tbuckley/cabot-search huggingface dataset:
Abstract 5357: Mutational and transcriptomic profiling identify distinct angiogenic and inflammatory subtypes of angiosarcoma
Authors: Jong Hyuk Kim, Kate Megquier, Aaron L. Sarver, Rachael Thomas, Chao Wang, Ingegerd Elvers, Elinor Karlsson, Matthew Breen, Kerstin Lindblad-Toh, Jaime F. Modiano
Journal: Cancer Research (2018)

Abstract Angiosarcoma is an aggressive, albeit rare cancer in humans. The cause of the vast majority of sporadic angiosarcomas is unknown, mortality is high, and no therapeutic targets have been identified to improve outcomes. Hemangiosarcoma (HSA) is a common cancer of dogs, and it shares histopathologic features with human angiosarcoma. In our previous work, canine HSAs were classified into angiogenic, inflammatory, and adipogenic subtypes based on transcriptional profiles. However, the genetic and molecular events that regulate transcriptional subtypes in angiosarcoma are not currently understood. Our goal was to use a comparative genomics approach to apply knowledge from appropriately powered canine studies to inform our research into human sarcomas. In this study, we identified recurrent mutations in RNASeq data from 93 HSAs and 16 nonmalignant controls, based on mutations first identified in exomes from 42 paired tumor and normal samples. In addition to identifying recurrent somatic mutations we also identified translocation fusions, allowing elucidation of oncogenic mechanisms for vascular endothelial growth factor receptors (VEGFR), phosphoinositide-3 kinase (PIK3) signaling pathways, and the p53 DNA damage repair pathway in canine HSA. Significantly, mutational signatures were associated with distinct molecular subtypes of canine hemangiosarcomas, and both the angiogenic and the inflammatory subtypes were apparent in RNASeq data from human angiosarcomas (n=14), suggesting that comparable etiologic mechanisms are operative in the canine and human disease. Our ongoing work seeks to understand how the molecular mechanisms give rise to molecular subtypes of angiosarcoma by defining the association between driver mutations, signaling pathway alterations and transcriptional patterns, which should allow us to identify rational therapeutic targets. Citation Format: Jong Hyuk Kim, Kate Megquier, Aaron L. Sarver, Rachael Thomas, Chao Wang, Ingegerd Elvers, Elinor Karlsson, Matthew Breen, Kerstin Lindblad-Toh, Jaime F. Modiano. Mutational and transcriptomic profiling identify distinct angiogenic and inflammatory subtypes of angiosarcoma [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 5357.
Selective Suppression of Endothelial Cell Apoptosis by the High Molecular Weight Form of Adiponectin
Authors: HidekiKobayashi, NoriyukiOuchi, ShinjiKihara, KennethWalsh, MasahiroKumada, YukiAbe, TohruFunahashi, YujiMatsuzawa
Journal: Circulation Research (2004)

Adiponectin is an adipocyte-derived, antiatherogenic protein that is present in serum as three isoforms. Total adiponectin levels are decreased in obese or diabetic humans or animal models. This study was designed to elucidate the relative isoform distribution of adiponectin in human disease states and identify the active form of adiponectin toward vascular endothelial cells. The percentage of high molecular weight form (HMW) per total adiponectin was significantly lower in patients with coronary artery disease than control subjects, whereas the hexamer form was similar and the trimer form was significantly higher. During weight reduction in obese subjects, the HMW form increased and the trimer and hexamer forms decreased. Recombinant adiponectin dose-dependently suppressed apoptosis and caspase-3 activity in human umbilical vein endothelial cells (HUVECs). Transduction with dominant-negative AMP-activated protein kinase (AMPK) abolished the suppressive effect of adiponectin on HUVECs. Gel filtration chro...
Abstract 526: Mechanistic studies of TAp63 regulated oncogenic long noncoding RNAs in breast cancer metastasis
Authors: Xiaobo Li
Journal: Cancer Research (2018)

Abstract Advanced breast cancer metastasis is the major cause of relapse. However, no effective treatment exists for the metastatic stage of breast cancer. Recently, regulatory long non-coding RNAs (lncRNAs) have been highlighted in p53 regulated genome protection in cancer metastasis; therefore approaches targeting lncRNAs is a promising strategy to treat breast cancer metastasis. Our laboratory aims to design such approaches through focusing on the p53 family member, TAp63 and its regulated lncRNAs. TAp63 has critical tumor suppressor function in breast cancer. Loss of function transforms mammary epithelial cells (MECs) into tumor initiating cells. Our lab showed that loss of TAp63 in mouse MECs induces the expression of several lncRNAs. A locus conservation strategy was applied to identify the homologous lncRNAs relevant in human breast cancer progression. Targeting these lncRNAs with CRISPR/CAS9 system in human breast cancer cell line in mouse xenograft model demonstrated that they are required for the tumorigenic and metastatic potential of human breast cancer cells in vivo. The high-throughput protein microarray screening method was used to identify proteins that interact with these lncRNAs and facilitate their oncogenic functions. Importantly, the expression of both protein and lncRNA is negatively correlated with patient survival in breast cancer dataset, and positively correlated with breast cancer progression in human tissue microarrays. We demonstrate the oncogenic effects of these lncRNAs in promoting breast cancer metastasis. Our data indicates that targeting lncRNAs directly or their effectors indirectly will provide innovative and effective therapeutics aiming the metastatic stage of breast cancer. Citation Format: Xiaobo Li. Mechanistic studies of TAp63 regulated oncogenic long noncoding RNAs in breast cancer metastasis [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 526.
Abstract 2: IL-10 Modulates Mobilization of Bone Marrow Endothelial Progenitor Cells and Enhances Their Survival and Angiogenic Properties in Ischemic Myocardium
Authors: PrasannaKrishnamurthy, MelissaThal, SureshVerma, EnedaHoxha, ErinLambers, VeronicaRamirez, GangjianQin, DouglasLosordo, RajKishore
Journal: Circulation Research (2011)

Endothelial progenitor cells (EPC) transplantation has been shown to enhance neovascularization and improve myocardial infarction (MI)-induced ventricular dysfunctions. However, persistent inflammation in the ischemic myocardium, adversely affect EPC survival and function, thereby compromising full benefits of EPC-mediated vascular repair. We hypothesized that modulation of IL-10 signaling in EPCs enhances their mobilization, survival and function in ischemic myocardium after MI. GFP-labeled EPC were transplanted intramyocardially after induction of MI, and the mice were treated with either saline or recombinant IL-10. EPC survival and EPC-mediated neovascularization and myocardial repair were evaluated. IL-10-treated mice showed increased number of GFP+EPCs retention that was associated with reduced EPC apoptosis in the myocardium (P<0.05). The engraftment of EPC into the vascular structures and the associated capillaries density was significantly higher in IL-10-treated mice (P<0.05). The above findings...
Epigenetics in ovarian cancer: premise, properties, and perspectives
Authors: Qilian Yang, Yuqing Yang, Nianxin Zhou, Kexin Tang, Wayne Bond Lau, Bonnie Lau, Wei Wang, Lian Xu, Zhengnan Yang, Shuang Huang, Xin Wang, Tao Yi, Xia Zhao, Yuquan Wei, Hongjing Wang, Linjie Zhao, Shengtao Zhou
Journal: Molecular Cancer (2018)

Malignant ovarian tumors bear the highest mortality rate among all gynecological cancers. Both late tumor diagnosis and tolerance to available chemical therapy increase patient mortality. Therefore, it is both urgent and important to identify biomarkers facilitating early identification and novel agents preventing recurrence. Accumulating evidence demonstrates that epigenetic aberrations (particularly histone modifications) are crucial in tumor initiation and development. Histone acetylation and methylation are respectively regulated by acetyltransferases-deacetylases and methyltransferases-demethylases, both of which are implicated in ovarian cancer pathogenesis. In this review, we summarize the most recent discoveries pertaining to ovarian cancer development arising from the imbalance of histone acetylation and methylation, and provide insight into novel therapeutic interventions for the treatment of ovarian carcinoma.
A Qualitative Distinction between the Beta-Receptor-Blocking and Local Anesthetic Actions of Antiarrhythmic Agents
Authors: Elliotshinebourne, Rogerwhite, Johnhamer
Journal: Circulation Research (1969)

Fragmented cardiac sarcoplasmic reticulum was isolated by differential centrifugation from canine myocardium. The effects of propranolol, quinidine, lidocaine (lignocaine) and tetracaine (amethocaine) on calcium uptake in sarcoplasmic reticulum in vitro were then measured. All the drugs are antiarrhythmic agents with local anesthetic activity, but propranolol and quinidine are known also to have beta-receptor-blocking actions in that they can prevent the cardiac effects of isoprenaline and depress the myocardium. Lidocaine and tetracaine do not generally depress the heart and had no effect on the calcium uptake, but propranolol and quinidine both significantly inhibited it. It was concluded that the antiarrhythmic actions of propranolol (and quinidine) may be independent of beta-receptor-blocking activity, and that the safety of lidocaine as an antiarrhythmic agent may be related to a lack of effect on the sarcoplasmic reticulum.
Abstract 13829: The Active Metabolite of Selexipag Relaxes Rat Pulmonary Artery via Selective Activation of IP Prostacyclin Receptors
Authors: Keith Morrison, Roland Ernst, Franck Haag, Daniel Bur, Martine Clozel
Journal: Circulation (2015)

Introduction: Selexipag is a selective IP prostacyclin receptor agonist in development for the treatment of pulmonary arterial hypertension. Preclinical studies demonstrate that selexipag and its active metabolite ACT-333679 relax rat extralobar pulmonary artery (EPA) ex vivo . It has been reported that the IP receptor antagonist CAY10441 does not inhibit relaxation to ACT-333679. Hypothesis: We hypothesized that relaxation of rat EPA to ACT-333679 could be inhibited by antagonism of IP receptors using a modified protocol. Methods: Rings of rat EPA were prepared using standard techniques. Relaxation to ACT-333679 was measured in EPA pre-contracted with PGF 2 α (10 μM). The effect of CAY10441, BWA868C and PF04418948 (selective antagonists of relaxant IP, DP 1 and EP 2 receptors, respectively) on relaxation to ACT-333679 was measured using 2 protocols: (1) EPA was incubated with each receptor antagonist prior to addition of increasing concentrations of ACT-333679; (2) each receptor antagonist was added after stabilization of relaxation to ACT-333679 (1 μM). Results: ACT-333679 relaxed EPA in a concentration-dependent manner (Figure 1A; control pEC 50 5.8 ± 0.1). CAY10441 (1 μM) did not inhibit relaxation to ACT-333679 when added prior to ACT-333679 (pEC 50 5.6 ± 0.1; not statistically significant vs control). However, CAY10441 (0.1-10 μM) reversed relaxation of EPA when added after sub-maximal relaxation to ACT-333679 (1 μM) was reached (relaxation 48.8 ± 9.8% of PGF 2 α contraction) (Figure 1B). BWA868C and PF04418948 did not inhibit relaxation of EPA when added before or after ACT-333679. Conclusion: Relaxation of EPA to ACT-333679 is inhibited by antagonism of IP receptors, but not DP 1 or EP 2 receptors. IP receptor activation by ACT-333679 is first required to observe the inhibitory effect of CAY10441 on vasorelaxation. ACT-333679 relaxes rat EPA via selective activation of IP prostacyclin receptors.
Abstract 4426: Automated miRNA purification from plasma, serum or exosomes
Authors: Michelle Mandrekar, Jami English, Douglas Horejsh, Chris Moreland, Herly Karlen, Marjeta Urh
Journal: Cancer Research (2018)

Abstract Introduction: MicroRNAs (miRNAs) are endogenous small noncoding RNAs 18-24 nucleotides in size that play important roles involving gene regulation associated with cancer, disease control and gene silencing. Because of the impact on disease progression, miRNA research is rapidly shifting towards biomarker discovery. Many of the commercially available miRNA purification methods involve organic extraction during preprocessing. Here, we describe a novel chemistry that enables RNA purification including smaller RNA such as miRNA. This chemistry offers significant advantages with a simple automated workflow, no organic extraction and minimal preprocessing. Method: In this study we show successful purification of small RNA, including miRNA, from 100uL to 500uL liquid samples utilizing a novel chemistry on the Maxwell® RSC instrument, which can process between 1 and 16 samples. Proteinase K and Lysis Buffer C are added to the liquid samples and incubated before being transferred to the Maxwell cartridge for miRNA isolation. Sample types tested include plasma, serum and isolated exosomes. The miRNA were evaluated using RT-qPCR including miR-16, miR-21, and let-7a. Results: The eluates had high levels of small RNA including miRNA at levels comparable to manual competitor methods that require organic extraction. Quantitative PCR showed that the eluates had little or no detectable DNA contamination. Integration of the chemistry onto this automated platform reduced hands-on time while maintaining high quality needed for use in downstream RT-qPCR amplification assays. Summary: This novel chemistry and method enables purification of small RNA from a range of samples types and volumes. The purified RNA has little or no detectable DNA contamination. Phenol extraction is not required, improving safety and simplifying waste disposal. Also, the automation of this workflow decreases manual hands-on time, saving scientist time and reducing the risk of RNase contamination. Citation Format: Michelle Mandrekar, Jami English, Douglas Horejsh, Chris Moreland, Herly Karlen, Marjeta Urh. Automated miRNA purification from plasma, serum or exosomes [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 4426.
Abstract 5606: Eradication of triple-negative breast cancer cells by targeting glycosylated PD-L1
Authors: Seung-Oe Lim, Chia-Wei Li, Mien-Chie Hung
Journal: Cancer Research (2018)

Abstract EGF signaling inhibits GSK3β-β-TrCP-mediated degradation of N-linked glycosylated programmed death ligand-1 (PD-L1), resulting in PD-L1 protein destabilization and enhanced immune checkpoint blockade efficacy. Here we show that EGF also mediates PD-L1 and receptor programmed cell death protein-1 (PD-1) interaction, requiring β-1,3-N-acetylglucosaminyl transferase (B3GNT3) expression in triple-negative breast cancer cells. Downregulation of B3GNT3 enhances cytotoxic T cell-mediated anti-tumor immunity. A monoclonal antibody targeting glycosylated PD-L1 (gPD-L1) blocks PD-L1/PD-1 interaction and promotes PD-L1 internalization and degradation. In addition to immune reactivation, drug-conjugated gPD-L1 antibody induces potent cell-killing effect as well as bystander-killing effect on adjacent cancer cells without PD-L1 expression with virtually no detectable toxicities. Our work suggests targeting protein glycosylation as a potential strategy to enhance immune checkpoint therapy. Citation Format: Seung-Oe Lim, Chia-Wei Li, Mien-Chie Hung. Eradication of triple-negative breast cancer cells by targeting glycosylated PD-L1 [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 5606.
Effectiveness of catch-up human papillomavirus vaccination on incident cervical neoplasia in a US health-care setting: a population-based case-control study
Authors: Michael J Silverberg, Wendy A Leyden, Jennifer O Lam, Steven E Gregorich, Megan J Huchko, Shalini Kulasingam, Miriam Kuppermann, Karen K Smith-McCune, George F Sawaya
Journal: The Lancet Child & Adolescent Health (2018)
Abstract 3975: Target engagement, thrombocytopenia, and efficacy induced by the dual Bcl2/xL inhibitor AZD4320 are quantitatively linked by a PK/PD model in leukemia xenografts
Authors: Francis D. Gibbons, Ammar Adam, Marie-Eve Beaudoin, Eric Gangl, Paul Secrist
Journal: Cancer Research (2018)

Abstract The proteins Bcl2 and Bcl-xL are often up-regulated in cancer, and hold in check the apoptosis that would normally be initiated by accumulation of the BH3-only proteins Bax and Bak in response to genomic dysregulation. AZD4320 potently disrupts that interaction, initiating the apoptotic cascade in Bcl-2 or Bcl-xL-dependent tumors. Because platelets are known to be dependent on Bcl-xL, thrombocytopenia is an expected on-target effect. AZD4320 was administered at dose levels 0.5-10 mg/kg, both intravenously and extravascularly, to immune-compromised mice inoculated subcutaneously with the RS4;11 model of acute lymphocytic leukemia (ALL). Drug concentrations were measured by liquid chromatography-mass spectrometry (LC-MS) in plasma and tumor. A cleaved-caspase-3 ELISA was used to assess apoptotic activity in the tumor. Parallel efficacy studies, were used to assess tumor growth compared to vehicle, following tumors from initial regression at tolerated doses to regrowth. Tumors were measured using calipers, and tumor volumes computed using an ellipsoid approximation. We present a mini-physiologically based pharmacokinetic/pharmacodynamic (mPBPK/PD) model that links drug concentrations in plasma and tumor to observed caspase activity and efficacy in an integrated manner, across multiple dose levels and schedules. The tumor is modeled as a pool of sensitive cells which can be triggered rapidly by AZD4320 to apoptose, from which point they transition gradually to death, reducing tumor volume. Cleaved caspase-3 is used as a marker of apoptosis, and modeled using a sigmoidal response function with steep slope parameter. In this way, we effectively capture the transient nature of the response, despite AZD4320's long residence in the tumor. Thrombocytopenia is described not as an effect on the megakaryocyte precursors, but as a linear concentration-dependent effect on circulating platelets. Feedback from the circulation to megakaryocytes drives increased production to fill the deficit. Parameters are well-estimated throughout. Together, these components provide a comprehensive means to investigate the effects of dose and schedule with a dual Bcl2/BCL-xL inhibitor. Citation Format: Francis D. Gibbons, Ammar Adam, Marie-Eve Beaudoin, Eric Gangl, Paul Secrist. Target engagement, thrombocytopenia, and efficacy induced by the dual Bcl2/xL inhibitor AZD4320 are quantitatively linked by a PK/PD model in leukemia xenografts [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 3975.
Abstract P243: Sugar-sweetened Beverage Consumption is Not Associated with Calcified Atherosclerotic Plaques in the Coronary Arteries: The NHLBI Family Heart Study
Authors: Yash R Patel, Tasnim F Imran, R C Ellison, Geraldo Heiss, Steven C Hunt, J J Carr, Donna K Arnett, James S Pankow, J M Gaziano, Luc Djousse
Journal: Circulation (2016)

Background: Sugar-sweetened beverage (SSB) intake is associated with higher risk of weight gain, diabetes, hypertension, cardiovascular disease and cardiovascular mortality. However, the association of SSB with subclinical atherosclerosis in the general population is unknown. Hypothesis: Our primary hypothesis is that higher intake of SSB is associated with a higher prevalence of atherosclerotic plaque in coronary arteries in NHLBI Family Heart Study. Methods: In a cross-sectional design, we studied 1990 participants of the NHLBI Family Heart Study without known coronary heart disease. SSB was assessed through a semi-quantitative food frequency questionnaire by asking how often participants consumed 1 glass of regular soda, diet soda, and fruit punch/kool-aid. Coronary-artery calcium (CAC) was measured by cardiac CT. We defined prevalent CAC using an Agatston score of at least 100 and used generalized estimating equations to calculate adjusted prevalence ratios of CAC in SAS 9.3 software. Results: Mean age and BMI were 55.0 years and 29.5 kg/m2 respectively, and 60% were female. In adjusted analysis for age, sex, BMI, smoking, alcohol use, physical activity, total calories, and field center, higher SSB consumption was not associated with higher prevalence of CAC (Table1). In a sensitivity analysis, there was no evidence of association between SSB and prevalent CAC when CAC cut points of 0, 50, 150, 200, and 300 were used. Conclusions: These data do not provide evidence for an association between SSB consumption and prevalent CAC in adult men and women.