tbuckley/cabot-search huggingface dataset:
Abstract 1051: Mutation detection in patient-derived xenografts by WES and RNAseq
Authors: Wubin Qian, Henry Q.X. Li, Sheng Guo
Journal: Cancer Research (2018)

Abstract Patient derived xenograft (PDX) is widely used in preclinical cancer research for drug efficacy evaluation, biomarker discovery and validation, drug mechanism and resistant mechanism study, tumor biology studies and so on. Many PDX libraries are now available to researchers1-4. A good library is composed of PDXs with high-quality characterization for genomics, pharmacology, histology, and clinical information associated with the originating patient tumors. Various technologies are used for genomic profiling of PDX models. For example, RNAseq is used for transcriptomic profiling to obtain data on gene expression, RNA-level mutations, gene fusion; whole exome sequencing (WES) is used to infer DNA-level mutations and gene copy numbers. In this study, we compared mutations inferred by RNAseq and WES for 600 PDX models with both datasets. We found that about 50% of mutations detected by WES were uncovered by RNAseq. The other half are missing because these mutation alleles were covered by insufficient reads (&amp;lt;5) or the mutations are located in poly-N regions, which make it hard to call mutations. By contrast, 99% of the RNAseq-based mutations were detected by WES. It is not surprising to see such difference. WES amplifies exons at DNA level, and is only affected by experimental variations such as hybridization efficacy. RNAseq yields more reads for genes with higher expression, therefore, mutations in genes with no or low expression cannot be reliably detected. Our results also indicate that there is limited RNA editing. We also examined mutation ratios and found good agreement between WES and RNAseq. Pearson's correlation coefficient is 0.91 and 0.81 between the two mutation ratios when homologous mutations are included and excluded, respectively. Overall, our study shows that RNAseq data is reliable to infer mutations in highly expressed genes and can be readily used for such when WES data is not available. References 1. Budinská E, Popovici V. The EurOPDX consortium: Sharing patient tumor-derived xenografts for collaborative multicentric preclinical trials. Molecular cancer therapeutics 2014;12:A8-A 2. Gao H, Korn JM, Ferretti S, Monahan JE, Wang Y, Singh M, et al. High-throughput screening using patient-derived tumor xenografts to predict clinical trial drug response. Nature medicine 2015;21:1318-25 3. Ledford, H. (2016). Us cancer institute to overhaul tumour cell lines. Nature, 530. 4. Guo, S., Qian, W., Cai, J., Zhang, L., Wery, J. P., &amp; Li, Q. (2016). Molecular pathology of patient tumors, patient derived xenografts and cancer cell lines. Cancer Research, 76(16), 4619. Citation Format: Wubin Qian, Henry Q.X. Li, Sheng Guo. Mutation detection in patient-derived xenografts by WES and RNAseq [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 1051.
Thromboxane A2 Regulates Vascular Tone via Its Inhibitory Effect on the Expression of Inducible Nitric Oxide Synthase
Authors: TakehiroYamada, TakayukiFujino, Koh-ichiYuhki, AkiyoshiHara, HidejiKaribe, OsamuTakahata, YujiOkada, Chun-YangXiao, KojiTakayama, ShuhkoKuriyama, TakanobuTaniguchi, TakahiroShiokoshi, YoshinobuOhsaki, KenjiroKikuchi, ShuhNarumiya, FumitakaUshikubi
Journal: Circulation (2003)

Background— Circulatory failure in sepsis arises from vascular hyporesponsiveness, in which nitric oxide (NO) derived from inducible NO synthase (iNOS) plays a major role. Details of the cross talk between thromboxane (TX) A2 and the iNOS–NO system, however, remain unknown. We intended to clarify the role of TXA2, via the cross talk, in vascular hyporesponsiveness. Methods and Results— We examined cytokine-induced iNOS expression and NO production in cultured vascular smooth muscle cells (VSMCs) and cytokine-induced hyporesponsiveness of the aorta from mice lacking the TXA2 receptor (TP−/− mice). The cytokine-induced iNOS expression and NO production observed in wild-type VSMCs were significantly augmented in TP−/− VSMCs, indicating an inhibitory effect of endogenous TXA2 on iNOS expression. Furthermore, in indomethacin-treated wild-type VSMCs, U-46619, a TP agonist, inhibited cytokine-induced iNOS expression and NO production in a concentration-dependent manner, effects absent from TP−/− VSMCs. In an ex ...
Abstract 14911: Development and Implantation of Tissue Engineered Self expandable Aortic Stent Grafts (bio Stent Grafts) Using In-body Tissue Architecture Technology in Beagles
Authors: HidetakeKawajiri, TakeshiMizuno, TakeshiMoriwaki, RyosukeIwai, KeiichiKanda, HitoshiYaku, YasuhideNakayama
Journal: Circulation (2014)

Background: Endovascular aortic repair became important treatment option, among aortic surgery with excellent outcomes. Although, endoleaks and migration remains as an issue to be mortified, and stent graft which assimilates to native aorta is desirable. We have developed autologous prosthetic tissues using “in-body tissue architecture” technology, which is a novel and practical approach based on the tissue encapsulation phenomenon of foreign materials in living bodies. Using this technology, we have fabricated the connective tissue covered stent grafts (bio stent grafts;BSGs), which is expected to show good biocompatibility. Materials and Methods: The preparation mold was assembled by insertion of an acryl rod (diameter: 8.6 mm, length: 40 mm) into a self-expanding nitinol stent (diameter: 9.0 mm, length: 35 mm). The molds (n=9) were embedded into the subcutaneous pouches of 3 beagles for 4 weeks. Upon trimming the excessive tissue and removing each rod, BSGs were obtained. Of 9 stent grafts, 3 were impl...
Abstract 45: Snai2 is a new target to mediate glucocorticoid signaling on breast cancer cell migration
Authors: Jun Ling, Adit Singhal, Zenaida P. Lopez-Dee, Brittany Porreca, Trinity Sprague
Journal: Cancer Research (2018)

Abstract Steroid hormone receptors such as estrogen and progesterone receptors are well studied in breast cancer pathology; they are also used as drug targets for breast cancer therapy in the clinic. In contrast, glucocorticoid (GC) as a ubiquitous stress activated steroid hormone is less investigated in breast cancer. However, GC is frequently used as a co-treatment for breast cancer chemotherapy that generates some controversial effects to even promote cancer progression or recurrence in certain subtypes of breast cancer. To address this clinical issue, we focused on investigating the specificity of GC signaling on breast cancer cell behaviors in this study. When breast cancer cells were treated by dexamethasone (Dex), they were more responsive to cell migration (measured by electric cell-substrate impedance sensing, ECIS) than the effects on cell proliferation and apoptosis, wherein MDA-231 (triple negative breast cancer) cell was more sensitive to Dex than MCF7 cell (luminal A subtype). Further gene expression analysis by qRT-PCR microarray revealed that the glucocorticoid receptor (GR) responsive gene patterns are different between these two subtypes of breast cancer cells. One of remarked changes was that Snai2 (a zinc finger transcriptional factor) was highly activated in both cell lines. Western blotting analysis confirmed that MDA-231 cells have much higher basal level of Snai2 but with less fold increase upon Dex treatment than MCF-7. GR response elements (GREs) were also identified in the promoter region of Snai2, thus confirming Snai2 as a new target gene of GR in breast cancer. When Snai2 was knocked out by CRISPR, it was found that the basal migration rate was decreased in both cell lines. More importantly, their response rates to Dex treatment were also decreased as compared to the wild type cells. These decreases in cell migration are similar to those treated by GR antagonist RU486, thus confirming that Snai2 is a mediator to regulate the effects of GC/GR signaling on breast cancer cell migration. In summary, this study identified Snai2 as a new target gene of GR to regulate cell migration and potentially metastasis in response to GC signaling. The differential regulation of different subtypes of breast cancer cells by GC signaling was also confirmed. (+ equal contribution; * Corresponding author). Citation Format: Jun Ling, Adit Singhal, Zenaida P. Lopez-Dee, Brittany Porreca, Trinity Sprague. Snai2 is a new target to mediate glucocorticoid signaling on breast cancer cell migration [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 45.
Angiotensin II Inhibits Neuronal Nitric Oxide Synthase Activation Through the ERK1/2-RSK Signaling Pathway to Modulate Central Control of Blood Pressure
Authors: Wen-HanCheng, Pei-JungLu, Wen-YuHo, Che-SeTung, Pei-WenCheng, MichaelHsiao, Ching-JiunnTseng
Journal: Circulation Research (2010)

Rationale: Angiotensin (Ang) II exerts diverse physiological actions in both the peripheral and central neural systems. It was reported that the activity of Ang II is higher in the nucleus tractus solitarii (NTS) of spontaneously hypertensive rats (SHRs) and that angiotensin type-1 receptors are colocalized with NAD(P)H oxidase in the neurons of the NTS, resulting in the induction of local reactive oxygen species production by Ang II. However, the signaling mechanisms of Ang II that induce hypertension remain unclear. Objective: The aim of this study was to investigate the possible signaling pathways involved in Ang II–mediated blood pressure regulation in the NTS. Methods and Results: Male SHRs were treated with losartan or tempol for 2 weeks, after which systolic blood pressure was observed to decrease significantly. Dihydroethidium staining showed many cells with high reactive oxygen species in the NTS of SHRs. The addition of losartan or tempol decreased the numbers of reactive oxygen species–positive...
Abstract 19191: Transfer of MicroRNAs From Cardiomyocytes Prevents the Growth of Cancer Cells
Authors: Laura Graciotti, Toru Hosoda, Fumihiro Sanada, Giulia Borghetti, Christian Arranto, Ramaswamy Kannappan, Silvana Bardelli, Marco Moccetti, Marcello Rota, Polina Goichberg, Piero Anversa, Tiziano Moccetti, Annarosa Leri
Journal: Circulation (2014)

The sporadic incidence of malignancies in the heart led us to test the possibility that translocation of miRs from cardiomyocytes to cancer cells may oppose the expansion of tumors in the myocardium. miR-1, miR-133a, and miR-499 were highly expressed in myocytes but were barely detectable in MCF7 breast cancer cells. To establish whether miRs migrated from myocytes to MCF7 via gap junction channels, the two cell classes were cultured together. In comparison with MCF7 plated alone, the quantity of miR-1 and miR-133a in MCF7 co-cultured with myocytes increased 45-fold and 20-fold, respectively. However, the expression of miR-499 was only 4-fold higher in MCF7 seeded with myocytes. Coupling with cardiomyocytes decreased by 20% the fraction of Ki-67-positive MCF7. To determine the relevance of gap junctions for the translocation of miRs, Cx43 was downregulated in MCF7 by shRNA. The increase in miR-1 and miR-133a in co-cultured MCF7 was attenuated but not abolished following Cx43 silencing. Unexpectedly, silen...
Arginine Vasopressin–Induced Potentiation of Unitary L-Type Ca2+ Channel Current in Guinea Pig Ventricular Myocytes
Authors: ShetuanZhang, YujiHirano, MasayasuHiraoka
Journal: Circulation Research (1995)

Abstract The effects of arginine vasopressin (AVP) on L-type Ca2+ channels were studied by recording single-channel activity from cell-attached patches on isolated guinea pig ventricular myocytes, with 100 mmol/L Ba2+ used as the charge carrier. Bath application of AVP (100 nmol/L) reversibly increased channel open probability by a factor of 2.92±1.43 (n=15) because of the increased number of channel openings and increased open times. AVP did not change the amplitudes of single-channel currents (1.17±0.10 pA in the control condition and 1.12±0.11 pA after AVP, at +20 mV; n=6). In our experimental conditions, in which myocytes were bathed in Ca2+-free high-potassium solutions, AVP-induced potentiation was observed without changes in [Ca2+]i measured by fura 2 fluorescence signals (estimated [Ca2+]i, ≈80 nmol/L). The AVP-induced increase in channel open probability was abolished by OPC-21268 (8 μmol/L), a specific blocker of V1 receptor, but not by a V2 blocker, OPC-31260 (5 μmol/L). AVP-induced potentiatio...
Abstract 1028: Patient-derived xenografts undergo mouse-specific tumor evolution
Authors: Uri Ben-David, Gavin Ha, Yuen-Yi Tseng, Noah F. Greenwald, Coyin Oh, Juliann Shih, James M. McFarland, Bang Wong, Jesse S. Boehm, Rameen Beroukhim, Todd R. Golub
Journal: Cancer Research (2018)

Abstract Patient-derived xenografts (PDXs) have become a prominent cancer model system, as they are presumed to faithfully represent the genomic features of primary tumors. Here we monitored the dynamics of copy number alterations (CNAs) in 1,110 PDX samples across 24 cancer types. We observed rapid accumulation of CNAs during PDX passaging, often due to selection of pre-existing minor clones. CNA acquisition in PDXs was correlated with the tissue-specific levels of aneuploidy and genetic heterogeneity observed in primary tumors. However, the particular CNAs acquired during PDX passaging differed from those acquired during tumor evolution in patients. Several CNAs recurrently observed in primary tumors gradually disappeared in PDXs, indicating that events undergoing positive selection in humans can become dispensable during propagation in mice. Importantly, the genomic stability of PDXs was associated with their response to chemotherapy and targeted drugs. These findings have important implications for PDX-based modeling of human cancer. Citation Format: Uri Ben-David, Gavin Ha, Yuen-Yi Tseng, Noah F. Greenwald, Coyin Oh, Juliann Shih, James M. McFarland, Bang Wong, Jesse S. Boehm, Rameen Beroukhim, Todd R. Golub. Patient-derived xenografts undergo mouse-specific tumor evolution [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 1028.
Peroxisome proliferator-activated receptor-gamma targeting nanomedicine promotes cardiac healing after acute myocardial infarction by skewing monocyte/macrophage polarization in preclinical animal models
Authors: Masaki Tokutome, Tetsuya Matoba, Yasuhiro Nakano, Arihide Okahara, Masaki Fujiwara, Jun-Ichiro Koga, Kaku Nakano, Hiroyuki Tsutsui, Kensuke Egashira
Journal: Cardiovascular Research (2018)

Monocyte-mediated inflammation is a major mechanism underlying myocardial ischaemia–reperfusion (IR) injury and the healing process after acute myocardial infarction (AMI). However, no definitive anti-inflammatory therapies have been developed for clinical use. Pioglitazone, a peroxisome proliferator-activated receptor-gamma (PPARγ) agonist, has unique anti-inflammatory effects on monocytes/macrophages. Here, we tested the hypothesis that nanoparticle (NP)-mediated targeting of pioglitazone to monocytes/macrophages ameliorates IR injury and cardiac remodelling in preclinical animal models. We formulated poly (lactic acid/glycolic acid) NPs containing pioglitazone (pioglitazone-NPs). In a mouse IR model, these NPs were delivered predominantly to circulating monocytes and macrophages in the IR heart. Intravenous treatment with pioglitazone-NPs at the time of reperfusion attenuated IR injury. This effect was abrogated by pre-treatment with the PPARγ antagonist GW9662. In contrast, treatment with a pioglitazone solution had no therapeutic effects on IR injury. Pioglitazone-NPs inhibited Ly6Chigh inflammatory monocyte recruitment as well as inflammatory gene expression in the IR hearts. In a mouse myocardial infarction model, intravenous treatment with pioglitazone-NPs for three consecutive days, starting 6 h after left anterior descending artery ligation, attenuated cardiac remodelling by reducing macrophage recruitment and polarizing macrophages towards the pro-healing M2 phenotype. Furthermore, pioglitazone-NPs significantly decreased mortality after MI. Finally, in a conscious porcine model of myocardial IR, pioglitazone-NPs induced cardioprotection from reperfused infarction, thus providing pre-clinical proof of concept. NP-mediated targeting of pioglitazone to inflammatory monocytes protected the heart from IR injury and cardiac remodelling by antagonizing monocyte/macrophage-mediated acute inflammation and promoting cardiac healing after AMI.
Abstract 3886: A large cancer pharmacogenomics combination screen powering crowd-sourced advancement of computational drug synergy predictions
Authors: Jonathan R. Dry, Michael P. Menden, Krishna Bulusu, Justin Guinney, Julio Saez-Rodriguez
Journal: Cancer Research (2018)

Abstract This abstract has been withheld from publication due to its inclusion in the AACR Annual Meeting 2018 Official Press Program. It will be posted online following its presentation. Citation Format: Jonathan R. Dry, Michael P. Menden, Krishna Bulusu, Justin Guinney, Julio Saez-Rodriguez. A large cancer pharmacogenomics combination screen powering crowd-sourced advancement of computational drug synergy predictions [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 3886.
Double-layered osmotic pump controlled release tablets of actarit: In vitro and in vivo evaluation
Authors: Yuenan Li, Hao Pan, Hongliang Duan, Jianting Chen, Zhihong Zhu, Jingxin Fan, Pingfei Li, Xinggang Yang, Weisan Pan
Journal: Asian Journal of Pharmaceutical Sciences (2018)

The aim of the study was to develop actarit double-layered osmotic pump tablets to overcome the weak points of actarit common tablets, such as short half-life and large plasma concentration fluctuations. Single factor experiment and orthogonal test were applied to optimize the formulation; the pharmacokinetic study was performed in beagle dogs adopting actarit common tablets as reference tablets. The optimal formulation was as follows: drug layer: 150 mg actarit, 240 mg PEO-N80, 50 mg NaCl; push layer: 140 mg PEO-WSR303, 20 mg NaCl; coating solution: 30 g cellulose acetate and 6 g PEG 4000 in 1000 ml 94% acetone solution, 60 mg coating weight gain. The pharmacokinetic study showed that Tmax was prolonged by the contrast of commercial common tablets with constant drug release rate, but the bioavailability was equivalent. And a good in vivo-in vitro correlation of the actarit osmotic pump tablets was also established. The designed actarit osmotic pump tablets can be applied for rheumatoid arthritis, proposing a promising replacement for the marked common products.
Shift of Macrophage Phenotype Due to Cartilage Oligomeric Matrix Protein Deficiency Drives Atherosclerotic Calcification
Authors: YiFu, ChengGao, YingLiang, MeiliWang, YaqianHuang, WeiMa, TuoyiLi, YitingJia, FangYu, WanlinZhu, QinghuaCui, YanhuiLi, QingboXu, XianWang, WeiKong
Journal: Circulation Research (2016)

Rationale:Intimal calcification is highly correlated with atherosclerotic plaque burden, but the underlying mechanism is poorly understood. We recently reported that cartilage oligomeric matrix protein (COMP), a component of vascular extracellular matrix, is an endogenous inhibitor of vascular smooth muscle cell calcification. Objective:To investigate whether COMP affects atherosclerotic calcification. Methods and Results:ApoE−/−COMP−/− mice fed with chow diet for 12 months manifested more extensive atherosclerotic calcification in the innominate arteries than did ApoE−/− mice. To investigate which origins of COMP contributed to atherosclerotic calcification, bone marrow transplantation was performed between ApoE−/− and ApoE−/−COMP−/− mice. Enhanced calcification was observed in mice transplanted with ApoE−/−COMP−/− bone marrow compared with mice transplanted with ApoE−/− bone marrow, indicating that bone marrow–derived COMP may play a critical role in atherosclerotic calcification. Furthermore, microarra...
Abstract 15934: Refractory Cardiogenic Shock in a Patient With Hypertrophic Obstructive Cardiomyopathy and Mitral Regurgitation Necessitating Intra-Aortic Balloon Pump Use
Authors: IndrajeetMahata, MichaelFaulx, Snigdhakola, SwetaSingh
Journal: Circulation (2014)

Introduction: Hypertrophic obstructive cardiomyopathy (HOCM) is a genetic disease due to a mutation in cardiac muscle protein resulting in left ventricular wall and septal hypertrophy. The presence of systolic anterior motion (SAM) of the mitral valve leads to dynamic left ventricular outflow tract (LVOT) obstruction. With increasing SAM of the anterior mitral leaflet there is resultant loss of coaptation leading to mitral regurgitation (MR). MR has been associated with HOCM but severe MR physiology causing refractory cardiogenic shock and requiring the use of afterload reduction through intra-aortic balloon pump (IABP) is rare and seems paradoxical to the conventional therapy for HOCM. Case summary: This is a case of 71year old female with HOCM, presenting with worsening shortness of breath. She had pulmonary vascular congestion on Chest X-ray and her Transthoracic Echocardiography demonstrated significant LVOT obstruction with moderate MR. She was being evaluated for myomectomy while being treated medic...