tbuckley/cabot-search huggingface dataset:
Abstract LB-324: A whole chromosome aberration phenotype in non-WNT/non-SHH tumors predicts outcome within standard-risk medulloblastomas from the HIT-SIOP-PNET4 clinical trial
Authors: Tobias Goschzik, Ed C. Schwalbe, Debbie Hicks, Dominique Figarella-Branger, Francois Doz, Stefan Rutkowski, Goran Gustafsson, Birgitta Lannering, Torsten Pietsch, Steve C. Clifford
Journal: Cancer Research (2018)

Abstract Introduction: Standard-risk medulloblastoma (SR-MB; 50-60% of patients) is currently defined by the absence of high-risk (e.g. metastatic disease, large-cell/anaplastic histology, MYC amplification) disease features. 75-85% survival rates are achieved, however the identification and validation of novel prognostic biomarkers will be essential to improve risk-adapted therapies, aimed at increased survival and reduced treatment-related late-effects. Experimental procedures: We undertook comprehensive analysis of the pan-European HIT-SIOP-PNET4 prospective clinical trial (2001-2006; age 4-21 years at diagnosis), encompassing central clinical and radiological review, and annotation of molecular pathological features to the WHO (2016) classification. Methods were developed and/or adapted to assess methylation-dependent molecular subgroup (MassArray), copy number aberrations (molecular inversion probe array) and mutational status in scant archival material previously refractory to analysis (n=136). Independent prognostic markers/predictive models for non-WNT/non-SHH patients (n=91) were identified by multivariate analyses, and validated in a representative independent cohort (n=70). Results: WNT (n=28; 21%) and Group 4 (n=76; 56%) tumors were enriched in SR-MB compared to published disease-wide estimates. Favorable-risk WNT disease was confirmed in patients &amp;lt;16.0 years at diagnosis. All events in SHH (4 of 17) occurred in tumors with TP53 mutation and/or chr17p loss. In non-WNT/non-SHH tumors, a novel whole chromosomal aberration (WCA) phenotype characterized by chr7 gain, chr8 loss, and/or chr11 loss, was identified in 42% of patients (38 of 91). This phenotype predicted an excellent prognosis (100% 5-year PFS) and its incorporation into novel survival models out-performed current risk-stratification schemes for SR-MB. Conclusion: A favorable-risk WCA phenotype identifies a large proportion (42%) of non-WNT/non-SHH SR-MB patients for whom therapy de-escalation should be considered in future biomarker-driven risk-adapted clinical trials; remaining patients (58%; 68% 5-year PFS) might benefit from more intensive and/or novel therapies. Citation Format: Tobias Goschzik, Ed C. Schwalbe, Debbie Hicks, Dominique Figarella-Branger, Francois Doz, Stefan Rutkowski, Goran Gustafsson, Birgitta Lannering, Torsten Pietsch, Steve C. Clifford. A whole chromosome aberration phenotype in non-WNT/non-SHH tumors predicts outcome within standard-risk medulloblastomas from the HIT-SIOP-PNET4 clinical trial [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-324.
Electrotonic Modulation of Cardiac Impulse Conduction by Myofibroblasts
Authors: MicheleMiragoli, GiedriusGaudesius, StephanRohr
Journal: Circulation Research (2006)

Structural remodeling of the myocardium associated with mechanical overload or cardiac infarction is accompanied by the appearance of myofibroblasts. These fibroblast-like cells express α-smooth muscle actin (αSMA) and have been shown to express connexins in tissues other than heart. The present study examined whether myofibroblasts of cardiac origin establish heterocellular gap junctional coupling with cardiomyocytes and whether ensuing electrotonic interactions affect impulse propagation. For this purpose, impulse conduction characteristics (conduction velocity [θ] and maximal upstroke velocity [dV/dtmax]) were assessed optically in cultured strands of cardiomyocytes, which were coated with fibroblasts of cardiac origin. Immunocytochemistry showed that cultured fibroblasts underwent a phenotype switch to αSMA-positive myofibroblasts that expressed connexin 43 and 45 both among themselves and at contact sites with cardiomyocytes. Myofibroblasts affected θ and dV/dtmax in a cell density-dependent manner; ...
Abstract 18045: Three Dimensional Collagen Scaffold Combined With Zebularine Treated Rat Bone Marrow Mesenchymal Stem Cells Improved Cardiac Differentiation in vitro
Authors: Asmat Salim, Rida-e-Maria Qazi, Kanwal Haneef, Irfan Khan, Nadia Naeem
Journal: Circulation (2017)

One of the strategies to improve the therapeutic potential of stem cells is the use of extracellular matrix as scaffold. This improves their retention, viability and differentiation potential. In a...
Activation of the Bone Morphogenetic Protein Receptor by H11Kinase/Hsp22 Promotes Cardiac Cell Growth and Survival
Authors: XiangzhenSui, DanLi, HongyuQiu, VincianeGaussin, ChristopheDepre
Journal: Circulation Research (2009)

H11 kinase/Hsp22 (H11K) is a chaperone promoting cardiac cell growth and survival through the activation of Akt, a downstream effector of phosphatidylinositol 3-kinase (PI3K). In this study, we tested whether H11K-induced activation of the PI3K/Akt pathway is mediated by the bone morphogenetic protein (BMP) signaling, both in a transgenic mouse model with cardiac-specific overexpression of H11K and in isolated cardiac myocytes. Microarrays in hearts from transgenic compared to wild-type mice showed an upregulation of the BMP receptors Alk3 and BMPR-II, and of their ligand BMP4 (P<0.01 versus wild type). Activation of the BMP pathway in transgenic mice was confirmed by increased phosphorylation of the “canonical” BMP effectors Smad 1/5/8 (P<0.01 versus wild type). In isolated myocytes, adenovirus-mediated overexpression of H11K was accompanied by a significant (P<0.01) increase in PI3K activity, phospho-Akt, Smad 1/5/8 phosphorylation and [3H]phenylalanine incorporation, and by a 70% reduction in H2O2-medi...
Abstract LB-082: ONC201 sensitizes resistant breast cancer cells to TRAIL through death receptor 5 upregulation
Authors: Marie D. Ralff, Jessica Wagner, Wafik S. El-Deiry
Journal: Cancer Research (2018)

Abstract ONC201 is a potent inducer of cancer cell death through the tumor necrosis factor related apoptosis inducing ligand (TRAIL) pathway. ONC201 and its structural analogs comprise a novel class known as the imipridones. The compound is being tested clinically against a range of solid tumors and hematological malignancies. We found that both triple negative and non-triple negative breast cancer cells are sensitive to ONC201. This was initially surprising, as the majority of non-triple negative breast cancer cells are resistant to TRAIL. In TRAIL-sensitive cells, ONC201 induced cell death in a TRAIL-dependent manner. In TRAIL-resistant cells, the effects of ONC201 are not pro-apoptotic but are rather anti-proliferative. Here we further investigate the effects of ONC201 in TRAIL-resistant breast cancers from multiple molecular subtypes. ONC201 has been previously shown to induce transcriptional upregulation of TRAIL receptor death receptor 5 (DR5). A known mechanism of TRAIL resistance in breast cancer is low cell surface DR5 expression. We hypothesized that pre-treatment with ONC201 would upregulate DR5 and lead to TRAIL sensitization in resistant cells. Our results confirm our hypothesis and show that treatment with ONC201 transcriptionally upregulates DR5 and increases its expression at the cell surface. In addition, pre-treatment with ONC201 sensitizes TRAIL-resistant breast cancer cells to the pro-apoptotic effects of TRAIL. Caspase-8 and PARP are cleaved when cells are treated with the combination of ONC201 and TRAIL, but not when treated with either compound alone. Annexin-V PI staining and quantitation of subG1 DNA content via flow cytometry further confirmed these results. Knockdown of DR5 abrogated TRAIL sensitization by ONC201. Natural killer (NK) cells are known to use TRAIL to kill targets like tumor cells. We are exploring the hypothesis that pre-treatment of tumor cells with ONC201 would increase their killing by NK cells. We are currently investigating the importance of the TRAIL pathway and DR5 upregulation by imipridone compounds in this sensitization to NK cell induced apoptosis. In summary, these results describe a novel mechanism by which ONC201 sensitizes breast cancer cells to the effects of apoptosis inducing ligand TRAIL. They also provide preclinical rationale for the testing of the compound against breast cancers in the clinic. Citation Format: Marie D. Ralff, Jessica Wagner, Wafik S. El-Deiry. ONC201 sensitizes resistant breast cancer cells to TRAIL through death receptor 5 upregulation [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-082.
Influence of Angiotensin on the Hemodynamic Response to Exercise in Normotensive Subjects
Authors: Runesannerstedt, Edvarnauskas
Journal: Circulation (1968)

The effect of exercise on the systemic hemodynamic response in 11 healthy men has been studied before and during an intravenous infusion of angiotensin sufficient to increase the resting mean arterial blood pressure an average of 29%. On exercise in the angiotensin period there was a significantly smaller rise of the systolic pressure than on exercise in the control state, and the response of the diastolic pressure was changed from a moderate increase to a decrease on an average. The increase in mean arterial pressure on exercise was almost abolished, being 4.3 mm Hg during the infusion compared with 20.6 mm Hg before infusion. The rise in cardiac output on exercise was significantly smaller during the angiotensin period, while at the same time there were no significant changes in the behavior of the heart rate, stroke volume, or systemic vascular resistance. The findings indicate that the vasoconstricting effects of angiotensin are largely overcome by the vasodilating effect of exercise in the working mu...
Adenovirus-Mediated Local Expression of Human Tissue Factor Pathway Inhibitor Eliminates Shear Stress–Induced Recurrent Thrombosis in the Injured Carotid Artery of the Rabbit
Authors: TakahiroNishida, HikaruUeno, NobuhikoAtsuchi, RyujiKawano, YujiroAsada, YoNakahara, Yu-ichiKamikubo, AkiraTakeshita, HisatakaYasui
Journal: Circulation Research (1999)

Abstract—The main cause of acute coronary syndrome may be recurrent thrombosis, which is initiated by the activation of the extrinsic coagulation pathway. Tissue factor (TF) pathway inhibitor (TFPI) efficiently inhibits an early step in this pathway by the formation of a complex with factor VIIa, TF, and factor Xa. We determined whether local TFPI gene transfer can inhibit thrombosis in an injured artery without inducing systemic side effects. Balloon-injured rabbit carotid arteries were infected with an adenoviral vector that expressed either human TFPI (AdCATFPI) or bacterial β-galactosidase (AdCALacZ). Two to 6 days after gene transfer, thrombosis was induced by the production of constant stenosis of the artery, and blood flow was measured continuously with an electromagnetic flow probe. A cyclic flow variation, which is thought to reflect the recurrent formation and dislodgment of mural thrombi, was observed in all AdCALacZ-infected arteries as well as in saline-infused arteries. In contrast, no cycli...
A New Level of Complexity
Authors: ThomasBoettger, ThomasBraun
Journal: Circulation Research (2012)

The discovery of the regulatory role of noncoding RNAs, and micro (mi)RNAs in particular, has added a new layer of complexity to our understanding of cardiovascular development. miRNAs regulate and modulate various steps of cardiovascular morphogenesis, cell proliferation, differentiation, and phenotype modulation. miRNAs simultaneously regulate multiple targets, and many miRNAs can bind to the same target, allowing for a complex pattern of regulation of gene expression. miRNA families are continuously added during evolution paralleling the increased complexity of the cardiovascular system in vertebrates compared with invertebrates. Several lines of evidence suggest that the appearance of miRNAs is at least in part responsible for the formation of complex organ systems and stable regulatory mechanisms in vertebrates. We review the current understanding of miRNAs during cardiovascular development. Further progress in this area will help to decipher quantitative changes in gene expression that provide robus...
The Effect of Age on Mean Spatial QRS and T Vectors
Authors: Ernstsimonson, Ancelkeys
Journal: Circulation (1956)

The differentiation between normal and abnormal changes in conventional electrocardiography is substantially improved by consideration of normal age trends. For clinical application of spatial vectorcardiography, consideration of age trends is equally important. On the basis of statistical evaluation of magnitude, azimuth and elevation of mean spatial QRS and T vectors in 105 healthy young men and 178 healthy older men, upper and lower limits were determined for each age group. The age differences were highly significant for all items of vector analysis.
Abstract 5719: RNA-based tumor neoantigens from intron retention
Authors: Claire A. Margolis, Alicia C. Smart, Dennis Adeegbe, Diana Miao, Meng Xiao He, Harold Pimentel, Tim Fugmann, Kwok-Kin Wong, Eliezer M. Van Allen
Journal: Cancer Research (2018)

Abstract Background: Tumor neoantigens contribute to cancer immunity and may influence selective immune checkpoint inhibitor response. Translation of nonsynonymous somatic mutations in tumor cells generates mutant peptides that can be recognized as foreign by the host immune system. Alterations in tumor RNA, rather than DNA, may also contribute to the tumor neoantigen landscape. Intron retention, a widespread feature of cancer transcriptomes, represents a novel source of tumor neoantigens. Methods: We developed an in silico pipeline leveraging existing tools and novel methods to computationally identify retained-intron neoantigens (RI-neoantigens) from transcriptome sequencing data. We applied our computational pipeline to three cohorts of melanoma patients (n = 89) treated with immune checkpoint blockade. Results: This approach identified a mean RI-neoantigen burden of 3,643 across cohorts, which augments the mean DNA-derived somatic neoantigen burden by roughly 4.5-fold. 3,253 RI-neoantigens were exclusively present in two or more patients who responded to immunotherapy. A subset of responder-exclusive RI-neoantigens were validated by peptide restimulation assay. A candidate RI-neoantigen from a cancer cell line was identified in complex with MHC I by mass spectrometry, supporting the hypothesis that aberrant splicing results in intron retention, which generates abnormal transcripts that are translated into immunogenic peptides and presented to the immune system. Conclusions: Our results demonstrate the contribution of transcriptional dysregulation to the overall burden of tumor neoantigens. Further study of RI-neoantigens may expand our understanding of tumor immunity and identify immunogenic peptide sequences for personalized cancer vaccines. Citation Format: Claire A. Margolis, Alicia C. Smart, Dennis Adeegbe, Diana Miao, Meng Xiao He, Harold Pimentel, Tim Fugmann, Kwok-Kin Wong, Eliezer M. Van Allen. RNA-based tumor neoantigens from intron retention [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 5719.
CXCL10/IP-10 Is a Biomarker and Mediator for Kawasaki Disease
Authors: Tai-MingKo, Ho-ChangKuo, Jeng-ShengChang, Shih-PingChen, Yi-MinLiu, Hui-WenChen, Fuu-JenTsai, Yi-ChingLee, Chien-HsiunChen, Jer-YuarnWu, Yuan-TsongChen
Journal: Circulation Research (2015)

Rationale:Kawasaki disease (KD), an acute febrile vasculitis, is the most common cause of acquired heart disease in childhood; however, diagnosing KD can be difficult. Objective:To identify unique proteomic biomarkers that can be used to facilitate earlier diagnosis of KD. Methods and Results:We enrolled 214 children with fever and clinical features suggestive of KD. Of those, only 100 were diagnosed with KD. Their plasma samples were globally analyzed for cytokines, chemokines, and cell adhesion molecules using an unbiased, large-scale, quantitative protein array. This study was conducted in 3 stages: discovery, replication, and blinded validation. During the discovery phase (n [KD]=37; n [control]=20), the expression of interleukin-17F, sCD40L, E-selectin, CCL23 (myeloid progenitor inhibitory factor 1), and CXCL10 (IFN-γ-inducible protein 10 [IP-10]) were upregulated during the acute phase in patients with KD when compared with that in the controls. A notable increase was observed in the IP-10 levels (K...
Increased Risks of Coronary Heart Disease and Stroke Among Spousal Caregivers of Cancer Patients
Authors: JianguangJi, BengtZöller, KristinaSundquist, JanSundquist
Journal: Circulation (2012)

Background—Spousal caregivers of cancer patients suffer psychological and physical burdens that may affect their risk of subsequently developing coronary heart disease and stroke. Methods and Results—Cancer patients were identified in the Swedish Cancer Registry, and information on their spouses was retrieved from the Swedish Multi-Generation Register. Follow-up of caregivers was performed from the date of the first diagnosis of cancer in their spouses through 2008. Standardized incidence ratios were calculated for spousal caregivers of cancer patients compared with those without an affected spouse. After the cancer diagnosis in wives, the risks of coronary heart disease, ischemic stroke, and hemorrhagic stroke in husbands were 1.13 (95% confidence interval [CI], 1.10–1.16), 1.24 (95% CI, 1.21–1.27), and 1.25 (95% CI, 1.18–1.32), respectively. The corresponding risks in wives with an affected husband were 1.13 (95% CI, 1.10–1.16), 1.29 (95% CI, 1.26–1.32), and 1.27 (95% CI, 1.19–1.34). The increases were ...
Broad Suppression of NADPH Oxidase Activity Exacerbates Ischemia/Reperfusion Injury Through Inadvertent Downregulation of Hypoxia-inducible Factor-1α and Upregulation of Peroxisome Proliferator–activated Receptor-α
Authors: ShoujiMatsushima, JunyaKuroda, TetsuroAgo, PeiyongZhai, YoshiyukiIkeda, ShinichiOka, Guo-HuaFong, RongTian, JunichiSadoshima
Journal: Circulation Research (2013)

Rationale:NADPH oxidase (Nox) 2 and Nox4 are major components of the Nox family which purposefully produce reactive oxidative species, namely O2− and H2O2, in the heart. The isoform-specific contribution of Nox2 and Nox4 to ischemia/reperfusion (I/R) injury is poorly understood. Objective:We investigated the role of Nox2 and Nox4 in mediating oxidative stress and myocardial injury during I/R using loss-of-function mouse models. Methods and Results:Systemic (s) Nox2 knockout (KO), sNox4 KO, and cardiac-specific (c) Nox4 KO mice were subjected to I/R (30 minutes/24 hours, respectively). Both myocardial infarct size/area at risk and O2− production were lower in sNox2 KO, sNox4 KO, and cNox4 KO than in wild-type mice. Unexpectedly, however, the myocardial infarct size/area at risk was greater, despite less O2− production, in sNox2 KO+cNox4 KO (double-KO) mice and transgenic mice (Tg) with cardiac-specific expression of dominant-negative Nox, which suppresses both Nox2 and Nox4, than in wild-type or single KO ...
Abstract 1656: First-in-class, fluorinated folate receptor specific agents that target tumor cells via inhibition of serine hydroxymethyltransferase 2 (SHMT2) and 5-aminoimidazole-4-carboxamide formyltransferase (AICARFTase)
Authors: Md Junayed Nayeen, Khushbu Shah, Aleem Gangjee, Aamod Dekhne, Zhanjun Hou, Larry H. Matherly
Journal: Cancer Research (2018)

Abstract Tumor-specific folate receptor (FR) targeting over the ubiquitous reduced folate carrier (RFC) allows for specific tumor targeting without the attending dose-limiting toxicity of all clinically used cytotoxic agents. In an attempt to provide selectivity for FRα and/or β, folic acid has been conjugated with a variety of cytotoxic payloads to alleviate dose-limiting toxicities since folic acid is not transported via RFC (the major tissue folate transporter) to any significant extent. These conjugates have been unsuccessful in clinical trials likely in part due to the instability of the linkers used for conjugation. Premature cleavage results in the cytotoxic component being released prior to tumor penetration, thus precluding any possibility of selective tumor targeting. We designed novel pyrrolo[3,2-d]pyrimidine compounds in which both the targeting component and the cytotoxic component are in the same molecule. These compounds do not require any conjugation or linkers and hence do not suffer any premature cleavage. In this report, we synthesized and evaluated a “first-in-class” series of fluorinated analogues that target FRα/β and have limited transport via RFC, thus providing selectivity for tumors expressing FRα and/or FRβ. Two lead molecules, AGF347 and AGF355, were potent inhibitors of KB human tumor cell proliferation in vitro (IC50 = 1.05 nM and 6.25 nM respectively). Based on protection experiments with glycine, thymidine, adenosine and 5-aminoimidazole-4-carboxamide (AICA), AGF347 and AGF355 were identified as dual inhibitors of serine hydroxymethyltransferase 2 (SHMT2), a key enzyme in mitochondrial one-carbon metabolism and reported oncodriver, and AICA ribonucleotide formyltransferase (AICARFTase), the 2nd folate-dependent step in de novo purine biosynthesis. These compounds are currently being evaluated in preclinical studies as potential candidates for clinical trials. Citation Format: Md Junayed Nayeen, Khushbu Shah, Aleem Gangjee, Aamod Dekhne, Zhanjun Hou, Larry H. Matherly. First-in-class, fluorinated folate receptor specific agents that target tumor cells via inhibition of serine hydroxymethyltransferase 2 (SHMT2) and 5-aminoimidazole-4-carboxamide formyltransferase (AICARFTase) [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 1656.
Abstract 16996: Cardiac Structure and Function Across the Dysglycemia Spectrum in a Contemporary Bi-Ethnic Elderly Population: The Atherosclerosis Risk in Communities (ARIC) Study
Authors: Hicham Skali, Deepak K Gupta, Amil M Shah, Susan Cheng, Brian Claggett, Natalie Bello, David Aguilar, Orly Vardeny, Kunihiro Matsushita, Elizabeth Selvin, Scott D Solomon
Journal: Circulation (2013)

Background: Dysglycemia, including pre-diabetes and overt diabetes mellitus (DM), is associated with an increased risk of death and cardiovascular (CV) morbidity including incident HF. Data regarding cardiac structure and function in subjects with dysglycemia without evidence of overt CV disease is inconsistent. Methods: We assessed measures of cardiac structure and function in 4594 participants (mean age 75±5 yrs; 62% female, 23% African-American) of the ARIC Visit 5 examination (2011-2013) without prevalent coronary heart disease or HF who underwent transthoracic echocardiography. Subjects were grouped across the dysglycemia spectrum as normal, impaired fasting glucose (IFG), or DM based on a medical history, antidiabetic medication use, fasting glucose and HbA1C levels. Results: IFG and DM were present in 54% and 28% of population, respectively. Subjects with worse dysglycemia category were more likely to be male, African-American, have hypertension, higher BMI and heart rate. In univariate analyses, s...