tbuckley/cabot-search huggingface dataset:
Abstract 5106: CRISPR/Cas9-based development of RNAi rat models for drug discovery
Authors: Prem K. Premsrirut, Chia-Lin Wang, Yu-Ting Yang, Lukas E. Dow, Johannes Zuber, Scott W. Lowe
Journal: Cancer Research (2018)

Abstract The cost of drug development has skyrocketed to an estimated $2.6B for every FDA approved drug primarily due to failures from lack of efficacy or safety. This suggests that our current preclinical validation process has been insufficient in predicting therapeutic potential and toxicity in humans. While genetically engineered animal models have been highlighted as the gold standard for dissecting cancer mechanisms and evaluating novel drug targets in vivo, the cost and long lead time to develop them previously prevented their routine use in the oncology drug discovery process. Now, with the advent of CRISPR/Cas9 technology, the speed and precision in which genetically engineered mouse models can be created is unprecedented. When combined with inducible RNA inteference technology, we we can not only generate cancer de novo in a few weeks time, but also mimic drug therapy via RNAi in the same mice, giving us advanced capabilities to perform preclinical studies in vivo. Despite the utility of mouse models, the rat has historically been the major model species in many biomedical fields, notably toxicology and carcinogenicity testing; and for many scientists, the rat still remains the preferred rodent due to their larger size for surgical manipulation, repeat blood sampling, and their cognitive and physiological characteristics that more closely resemble humans than their mouse counterparts. Here, we take advantage of our two-step engineering approach and exploit the efficiency of CRISPR-based targeting to develop RNAi rat models that enable inducible and reversible gene silencing to simulate therapeutic regimes. We demonstrate that our approach allows us to rapidly generate RNAi rat models and mimic the function of the targeted small molecule inhibitors, such as BET inhibitors targeting Brd4. We compare our results to our Brd4 RNAi mice and demonstrate organism variances that provide valuable insight to cross-species differences. These results demonstrate that our high-throughput system currently used to generate RNAi mice is also applicable to the rat system and, by extension, other mammalian models. Inducible RNAi rat models will undoubtedly be powerful tools that can be used to model human cancers, to mimic the action of putative drugs, and to assess the potential of therapeutic targeting strategies in vivo prior to the costly drug development, ultimately guiding the development of safer and more effective drugs. Citation Format: Prem K. Premsrirut, Chia-Lin Wang, Yu-Ting Yang, Lukas E. Dow, Johannes Zuber, Scott W. Lowe. CRISPR/Cas9-based development of RNAi rat models for drug discovery [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 5106.
Imaging of Oxygen Transfer Among Microvessels of Rat Cremaster Muscle
Authors: HirosukeKobayashi, NaosadaTakizawa
Journal: Circulation (2002)

Background— The proximity of capillaries, arterioles, and venules provides complex spatial relationships that lead to oxygen transfer among microvessels. Although a conceptual image of complex oxygen transfer among microvessels has been hypothesized, in vivo mapping of oxygen saturation (So2) levels in microvessels had never been performed. Methods and Results— The oxygen profile of the arterioles and venules of the rat cremaster muscle during normoxia and hypoxia was visualized by preparing pseudo-color images of So2 levels based on microspectrophotometry data obtained by using 3 different optical filters and a cooled CCD camera. The So2 images showed lower So2 levels in arterioles close to their walls, and the So2 levels in the paired venules showed higher So2 levels close to the arterioles. There were capillaries that crossed the microvessels whose So2 levels changed as they crossed the microvessels. The So2 levels were lower close to the vessel wall than in the centerline level of the microvessels, an...
Abstract 1164: Pdx model of pleural effusion of lung cancer patient for testing on targeted drug sensitivity and resistance
Authors: Feifei Zhang, Zhen Zhou, Yuan Long, Wenhua Xu, Shizhu Zhao, Yang Yang, Hui Liu, Jijun Cheng, Shun Lu, Danyi Wen
Journal: Cancer Research (2018)

Abstract Advanced lung cancer of late stage patients is selectively sensitive to available targeted therapeutics and often develops resistance to early sensitive drug treatment. Surgery tumor tissues are usually not available to establish patient-derived xenograft (PDX) models which is critical to evaluate drug sensitivity and resistance. We applied CD45 magnet beads to enrich the tumor cell population from pleural effusion specimens of advanced lung cancer. Valuable drug-resistant PDX models were successfully established both from pleural effusion and from routine surgery tissues. Genetic profiling of the PDX models revealed TKI drug-associated EGFR mutations (L858R, T790M, Exon19del, C797S). In particular we successfully established a clinically AZD9291-resistant EGFR triple mutant (Ex19del, T790M, C797S) PDX model. In vivo efficacy results with gefitinib, erlotinib and AZD9291 well matched corresponding gene mutations among the models. Interestingly, we successfully induced AZD9291-resistant clones in vivo using an EGFR double mutant (L858R, T790M) PDX model, and NGS revealed mutations in kinases involved in other signaling pathways, indicating potential therapeutic options against resistance emergence. In conclusion, these precious PDX models provide insight into resistance mechanisms as well as serve as models to test potency of many drugs including current investigational TKIs. Citation Format: Feifei Zhang, Zhen Zhou, Yuan Long, Wenhua Xu, Shizhu Zhao, Yang Yang, Hui Liu, Jijun Cheng, Shun Lu, Danyi Wen. Pdx model of pleural effusion of lung cancer patient for testing on targeted drug sensitivity and resistance [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 1164.
Visceral Adipose Tissue-derived Serine Proteinase Inhibitor Inhibits Apoptosis of Endothelial Cells as a Ligand for the Cell-Surface GRP78/Voltage-dependent Anion Channel Complex
Authors: AtsukoNakatsuka, JunWada, IzumiIseda, SanaeTeshigawara, KanjiHigashio, KazutoshiMurakami, MotokoKanzaki, KentaroInoue, TakahiroTerami, AkihiroKatayama, KazuyukiHida, JunEguchi, DaisukeOgawa, YasushiMatsuki, RyujiHiramatsu, HideoYagita, ShigeruKakuta, YoichiroIwakura, HirofumiMakino
Journal: Circulation Research (2013)

Rationale:Visceral adipose tissue-derived serine proteinase inhibitor (vaspin) is an adipokine identified from visceral adipose tissues of genetically obese rats. Objective:The role of vaspin in the diabetic vascular complications remains elusive, and we investigated the effects of vaspin on the vascular function under the diabetic milieu. Methods and Results:Adenovirus carrying the full length of the vaspin gene (Vaspin-Ad) ameliorated intimal proliferation of balloon-injured carotid arteries in diabetic Wistar rats. The expression of Ccl2, Pdgfb, and Pdgfrb genes was significantly reduced by the treatment of Vaspin-Ad. In cuff-injured femoral arteries, the intimal proliferation was ameliorated in vaspin transgenic (Vaspin Tg) mice. The application of recombinant vaspin and Vaspin-Ad promoted the proliferation and inhibited the apoptosis of human aortic endothelial cells. Adenovirus expressing vaspin with calmodulin and streptavidin-binding peptides was applied to human aortic endothelial cells, subjecte...
Abstract 20445: Pras40 Prevents Development of Diabetic Cardiomyopathy
Authors: MirkoVolkers, ShirinDoroudgar, ChristopherGlembotski, MarkSussman
Journal: Circulation (2014)

Introduction: Diabetes is a multi organ disease and diabetic cardiomyopathy can result in heart failure, which is a leading cause of morbidity and mortality in diabetic patients. Defects in mTOR signaling are believed to contribute to metabolic dysfunctions in diabetic liver and hearts, but evidence is missing that mTOR activation is causal to the development of diabetic cardiomyopathy. PRAS40 (Proline Rich Akt Substrate of 40kDa) is a specific component of mTORC1 that interacts with RAPTOR to inhibit mTORC1 kinase activity Methods and Results: The db/db mouse exhibits key characteristics of T2DM, namely hyperinsulinemia, insulin resistance, hyperglycemia, and develops diabetic cardiomyopathy with decreased cardiac function. Selective mTORC1 inhibition in cardiomyocytes from db/db mice in vivo was achieved using PRAS40 delivered via recombinant cardiotropic adeno-associated vector serotype 9 (AAV9) driven by a cardiomyocyte-specific myosin light chain (MLC2v) promoter construct. Myocardial dysfunction was...
Abstract 20372: Therapeutically Reduced Air Pressure Improves Left Ventricular Function After Acute Myocardial Infarction in Mice
Authors: Anmol Shahid, Michael S McMurtry
Journal: Circulation (2016)

Introduction: Humans living at higher elevations have lower risk for myocardial infarction (MI) and better post-MI survival. We have shown that acute reductions in air pressure enhance arterial vas...
Epidemiology of Cardiovascular Disease in India
Authors: S. PADMAVATI
Journal: Circulation (1962)

INDIA is fertile ground for the cardiovascular epidemiologist.With a population of 430 million and an area of 1,266,922 square miles, it offers great variety in ethnic groups and food habits.The population in the North is a mixture of the original Indo-Aryans with successive waves of invaders from the North- west.That in the South is not quite so mixed, a large Dravidian element still being present.In addition, there are many so-called aborig- inals with primitive ways of life.Food habits vary.The carbohydrate eaten may be rice, wheat, or millets.The common cooking oils and fats used in the different regions vary in their effect on the serum cholesterol levels.'Thus coconut oil used in the Southwest and mustard oil used in Bengal have a cholesterol- raising effect, while sesame oil and safflower oil used in parts of the South and Central India have the opposite effect.Although it is not our confirmed belief that the diet and its fat content are the only causes of coronary atherosclerosis, it would be proper to summarize here the data available at present on this aspect.Epidemiologic studies carried out over the past 5 years in four Indian cities* suggest these tentative conclusions: 1.The great majority of people (the low-income group) have a diet of low-fat content irrespective of the type of fat eaten From the Department of Medicine, Lady Hardinge
Abstract 12033: Impact of n-3 Polyunsaturated Fatty Acids on Mortality of Patients With Hospitalized Heart Failure Patients
Authors: ShunsukeWatanabe, AkiomiYoshihisa, YukiKanno, MaiTakiguchi, ShunsukeMiura, AkihikoSato, TakeshiShimizu, YuichiNakamura, HiroyukiYamauchi, TakashiOwada, SatoshiAbe, SatoshiSuzuki, MasayoshiOikawa, NobuoSakamoto, TakayoshiYamaki, KoichiSugimoto, HiroyukiKunii, KazuhikoNakazato, HitoshiSuzuki, Shu-ichiSaitoh, YasuchikaTakeishi
Journal: Circulation (2015)

Background: Intake of n-3 polyunsaturated fatty acids (n-3 PUFA), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), lowers risk of atherosclerotic cardiovascular events, particularly ischemic heart disease. In addition, a ratio of EPA/arachidonic acid (AA) is recently recognized as a risk marker of ischemic heart disease. In contrast, prognostic impact of the EPA, DHA and EPA/AA ratio on patients with heart failure (HF) still remains unclear. Methods and Results: Consecutive 577 patients admitted for HF were divided into 2 groups based on median levels of EPA/AA ratio: low EPA/AA (EPA/AA ≤ 0.32 mg/dl, n=291) and high EPA/AA (0.32 < EPA/AA, n=286) groups. We compared laboratory data, echocardiographic findings and cardio-pulmonary exercise test results, and prospectively followed cardiac and all-cause mortality. The low EPA/AA group, as compared to the high EPA/AA group, had lower levels of EPA and DHA (EPA: 33.9 vs. 86.8 μg/ml, P<0.003; DHA: 107.0 vs. 150.5 μg/ml, P<0.001), and higher ...
Effects of Methionine-Induced Hyperhomocysteinemia on Endothelium-Dependent Vasodilation and Oxidative Status in Healthy Adults
Authors: Chia-LunChao, Tsung-LiKuo, Yuan-TehLee
Journal: Circulation (2000)

Background—Homocysteine-mediated endothelial dysfunction has been proposed to occur via oxidative stress mechanisms in humans. However, there is controversy regarding the effects of homocysteine on endothelial function and oxidative status, which may in part result from age discrepancy across the studies. The present study was designed to investigate the aging effect on the relationship between endothelium-dependent vasodilation and oxidative status in methionine-induced hyperhomocysteinemia. Methods and Results—Plasma homocysteine, phosphatidylcholine hydroperoxide (PCOOH), P-selectin levels, and brachial artery flow-mediated vasodilation were measured at baseline and 4 hours after an oral methionine load (0.1 g/kg) in 15 younger (21 to 40 years) and 15 older (55 to 70 years) healthy adults. Homocysteine increased from 7.3±1.3 μmol/L at baseline to 22.7±5.2 μmol/L at 4 hours in younger (P<0.001) and from 7.4±1.4 to 24.3±4.5 μmol/L in older adults (P<0.001). PCOOH levels were not significantly different b...
Epsin deficiency promotes lymphangiogenesis through regulation of VEGFR3 degradation in diabetes
Authors: Hao Wu, H.N. Ashiqur Rahman, Yunzhou Dong, Xiaolei Liu, Yang Lee, Aiyun Wen, Kim H.T. To, Li Xiao, Amy E. Birsner, Lauren Bazinet, Scott Wong, Kai Song, Megan L. Brophy, M. Riaj Mahamud, Baojun Chang, Xiaofeng Cai, Satish Pasula, Sukyoung Kwak, Wenxia Yang, Joyce Bischoff, Jian Xu, Diane R. Bielenberg, J. Brandon Dixon, Robert J. D’Amato, R. Sathish Srinivasan, Hong Chen
Journal: Journal of Clinical Investigation (2018)

Impaired lymphangiogenesis is a complication of chronic complex diseases, including diabetes. VEGF-C/VEGFR3 signaling promotes lymphangiogenesis, but how this pathway is affected in diabetes remains poorly understood. We previously demonstrated that loss of epsins 1 and 2 in lymphatic endothelial cells (LECs) prevented VEGF-C–induced VEGFR3 from endocytosis and degradation. Here, we report that diabetes attenuated VEGF-C–induced lymphangiogenesis in corneal micropocket and Matrigel plug assays in WT mice but not in mice with inducible lymphatic-specific deficiency of epsins 1 and 2 (LEC-iDKO). Consistently, LECs isolated from diabetic LEC-iDKO mice elevated in vitro proliferation, migration, and tube formation in response to VEGF-C over diabetic WT mice. Mechanistically, ROS produced in diabetes induced c-Src–dependent but VEGF-C–independent VEGFR3 phosphorylation, and upregulated epsins through the activation of transcription factor AP-1. Augmented epsins bound to and promoted degradation of newly synthesized VEGFR3 in the Golgi, resulting in reduced availability of VEGFR3 at the cell surface. Preclinically, the loss of lymphatic-specific epsins alleviated insufficient lymphangiogenesis and accelerated the resolution of tail edema in diabetic mice. Collectively, our studies indicate that inhibiting expression of epsins in diabetes protects VEGFR3 against degradation and ameliorates diabetes-triggered inhibition of lymphangiogenesis, thereby providing a novel potential therapeutic strategy to treat diabetic complications.
Computer Simulation of the Propagation Process in Excitation of the Ventricles
Authors: Mitsuharuokajima, Tetsurofujino, Toshijikobayashi, Kazuoyamada
Journal: Circulation Research (1968)

Simulation by a digital computer of propagated excitation in the ventricular myocardium has been accomplished. Experience with the program in normal conduction and in one example of abnormal conduction, an extrasystole, is presented. Results of the simulation process were in harmony with observations in animal experiments. This justifies attempts to apply this scheme to the analysis of abnormal ventricular excitation caused by other disturbances. A crucial role of the Purkinje network in determining the course of excitation spread was recognized in the simulated process of both normal beats and extrasystoles. New knowledge is expected from this scheme when applied to other types of abnormal excitation. The possibility of combining the scheme with a method of reconstruction of QRS complexes by means of transfer impedance values was pointed out.
Nitroglycerin Induces Late Preconditioning Against Myocardial Infarction in Conscious Rabbits Despite Development of Nitrate Tolerance
Authors: MichaelHill, HitoshiTakano, Xian-LiangTang, EitaroKodani, GreggShirk, RobertoBolli
Journal: Circulation (2001)

Background— Recent studies suggest that the late phase of ischemic preconditioning (PC) can be mimicked by pretreatment with NO donors. The ability of clinically relevant NO donors to induce PC against infarction, however, has not been evaluated. Furthermore, it is unknown whether tolerance to the hemodynamic actions of nitrates also extends to their PC effects. Methods and Results— Conscious rabbits underwent a 30-minute coronary occlusion and 3 days of reperfusion. A 60-minute intravenous (IV) infusion of nitroglycerin (NTG) ending 1 hour before occlusion reduced infarct size, indicating an early PC effect. When the time interval between NTG infusion and occlusion was extended to 24 or 72 hours, the infarct-sparing action of NTG became even more pronounced, indicating a robust late PC effect. Transdermal NTG patches elicited a late PC effect that was (1) equivalent to that induced by IV NTG, demonstrating the efficacy of transdermal NTG as an alternative form of NTG delivery for inducing late PC, and (2...
Abstract LB-206: Inhibition of MYC by the SMARCB1 tumor suppressor
Authors: April M. Weissmiller, Jing Wang, Shelly L. Lorey, Gregory C. Howard, Ernest Martinez, Qi Liu, William P. Tansey
Journal: Cancer Research (2018)

Abstract The SMARCB1 tumor suppressor (SNF5) is a known interaction partner of the oncoprotein c-MYC (MYC), and thought to serve as a co-activator of its transcriptional properties. This role of SNF5, however, is at odds with the tumor suppressor function of SNF5, and with findings that loss of SNF5 is associated with activation of MYC target gene signatures. We have used biochemical, genetic, and genome-wide approaches to reexamine the relationship of SNF5 with MYC within the context of malignant rhabdoid tumor (MRT), an aggressive childhood cancer in which SNF5 is lost. We find that, consistent with activation of MYC target gene signatures in tumors that lack SNF5, MYC function is important for multiple aspects of MRT biology. Surprisingly, SNF5 is capable of inhibiting MYC binding to E boxes in vitro and globally within the context of chromatin. Using ATAC-seq, RNA-seq, and PRO-Seq, we demonstrate that regulation of MYC binding by SNF5 is independent of the role of SNF5 in chromatin remodeling, but instead is responsible for controlling RNA polymerase pause release at MYC-regulated genes. These findings inform a novel model of MRT tumorigenesis in which loss of SNF5 derepresses MYC function, raising the possibility that MYC contributes to disease progression in this malignancy. Citation Format: April M. Weissmiller, Jing Wang, Shelly L. Lorey, Gregory C. Howard, Ernest Martinez, Qi Liu, William P. Tansey. Inhibition of MYC by the SMARCB1 tumor suppressor [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-206.
Further Considerations Regarding Duration of Antibiotic Therapy for Sinusitis—Reply
Authors: Laura M. King, Lauri A. Hicks, Katherine E. Fleming-Dutra
Journal: JAMA Internal Medicine (2018)

In Reply We appreciate the response to our article1 by Chang and colleagues and their suggestion to evaluate prescribing for adults with sinusitis by specialty, particularly because previous studies have found that outpatient antibiotic prescribing practices vary by clinician specialty.2,3
Abstract 12718: Better Than Bazett: Accounting for Recent Heart Rate History Improves QT Correction in Atrial Fibrillation
Authors: Fady S Riad, Eathar Razak, Samir Saba, Alaa Shalaby, Jan Nemec
Journal: Circulation (2016)

Introduction: QT interval prolongation is associated with a risk of polymorphic ventricular tachycardia. The QT interval shortens with increasing heart rate and correction for this effect is necessary for meaningful QT interval assessment. The best way to correct the QT interval during atrial fibrillation (AF) is uncertain. Methods: Digitized Holter recordings were analyzed from patients with AF. Models of QT interval dependence on RR intervals were tested by sorting the beats into 20 bins based on corrected RR interval and assessing ST-T variability within the bins. Less variability indicated better model performance. Signal-averaging within bins was then performed to determine QT/RR dependence. Finally, standard deviation of QTc estimates was calculated for each model as a measure of real world utility. Results: Data from 30 patients (29 men, 69.3±7.3 years) were evaluated. QT behavior in AF is well described by a linear function (slope ~0.19) of steady-state corrected RR interval, which combines an “immediate response” component (weight ~ 0.18) with an exponential weight function (time-constant 120 s) over the preceding 3 minutes. This model performs significantly (p&lt;0.0001) better than models based on instantaneous RR interval only, provides better QT/RRc correlation, and results in more consistent QTc estimates. It also outperforms models based on shorter time-constants and other previously proposed models on all parameters. Conclusions: QT interval accommodation during AF is well described by a formula combining a small “immediate response” to instantaneous RR interval change and an exponentially weighted “history” of RR intervals over the preceding 3 minutes. This model may improve detection of repolarization delay in AF. QT response to heart rate changes in AF is similar to previously published QT dynamics during atrial pacing and in sinus rhythm.
This Is My Body
Authors: Kathryn E. Norman
Journal: JAMA (2018)

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