB3616, a highly potent and selective small-molecule CDK4/6 inhibitor [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 5778.
Abstract P110: Serum Uric Acid, Gout, and Venous Thromboembolism: The Atherosclerosis Risk in Communities Study
Authors: Yasuhiko Kubota, Mara McAdams DeMarco, Aaron R. Folsom
Journal: Circulation (2016)

Introduction: Some rheumatologic diseases, including rheumatoid arthritis and systemic lupus erythematosusa are associated positively with occurrence of venous thromboembolism (VTE). Chronic inflammation accompanying these rheumatologic diseases is considered to increase the risk of VTE. Gout, which is caused by hyperuricemia, is the most common rheumatologic inflammatory arthritis. In addition, hyperuricemia, itself, has proinflammatory effects on vascular cells. Hyperuricemia and gout therefore may increase the risk of VTE, but, so far there has been no study investigating these associations. Hypothesis: We assessed the hypothesis that hyperuricemia or gout are positively associated with the risk of VTE. Methods: The Atherosclerosis Risk in Communities Study measured serum uric acid (SUA) in 15,063 men or women, aged 45-64, without history of VTE or anticoagulant use and followed them for VTE from 1987 to 2011. Of these participants, 10,982 men or women provided information on gout history. Hazard ratios (HRs) of VTE were estimated using Cox proportional hazards models adjusted for age, sex, race, center, body mass index, diabetes, smoking, eGFR, vonWillebrand factor, factor VIII, and gout medication across levels of SUA [median (range) mg/dL: 4.6 (≤5.2), 5.7 (5.2-6.2), 6.7 (6.2-7.2), 7.7 (7.2-8.2), 8.5 (8.2-8.9), and 9.6 (≥8.9)] or gout history (yes or no). Results: We documented 688 incident VTEs [265 unprovoked and 423 provoked VTEs (232 not cancer related and 191 cancer related VTEs)]. Age, sex, and race-adjusted HRs [95% confidential interval (CI)] for total VTE were 1.00, 1.31 (1.04-1.65), 1.34 (1.05-1.70), 1.81 (1.39-2.35), 1.81 (1.25-2.60), and 2.85 (2.06-3.95) (P for trend&lt;0.001) across levels of SUA. After adjustment for the other VTE risk factors, those in the highest vs. lowest level of SUA had HRs (95% CI; P for trend) of 1.72 (1.22-2.45; 0.006) for total VTE, 1.83 (1.08-3.09; 0.128) for unprovoked VTE, and 1.61 (1.00-2.58; 0.022) for provoked VTE. On the other hand, we observed no significant association between the gout history and the incidence of VTE. Conclusions: In conclusion, elevated SUA was associated with a higher risk of VTE, suggesting that elevated SUA might be a novel risk factor for VTE.
Coronary Artery Disease and Polymorphisms in a Receptor Mediating Shear Stress–Dependent Platelet Activation
Authors: MitsuruMurata, YumikoMatsubara, KoichiKawano, TakeruZama, NobuoAoki, HideakiYoshino, GentaroWatanabe, KyozoIshikawa, YasuoIkeda
Journal: Circulation (1997)

Background Platelets play pivotal roles in coronary thrombosis, and antiplatelet therapies are widely used for coronary artery disease (CAD). However, the effects of genetic variation in platelets on CAD are poorly understood. We have assessed the association between CAD and polymorphisms in a platelet receptor for von Willebrand factor, the glycoprotein (GP) Ib/IX complex, which mediates shear stress–dependent platelet activation. Methods and Results Genotypes of the α-chain of the receptor (GP Ibα, 145Thr/Met) were determined in 91 patients with myocardial infarction (MI) or angina pectoris whose lesions were confirmed by coronary angiography as well as in 105 individuals from the general population with no history of angina or other heart diseases and normal resting ECGs. There was no homozygote for Met/Met in either the control or patient groups. The prevalence of the Thr/Met genotype (T/M) in all patients was not significantly different from that in the control group. However, the frequency of T/M wa...