tbuckley/cabot-search huggingface dataset:
Abstract 2310: Targeting transcription-associated CDKs is an effective way to combat glioblastoma and medulloblastoma with minimal effect on primary neurons
Authors: Isha Bhutada, Srikumar Chellappan, Jaya Padmanabhan
Journal: Cancer Research (2018)

Abstract Glioblastoma multiforme (GBM) is the most prevalent and malignant brain tumor in adults. Currently there are no effective therapies to manage the disease efficiently. Medulloblastoma is the most common type of pediatric tumor and accounts for approximately 15% of all pediatric brain tumors. We aimed to determine if targeting the transcription-associated cyclin-dependent kinases, cdk7 and cdk9, using specific inhibitors, could interfere with the growth and metastatic properties of glioblastoma and medulloblastoma cell lines. We tested the effectiveness of Flavopiridol, a known inhibitor of cdk4, cdk6, pTEFb and cdk9; THZ1, a cdk7 inhibitor; and SNS032, which is known to inhibit cdk2, cdk7 and cdk9, on U87 and SNB19 glioblastoma, H4 neuroglioma and Daoy medullobastoma cells. Treatment with these pharmacological agents showed very strong cytotoxic effects on these cancer cells as measured by MTT (3-(4, 5-dimethylthiazol-2yl)-2, 5-diphenyl tetrazolium bromide) assay. Among these agents the cdk7 inhibitor was most effective and showed efficacy at nanomolar concentrations. Additionally, the inhibitors interfered with the cancer cell migration, as measured by wound healing assay, and anchorage independent growth, as measured by soft agar colony formation. In stark contrast, the inhibitors had no cytotoxic effects on primary neurons. Mechanistically, western blot analysis showed that the tumor cells treated with the inhibitors had reduced levels of Pol II C-terminal domain phosphorylation, indicative of its inhibition and suppression of transcription. Furthermore, inhibitor treatment resulted in a significant reduction in p70S6 kinase phosphorylation, suggesting that in addition to the transcriptional machinery, the translational machinery is also affected upon treatment with the aforementioned cdk inhibitors. Immunostaining analysis of the cells showed a marked reduction in the levels of P-Pol II and P-p70S6 kinase upon inhibitor treatment, confirming that the cdk inhibitors indeed interfere with both transcription and translation. These inhibitors appear to be working in a p53-dependent fashion. These novel findings shed light on potential mechanisms that can be targeted to combat both glioblastoma and medulloblastoma effectively. More specifically, our studies imply that cdk7 and cdk9 inhibitors may serve as potential therapies for effective management of brain tumor. Citation Format: Isha Bhutada, Srikumar Chellappan, Jaya Padmanabhan. Targeting transcription-associated CDKs is an effective way to combat glioblastoma and medulloblastoma with minimal effect on primary neurons [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 2310.
Major Contribution of the P2Y1 Receptor in Purinergic Regulation of TNFα-Induced Vascular Inflammation
Authors: MurielleZerr, BéatriceHechler, MoniqueFreund, StéphanieMagnenat, IsabelleLanois, Jean-PierreCazenave, CatherineLéon, ChristianGachet
Journal: Circulation (2011)

Background—Atherosclerosis is an inflammatory disease, and extracellular nucleotides are one of the factors possibly involved in vascular inflammation. The P2Y1 receptor for adenosine 5|o:-diphosphate has been shown to be involved in the development of atherosclerosis in apolipoprotein E–deficient mice. Our aim is to determine whether the endothelial P2Y1 receptor plays a role in leukocyte recruitment during vascular inflammation and characterize underlying mechanisms. Methods and Results—We show here that the P2Y1 receptor plays a role in leukocyte recruitment in inflamed mouse femoral arteries. Moreover, in wild-type bone marrow–transplanted chimeric P2Y1-deficient mice with an apolipoprotein E–deficient background, a strong reduction of adhesion molecule–dependent leukocyte recruitment was observed after local injection of tumor necrosis factor α and interleukin 1β, excluding a role for the platelet or other hematopoietic cell type P2Y1 in these events. Similarly, the in vitro adhesion of isolated mous...
Abstract 3612: Elevated TGFa levels in chronic mylogenous leukemia (CML) patient plasma measured by a highly sensitive single molecule array immunoassay
Authors: Ahmed Chenna, Li Cai, Christos Petropoulos, John W. Winslow
Journal: Cancer Research (2018)

Abstract Introduction: Recent reports suggest that cytokine and growth factor profiling are prognostic in myelodisplasias and CML. TGF-α and IL-6 plasma levels selectively identified CML patients failing to achieve an early molecular response (EMR), or progressed on imatinib therapy (Nievergall et al, 2016). In patients failing to achieve EMR, the median TGFα concentrations were in the low pg/mL range while IL-6 levels were sub-pg/mL or undetectable. Thus, to accurately and reproducibly measure TGFα and IL-6 levels in blood as prognostic or predictive markers of imatinib response, there is a need for highly sensitive immunoassays. Here we demonstrate the utility of using a digital immunoassay to measure sub-pg/mL levels of TGFα and IL-6 in CML plasma samples assessed for BCR-ABL fusion transcripts. Methods: Single molecule array immunoassays (Simoa) for TGFα and IL-6 were performed on the HD-1 platform (Quanterix), qualified based on precision, reproducibility, linearity, sensitivity according to kit specifications. CML blood samples were obtained from CMBP, LabCorp, Inc, following BCR-ABL e1b2, b2b2, and b3b2 transcript fusion testing by RT-PCR. Results: TGFα and IL-6 concentrations in the plasma of 77 CML patients were determined and compared to levels in healthy controls. TGFα in CML plasma was elevated and ranged ~20-fold (6.13-118.6 pg/mL), in contrast to the low levels and narrow range in healthy controls (range = 1.11-3.17 pg/mL). Median TGFα levels were 10-fold higher in CML patient plasma (median = 18.8 pg/mL) relative to healthy controls (median = 1.8 pg/mL; p &amp;lt;0.0001). IL-6 levels ranged broadly in CML plasma (0.12-12.6 pg/mL) relative to healthy controls (0.3-1.04pg/mL), though median levels were not significantly different (CML = 0.61 vs 0.69, p = 0.873). TGFα and IL-6 concentrations were not significantly correlated. TGFα levels appear elevated in CML samples expressing all 3 BCR-ABL transcripts, however, a larger number of samples enriched in fusion transcripts are being assessed to confirm possible correlations. Conclusions: We have qualified novel highly sensitive single molecule array immunoassays to measure TGFα and IL-6 in the plasma of CML patients and healthy controls, and found significantly elevated levels of TGFα in CML plasma. These results support further investigation of TGFα and IL-6, using sensitive immunoassays, as potential prognostic and predictive markers of CML disease progression and treatment outcome. Citation Format: Ahmed Chenna, Li Cai, Christos Petropoulos, John W. Winslow. Elevated TGFa levels in chronic mylogenous leukemia (CML) patient plasma measured by a highly sensitive single molecule array immunoassay [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 3612.
Abstract P037: School Lunch is Associated with Increased Cardiovascular Risk Among Middle-school Children
Authors: Rosa S de Visser, Rachel Sylvester, Qingmei Jiang, Eva Kline-Rogers, Jean DuRussel-Weston, Kim A Eagle, Elizabeth A Jackson
Journal: Circulation (2016)

Introduction: Millions of children consume school lunches daily. Children from low-income families are eligible for free or reduced-price school meals. While studies show improvement in the nutritional quality of school lunches, the effect of school lunch or lunch brought from home on cardiovascular risk factors among children is unknown. Hypothesis: We hypothesized that frequently consuming school lunch is associated with increased cardiovascular risk factors when compared with lunch brought from home. Methods: All 15,742 sixth graders enrolled in Project Healthy Schools, a school-based wellness intervention, were included in this cross-sectional study (2004-2015). We examined 10,169 behavioral surveys and 1,845 physiological screenings. We compared self-reported diet, physical activity (PA), sedentary behaviors and physiologic parameters (height, weight, blood pressure (BP) and heart rate) in 2 groups, children who reported eating school lunch daily and those who eat home-prepared lunch daily. The groups were further stratified by socioeconomic status (SES); low SES (&lt;$35,000) or high SES (&gt;$50,000) based on the median household income of the school region. Students in the middle SES range ($35,000-$50,000) were excluded from analysis (n=4230). Results: School lunch students were associated with less healthy behaviors (PA, diet [fruit/vegetable servings, meat and sugary beverage intake], and sedentary activities) and physiologic measures (percent of overweight/obesity, systolic BP and recovery heart rate) compared with students bringing lunch from home in low and high SES groups (Table 1). Conclusions: In this large cohort of children, we observed frequent school lunch consumption, even after adjustment for SES, was associated with less healthy behaviors and physiologic parameters. Further research is warranted to determine whether healthier school lunches would improve cardiovascular health characteristics and health behaviors in middle-school students.
Cardiovascular Effects of an Ultra–Short-Acting Nitric Oxide–Releasing Compound, Zwitterionic Diamine/NO Adduct, in Dogs
Authors: PingZhang, AkitoshiOhara, TakashiMashimo, JianhuaSun, SatoshiShibuta, KojiTakada, HiroakiKosaka, MasaruTerada, IkutoYoshiya
Journal: Circulation (1996)

Background This study was conducted to clarify the cardiovascular effects of a new NO-releasing compound, NOC-7, and to compare it with other nitrovasodilators, sodium nitroprusside (SNP) and nitroglycerin, in dogs anesthetized with pentobarbital. Methods and Results A bolus injection of NOC-7 decreased mean aortic blood pressure in a dose-dependent manner. The onset was rapid and the recovery quick. Continuous infusion of NOC-7 decreased mean aortic pressure from 115±3.9 to 84±2.9 mm Hg and infusion of SNP, from 118±3.8 to 87±3.1 mm Hg. The optimum doses of NOC-7 and SNP were determined to be 2.73±0.77 and 11.5±6.1 μg·kg−1·min−1, respectively. During infusion of NOC-7, heart rate and cardiac output were increased (P<.05), pulmonary artery pressure was not changed, and systemic and pulmonary vascular resistances were decreased (P<.05). Electromagnetic flowmetry showed that portal venous and internal carotid arterial blood flow were increased (P<.05) and that hepatic and renal arterial blood flows were not...
DDX24 Mutations Associated With Malformations of Major Vessels to the Viscera
Authors: Pengfei Pang, Xiaojun Hu, Bin Zhou, Junjie Mao, Yu Liang, Zaibo Jiang, Mingsheng Huang, Ruihong Liu, Youyong Zhang, Jiesheng Qian, Jinsong Liu, Jinxin Xu, Yaqin Zhang, Maoheng Zu, Yiming Wang, Huanhuan He, Hong Shan
Journal: Hepatology (2018)

Vascular malformations present diagnostic and treatment challenges. In particular, malformations of vessels to the viscera are often diagnosed late or incorrectly due to the insidious onset and deep location of the disease. Therefore, a better knowledge of the genetic mutations underlying such diseases is needed. Here, we evaluated a four‐generation family carrying vascular malformations of major vessels that affect multiple organs, which we named “multiorgan venous and lymphatic defect” (MOVLD) syndrome. Genetic analyses identified an association between a mutation in DEAD‐box helicase 24 ( DDX24 ), a gene for which the function is largely unknown, and MOVLD. Next, we screened 161 patients with sporadic vascular malformations of similar phenotype to our MOVLD family and found the same mutation or one of the two additional DDX24 mutations in 26 cases. Structural modeling revealed that two of the mutations are located within the adenosine triphosphate–binding domain of DDX24. Knockdown of DDX24 expression in endothelial cells resulted in elevated migration and tube formation. Transcriptomic analysis linked DDX24 to vascular system–related functions. Conclusion : Our results provide a link between DDX24 and vascular malformation and indicate a crucial role for DDX24 in endothelial cell functions; these findings create an opportunity for genetic diagnosis and therapeutic targeting of malformations of vessels to the viscera.
Highly sensitive/selective 3D nanostructured immunoparticle-based interface on a multichannel sensor array for detecting amyloid-beta in Alzheimer's disease
Authors: Ta-Chung Liu, Yi-Chao Lee, Chiung-Yuan Ko, Ren-Shyan Liu, Chien-Chih Ke, Yu-Chun Lo, Pei-Sung Hong, Chao-Yi Chu, Ching-Wen Chang, Pu-Wei Wu, You-Yin Chen, San-Yuan Chen
Journal: Theranostics (2018)

Accumulation of β-amyloid (Aβ) peptides is highly associated with Alzheimer's disease (AD) progression in prevailing studies.The successful development of an ultrasensitive detection assay for Aβ is a challenging task, especially from blood-based samples.Methods: We have developed a one-step electrophoresis/electropolymerization strategy for preparing a CSIP hierarchical immunoelectrochemical interface that is easily integrated into a PoCT device.The interface includes conductive silk fibroin-based immunoparticles (CSIPs) via electropolymerized Poly(3,4-ethylenedioxythiophene) (PEDOT) bridging to enable on-site electrochemical detection of serum amyloid-β42 (Aβ42) and -β40 (Aβ40) peptides from an AD blood test.In addition, micro-positron emission tomography (microPET) neuroimaging and behavioral tests were simultaneously performed.Results: This nanostructured conductive interface favors penetration of water-soluble biomolecules and catalyzes a redox reaction, providing limits of detection (LOD) of 6.63 pg/mL for Aβ40 and 3.74 pg/mL for Aβ42.Our proof-of-concept study confirms that the multi-sensing electrochemical immunosensor array (MEIA) platform enables simultaneous measurement of serum Aβ42 and Aβ40 peptide levels and is more informative in early stage AD animals than amyloid-labeling Aβ plaque PET imaging and behavioral tests. Conclusion:We believe this study greatly expands the applications of silk fibroin-based materials, is an important contribution to the advancement of biomaterials, and would also be valuable in the design of new types of multichannel electrochemical immunosensor arrays for the detection of other diseases.
Abstract 4334: Linked read whole genome sequencing reveals pervasive chromosomal level instability and novel rearrangements in brain metastases from colorectal cancer
Authors: Li C. Xia, John M. Bell, Christina Wood-Bouwens, Daniel A. King, GiWon Shin, Stephanie Greer, Ian D. Connolly, Melanie H. Gephart, Hanlee P. Ji
Journal: Cancer Research (2018)

Abstract Little is known about the genomic features of brain metastases from colorectal cancer (CRC) and the contributing genetic factors. We conducted an analysis of large-scale structural aberrations, including chromosome aneuploidies, with a method called linked-read whole genome sequencing and a new somatic rearrangement detection software tool (ZoomX) to better understand the genomic architecture of brain metastases from CRC. We resolved on average 145 distal inter- and intra-chromosomal somatic junctions per sample with their exact haplotype information and basepair level breakpoints. In addition, we used a new haplotyping method based on these imbalances to generate cancer chromosome haplotypes of up to 146 Mbp long. We identified extensive chromosomal-level instability (CIN) in these cancer genomes, with an average of 90 large-scale copy number aberrations per sample in sizes ranging from hundreds of Kbp to hundreds of Mbp. A substantial fraction of CIN is likely attributable to earlier chromothripsis events. For example, we identified multiple chromothripsis events disrupting the loci of known cancer genes such as TP53, an essential colon cancer driver. We identified novel rearrangements including an oncogenic gene fusion; e.g. SET/DPP10 among these metastatic samples. A majority of chromosome arms demonstrated an allelic imbalance across all of the samples. In summary, the analysis revealed pervasive chromosome-level genome instability as a potential contributor to devastating brain invasion by CRC. It also demonstrated the advantages of linked-read whole genome sequencing. This approach is cost-effective and represents a high-resolution tool to assess genome-wide rearrangements and to generate megabase-scale haplotypes. Citation Format: Li C. Xia, John M. Bell, Christina Wood-Bouwens, Daniel A. King, GiWon Shin, Stephanie Greer, Ian D. Connolly, Melanie H. Gephart, Hanlee P. Ji. Linked read whole genome sequencing reveals pervasive chromosomal level instability and novel rearrangements in brain metastases from colorectal 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 4334.
Opioids vs Nonopioids for Chronic Back, Hip, or Knee Pain
Authors: Marcelo E. Bigal
Journal: JAMA (2018)

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Abstract 19651: The Current Model for Recognition and Modification of Risk Factors for Atrial Fibrillation is Ineffective
Authors: Augustus Mealor, John Ferguson, Ken Bilchick, Will Camnitz, Andrew Darby, Michael Mangrum, Rohit Malhotra, Pamela Mason, Michele Murphu
Journal: Circulation (2016)

Introduction: There is growing data that successful modification of risk factors (RF) for atrial fibrillation (AF) can significantly improve the outcomes of AF therapies. These RFs include obesity,...
Abstract 4349: Higher level of tumor mutational burden and 11q13 amplification in Chinese hepatocellular carcinoma patients
Authors: Xiaofeng Tang, Le Fan, Gang Chen, Weidong Guo, Fabo Qiu, Jun Wang, Jun Guo, Lijuan Chen, Peng Zhang, Weiwei Shi, Kai Wang, Weifeng Wang
Journal: Cancer Research (2018)

Abstract Introduction: The approval of immune checkpoint inhibitor (ICPI) for hepatocellular cancer (HCC) has changed the landscape of HCC treatment, which is the second most common and lethal malignancy in China. Several genomic features associated with ICPI efficacy in various types of cancers has been reported as potential predictive biomarkers. The application of comprehensive genomic profiling (CGP) on HCC might be useful in identifying ICPI responders or avoiding adverse effect. Experimental procedure: Comprehensive genomic profiling of 107 advanced HCC was performed on the FFPE tumor samples and matched blood by using a 450-gene next generation sequencing assay. The cohort of HCC patients comprises 86 males (median age = 56) and 21 females (median age = 52) whose gender disparity is in the normal range of HCC epidemiological statistic study from Asia-Pacific region. The ICPI therapy related genomic alterations such as tumor mutational burden (TMB) and 11q13 amplification were subsequently analyzed. Result: CGP revealed signature genomic alterations in HCC as previously reported but with exceptional higher frequency of TP53 mutations at 66.3% of the pts and relatively low rate of TERT variants at 32.7%. Higher level of TMB high values (&amp;gt;20 muts/Mb) was found in a significantly larger portion of the Chinese HCC patients (N=10, 9.3%), compared to only 1% in Western population (p-value 1.5E-05). The median TMB of the Chinese HCC cohort was 7.2 muts/Mb. In addition, 11q13 amplifications (FGF3, FGF4, FGF19 and CCND1) were detected in 6.5% of the Chinese HCC patients, which was associated with ICPI hyper-progression in a variety of cancers. The 7 patients with 11q13 amplifications had a median age of 65 yrs (range 52-78) which is significantly higher than the median age of the rest cohort at 55 yrs (range 28-79, p=0.02). The median TMB was 8 muts/Mb. Conclusion: Our preliminary results found that TMB high values were more commonly detected in Chinese HCC patients compared to Western population. It may indicate that more Chinese HCC patients could benefit from ICPI treatments. However, the high incidence of 11q13 amplifications related to hyper-progression response in the same cohort was observed. Therefore, the application of comprehensive genomic profiling companion diagnosis might be necessary in guiding the regimen and ICPI treatments. Citation Format: Xiaofeng Tang, Le Fan, Gang Chen, Weidong Guo, Fabo Qiu, Jun Wang, Jun Guo, Lijuan Chen, Peng Zhang, Weiwei Shi, Kai Wang, Weifeng Wang. Higher level of tumor mutational burden and 11q13 amplification in Chinese hepatocellular carcinoma patients [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 4349.
Characterization of Atrioventricular Nodal Reentry With Continuous Atrioventricular Node Conduction Curve by Double Atrial Extrastimulation
Authors: Chi-TaiKuo, Kuo-HungLin, Nye-JanCheng, Po-HsienChu, Tsu-ShiuHsu, Cheng-WenChiang, Ying-ShiungLee
Journal: Circulation (1999)

Background—Characterization of typical atrioventricular nodal reentrant tachycardia (AVNRT) with continuous AVN conduction (A1A2/A2H2) curves by double atrial extrastimulation (A1A2A3) has never been systematically studied. Methods and Results—This study was composed of 33 patients with typical AVNRT and continuous AVN conduction curves (group 1) and 103 patients with AVNRT and discontinuous AVN conduction curves (group 2). Using A1A2A3 with predefined fast pathway–conducted A2, we examined the effects of slow pathway ablation on the A2A3/A3H3 curves in both groups. In group 1, anterograde AVN effective refractory period (272±33 versus 277±47 ms, P>0.05) and AVN Wenckebach block cycle length (320±45 versus 343±59 ms, P>0.05) remained unchanged after ablation. A2H2max was shorter in group 1 than group 2 (237±89 versus 395±72 ms, P 0.05) after ablation. A1A2A3 could fur...
Letter by Guettrot-Imbert et al Regarding Article, “Early Diagnosis and Treatment of Atrioventricular Block in the Fetus Exposed to Maternal Anti-SSA/Ro-SSB/La Antibodies”
Authors: GaëlleGuettrot-Imbert, NathalieCostedoat-Chalumeau, ZahirAmoura
Journal: Circulation (2009)