tbuckley/cabot-search huggingface dataset:
Abstract 4414: Radiation-induced miR-5094 expression inhibits cell proliferation by targeting STAT5b
Authors: Nan Ding, Junrui Hua, Jinpeng He, Wenjun Wei, Hailong Pei, Guangming Zhou, Jufang Wang, Altaf A. Wani, Qianzheng Zhu
Journal: Cancer Research (2018)

Abstract MicroRNAs (miRNAs) are highly conserved small non-coding RNAs that alter protein expression and regulate multiple intracellular processes including cellular stress response. We previously uncovered several novel miRNAs, whose expressions are induced by X-rays irradiation in HeLa cells, using a miRNA array. Here, we examined the function of miR-5094 during cellular radiation response. With software predictions and confirmatory experiments, we identified the signal transduction and activator of transcription 5b (STAT5b), a known regulator of proliferation and survival, as a target of miR-5094. The study also showed that both miR-5094 induction by X-rays irradiation and miR-5094 mimics transfection decreased STAT5b expression, down-regulated STAT5b downstream genes, and consequently, reduced the cell survival and cell viability. Knockdown of miR-5094 by miRNA inhibitor after radiation partially reversed these suppressive effects. As STAT5b plays an important role in lymphocyte proliferation, we further confirmed the proliferation inhibitory effects of miR-5094/STAT5b pathway on Jurkat cells and human peripheral blood CD4+ T cells during cell radiation response. In conclusion, our study provided the first evidence that radiation induces upregulation of miR-5094, which in turn inhibits cell proliferation via targeting STAT5b. Citation Format: Nan Ding, Junrui Hua, Jinpeng He, Wenjun Wei, Hailong Pei, Guangming Zhou, Jufang Wang, Altaf A. Wani, Qianzheng Zhu. Radiation-induced miR-5094 expression inhibits cell proliferation by targeting STAT5b [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 4414.
Acute Myocardial Infarction Caused by Extension of a Proximal Aortic Dissection Flap Into the Right Coronary Artery
Authors: Sang-HoonNa, Tae-JinYoun, Young-SeokCho, CheongLim, Woo-YoungChung, In-HoChae, Dong-JuChoi, Joong-HaengChoh
Journal: Circulation (2006)
Abstract P230: Vitamin E Supplementation and Cardiovascular Disease: Is There Effect Modification by Baseline Diet Quality and Vitamin E Intake?
Authors: Susanne Rautiainen, J. Michael Gaziano, William G Christen, Vadim Bubes, Gregory Kotler, Robert J Glynn, JoAnn E Manson, Julie E Buring, Howard D Sesso
Journal: Circulation (2018)

Background: Large-scale trials have not supported a role of vitamin E supplementation in reducing the risk of cardiovascular disease (CVD). We investigated whether baseline diet quality and vitamin E intake modified the effect of randomized vitamin E supplementation on the risk of CVD in the Physicians’ Health Study II (PHS II). Methods: The PHS II was a randomized, double-blind, placebo-controlled trial testing 400 IU synthetic α-tocopherol on alternate days. 14,641 men aged ≥50 years were included. 13,316 men (91%) completed a 116-item food frequency questionnaire and were included in our intention-to-treat analysis. We examined effect modification by baseline diet quality as assessed by dietary patterns (tertiles of the Alternate Healthy Eating Index [AHEI] and Alternate Mediterranean Diet [AMED]), and by dietary and supplemental vitamin E intake. Results: During a mean 8.0 years of follow-up, baseline diet quality or vitamin E intake did not modify the effect of vitamin E use on the primary endpoint of major CVD events ( Table ). However, AHEI modified the effect of randomized vitamin E use on the secondary endpoint of MI (P, interaction=0.02), with a statistically significant 39% lower risk among men in the lowest tertile of the AHEI. A similar and statistically significant 37% lower risk of MI was observed in the lowest category of the AMED (P, interaction=0.08). There was no evidence that diet quality modified the effect of vitamin E use on risks of stroke or CVD mortality, and baseline dietary and supplemental vitamin E intake did not modify the effects on any outcome. Conclusion: Diet quality did not modify the effect of vitamin E supplementation on most CVD outcomes but did modify its effect on MI. Given concerns about multiple comparisons and the need for replication, our findings should be interpreted with caution.
Abstract 3499: The mutational status of residue Y842 in FLT3 predicts the drug response in acute myeloid leukemia
Authors: Julhash U. Kazi, Lars Rönnstrand
Journal: Cancer Research (2018)

Abstract The type III receptor tyrosine kinase FLT3 plays important roles in the development of early hematopoietic progenitor cells and is found to be mutated in around 35% of all cases of acute myeloid leukemia (AML). AML is a heterogeneous disease that affects the myeloid lineage of blood cells. Wild-type FLT3 needs its ligand, FL, for signal transduction. However, the oncogenic mutants are constitutively active even in the absence of ligand. Similar to the other type III receptor tyrosine kinases, such as KIT, CSF1R, PDGFRA and PDGFRB, ligand binding to the FLT3 induces dimerization, activation of the receptor and auto-phosphorylation. Tyrosine phosphorylation sites in FLT3 create docking sites for interacting proteins which transduce signals linked to survival and proliferation, among other things. Although the most common mutations in FLT3 includes the internal tandem duplication (ITD) mutations in the juxtamembrane domain of FLT3, point mutations in the kinase domain also occur. The so-called activation loop tyrosine residue is well conserved in all receptor tyrosine kinases and has long been known to be essential for the activity of some but not all receptor tyrosine kinases. Recently we have shown that activation loop tyrosine residue in KIT is not essential for its activation but plays an important role in regulating receptor stability and downstream signaling. The activation loop tyrosine residue in FLT3 (Y842) has been found to be mutated in some AML patients and acquired mutations of this residue results in drug resistance when combined with FLT3-ITD. We observed that different Y842 mutants (Y-to-F, Y-to-C and Y-to-H) display differential binding affinity for kinase inhibitors. Expression of Y-to-F mutant in myeloid cells resulted in impaired activation of ERK1/2 through reduced recruitment of SHP2 to the receptor. Furthermore, mice xenografted with myeloid cells expressing this Y-to-F mutant of FLT3, in FLT3-ITD background, resulted in delayed tumor formation. Gene set enrichment analysis (GESA) demonstrated that the Y-to-F mutation causes suppression of anti-apoptotic genes. Taken together, our data suggest that the activation loop tyrosine residue in FLT3 plays an important role in FLT3 downstream signaling and drug sensitivity. Citation Format: Julhash U. Kazi, Lars Rönnstrand. The mutational status of residue Y842 in FLT3 predicts the drug response in acute myeloid leukemia [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 3499.
Enhancement of Monocyte Procoagulant Activity by Adhesion on Vascular Smooth Muscle Cells and Intercellular Adhesion Molecule-1–Transfected Chinese Hamster Ovary Cells
Authors: NikolausMarx, Franz-JosefNeumann, DietlindZohlnhöfer, TimmDickfeld, AlmuthFischer, SusanneHeimerl, AlbertSchömig
Journal: Circulation (1998)

Background—Plaque erosion is a frequent finding in sudden death due to coronary thrombosis. The present study sought to investigate whether monocyte adhesion to human aortic vascular smooth muscle cells (VSMCs) induces procoagulant activity (PCA) and whether this could be mediated by intercellular adhesion molecule-1 (ICAM-1). Methods and Results—We incubated mononuclear cells (MNCs) with VSMCs and ICAM-1–transfected Chinese hamster ovary (CHO) cells, investigated monocyte tissue factor (TF) mRNA expression by Northern blot analysis and TF protein expression by ELISA, and measured PCA. Incubation of MNCs with VSMCs for 6 hours increased PCA from 0.7±0.1 to 166.0±37.9 mU/105 cells (P=0.007), which could be inhibited in a dose-dependent manner by the addition of blocking anti–ICAM-1 monoclonal antibodies. Prestimulation of VSMCs with interleukin-1β enhanced surface ICAM-1 expression significantly but did not induce PCA in VSMCs. Incubation of MNCs with prestimulated VSMCs led to a further increase in PCA to...
MRI for degenerative meniscal lesions: cease and desist! A three-step action plan
Authors: Dylan Meng, Kieran O’Sullivan, Ben Darlow, Peter B O’Sullivan, Guri Ranum Ekås, Bruce B Forster
Journal: British Journal of Sports Medicine (2018)

An increasingly common clinical situation is a middle-aged to elderly patient presenting with knee pain with no major inciting event. Although many of these patients end up with a diagnosis of a degenerative meniscal lesion, meniscal lesions are equally prevalent in patients with or without knee pain1 and therefore offer a poor explanation for knee pain.

Meniscal lesions are often comorbid with other knee joint pathology which complicates investigating the underlying cause behind the patient’s symptoms.2 Despite this, MRI of the knee is frequently used to confirm the presence of meniscal lesions, attribute them as the cause of the patient’s knee pain and conclude that knee arthroscopic surgery is required.3 

Guidelines now recommend against arthroscopy for patients with degenerative knee conditions2 4 so the utility of MRI in this common clinical scenario is increasingly questionable, with the exception of those cases in which red flags such as sarcoma or infection are suspected. In a previous editorial,5 we discussed the negative effects of lumbar spine over-imaging, including additional cost, downstream testing, risks associated with …
Association of skin hyperpigmentation disorders with digital ulcers in systemic sclerosis: Analysis of a cohort of 239 patients
Authors: Vaianu Leroy, Pauline Henrot, Thomas Barnetche, Muriel Cario, Anne-Sophie Darrigade, Pauline Manicki, Marie-Sylvie Doutre, Estibaliz Lazaro, Joel Constans, Damien Barcat, Jean-Philippe Vernhes, Christophe Richez, Alain Taieb, Marie-Elise Truchetet, Julien Seneschal
Journal: Journal of the American Academy of Dermatology (2018)
Abstract 18980: Aortic Distensibility May Be Associated With the Characteristics of Coronary Atherosclerosis Plaque
Authors: Seung-Pyo Hong, Kyung-Ryun Bae, Seung-Woon Jun, Young-Soo Lee, Jin-Bae Lee, Jae-Kean Ryu, Ji-Yong Choi, Kee-Sik Kim, Sung-Gug Chang
Journal: Circulation (2013)

Purpose: Aortic distensibility (AD) has been shown to be inversely proportional to disease severity and presence of cardiovascular risk factors. MDCT can simultaneously characterize coronary and thoracic aortic atherosclerotic plaque morphology by delineating between calcified, mixed, non-calcified lesions. This study aimed to access relation between the characteristics of coronary plaque and AD in cardiac MDCT. Methods: The study was a retrospective analysis of the findings in 69 patients who performed cardiac MDCT for evaluation of chest pain symptoms. The 69 subjects was performed 64 channel cardiac MDCT and Scan data were reconstructed at 20 phases between 0% and 95% of the R-R intervals with an increment of 5%. Pixel-based measurements of arterial dimensions were performed at 1 cross-section of the descending aorta in a transverse plane at the aortic valve level. End diastole area was measured at 95% of R-R interval and end systolic area was measured at 35% of R-R interval. Aortic distensibility was calculated as follows: AD= (end systolic area - end diastolic area)/ (end diastolic area х pulse pressure). Coronary plaques in cardiac MDCT were categorized as calcified, mixed, or non-calcified. Results: Descending AD were lower in patients with any coronary plaque, calcified or mixed plaque than those without (mixed: p&lt;0.001, calcified: p=0.041) but not with non-calcified coronary plaque (p=0.497). In multivariate logistic regression analysis, descending AD (p = 0.011, HR 6.446) is independently associated with mixed coronary plaque after adjustment of age, sex, body mass index. The cutoff value of descending AD for prediction of mixed plaque in cardiac MDCT was 1.6 X 10 -3 mmHg with 69.2% of sensitivity and 69.2% of specificity (Fig). Conculsions: Descending AD may be associated with the mixed or calcified plaque in by MDCT. Especially, Descending AD might be associated with mixed coronary plaque.
Abstract 573: BRAF, KRAS, and NRAS mutations in archival tumor samples and samples of cell-free DNA from serum and bone marrow aspirates from patients with multiple myeloma
Authors: Filip Janku, Qian Li, Helen J. Huang, Yafei Wang, Zeng Cao, George Karlin-Neumann, Zhiqiang Liu
Journal: Cancer Research (2018)

Abstract Background: Oncogenic mutations in BRAF, KRAS and NRAS genes have been reported in multiple myeloma and can be explored as biomarkers for selection of targeted therapies. Methods: Unamplified DNA from archival tumor tissue samples and cell-free DNA (cfDNA) from serum and bone marrow aspirates from patients with multiple myeloma was tested for BRAF V600, KRAS G12/G13, NRAS G12/G13 and NRAS Q61 mutations using multiplex assays for droplet digital PCR (Bio-Rad). Agreement among methods was evaluated and results were compared to clinical outcomes. Results: Of 88 patients with multiple myeloma (stage I, 13 [15%]; stage II, 26 [30%]; stage III, 34 [39%]; stage unknown, 15 [17%]), 4 (5%) patients were found to have BRAF V600 mutation (all confirmed V600E), 15 (17%) KRAS G12/G13 mutation, 3 (3%) NRAS G12/G13 mutation and 16 (18%) NRAS Q61 mutation in archival tumor tissue. Most mutations were subclonal with a median variant allelic frequency (VAF) 1.55% (range, 0.13%-34%). Survival data were available for 47 patients and patients with high mutation VAF had a trend to shorter survival than patients with low mutation VAF (25.3 months vs. not reached, P=0.087). Of 88 patients, 22 (25%) had simultaneous serum cfDNA collection, which demonstrated BRAF V600 mutation in 7 (32%; 3 confirmed as V600E), KRAS G12/G13 mutation in 2 (9%), NRAS G12/G13 mutation in 0 (0%) and NRAS Q61 mutation in 4/22 (18%) of samples and median VAF was 2.9% (range, 0.34%-18.8%). Agreement rates for serum compared to tissue were 73% for BRAF V600, 95% for KRAS G12/G13, 100% for NRAS G12/G13 and 95% for NRAS Q61. In addition, 13 (15%) patients had simultaneous bone marrow aspirate cfDNA collection, which demonstrated BRAF V600 mutation in 1 (8%; confirmed as V600E), KRAS G12/G13 mutation in 0 (0%), NRAS G12/G13 mutation in 0 (0%) and NRAS Q61 mutation in 1 (8%) of samples. Agreement rates for bone marrow aspirates compared to tissue were 100% for BRAF V600, 92% for KRAS G12/G13, 100% for NRAS G12/G13 and 100% for NRAS Q61. Conclusion: Common oncogenic mutations in BRAF, KRAS and NRAS genes are prevalent with relatively low VAF in multiple myeloma and can be detected with sensitive techniques such as ddPCR. Their prognostic significance and therapeutic utility needs to be further investigated. Citation Format: Filip Janku, Qian Li, Helen J. Huang, Yafei Wang, Zeng Cao, George Karlin-Neumann, Zhiqiang Liu. BRAF, KRAS, and NRAS mutations in archival tumor samples and samples of cell-free DNA from serum and bone marrow aspirates from patients with multiple myeloma [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 573.
Abstract 5440: Role of tyrosine phosphorylation of β-catenin in EGFR-mutant lung cancer
Authors: Masanori Fujii, Sohei Nakayama, Kohei Shimizu, Hisashi Takei, Mariko Ando, Eunyoung Heo, ikei Kobayashi, Gilbert Pan, Hiroyuki Inuzuka, Susumu Kobayashi
Journal: Cancer Research (2018)

Abstract Wnt/ β-catenin signaling plays a key role in the pathogenesis of colon and other cancers. Emerging evidence indicates that oncogenic β-catenin regulates several biological processes essential for cancer initiation and progression. The role of β-catenin in lung cancer with epidermal growth factor receptor (EGFR) activating mutations has not been fully understood; however, recent studies suggest that co-occurring genetic alterations in CTNNB1 might cooperate with mutant EGFR in promoting tumor progression and treatment resistance to EGFR-tyrosine kinase inhibitors (EGFR-TKIs). This sheds new light on this pathway in EGFR-mutant lung cancer. We previously demonstrated that β-catenin plays an essential role in lung tumorigenesis driven by EGFR mutants, particularly EGFR-T790M. We also found that β-catenin is activated through tyrosine-phosphorylation by EGFR mutants. In this study, we identified five tyrosine phosphorylation sites (Y5) of β-catenin by mass spectrometry. Tyrosine phosphorylation at these sites may be critical in β-catenin stability, nuclear translocation and its role as a transcriptional switch in oncogenesis. Firstly, we demonstrated that tyrosine phosphorylation of β-catenin disrupts the binding of a main ubiquitin ligase β-Trcp1, leading to an escape from degradation. Secondly, in contrast to known transcriptional activity with TCF/LEF, β-catenin that is tyrosine phosphorylated by mutant EGFR was found to form a complex with a transcriptional regulator, YAP1, and a transcriptional factor, TBX5. Immunoprecipitation experiments suggested Y5 tyrosine phosphorylation of β-catenin plays a critical role in the interaction between β-catenin and TBX5. Moreover, this complex may regulate anti-apoptotic genes, including BCL2L1, which encodes Bcl-xL. Combination treatment with osimertinib, a 3rd generation EGFR-TKI, and dasatinib suppressed Y5 tyrosine phosphorylation of β-catenin, leading to reduced Bcl-xL expression. Subsequent TBX5 knockdown in vitro decreased Bcl-xL expression while Bcl2l1 knockout in vivo mouse models suppressed lung tumor development. These observations suggest that β-catenin-YAP1-TBX5 complex contributes to EGFR-T790M lung cancer and may serve to explain the underlying mechanism for EGFR-TKIs resistance and for the effectiveness of combination therapy with osimertinib and dasatinib. Citation Format: Masanori Fujii, Sohei Nakayama, Kohei Shimizu, Hisashi Takei, Mariko Ando, Eunyoung Heo, ikei Kobayashi, Gilbert Pan, Hiroyuki Inuzuka, Susumu Kobayashi. Role of tyrosine phosphorylation of β-catenin in EGFR-mutant lung 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 5440.
Disruption of Bardet-Biedl syndrome ciliary proteins perturbs planar cell polarity in vertebrates
Authors: Alison J Ross, Helen May-Simera, Erica R Eichers, Masatake Kai, Josephine Hill, Daniel J Jagger, Carmen C Leitch, J Paul Chapple, Peter M Munro, Shannon Fisher, Perciliz L Tan, Helen M Phillips, Michel R Leroux, Deborah J Henderson, Jennifer N Murdoch, Andrew J Copp, Marie-Madeleine Eliot, James R Lupski, David T Kemp, Hélène Dollfus, Masazumi Tada, Nicholas Katsanis, Andrew Forge, Philip L Beales
Journal: Nature Genetics (2005)
Muscle Sympathetic Nerve Activity Averaged Over 1 Minute Parallels Renal and Cardiac Sympathetic Nerve Activity in Response to a Forced Baroreceptor Pressure Change
Authors: AtsunoriKamiya, ToruKawada, KentaYamamoto, DaisakuMichikami, HidetoAriumi, TadayoshiMiyamoto, KazunoriUemura, MasaruSugimachi, KenjiSunagawa
Journal: Circulation (2005)

Background— Despite the accumulated knowledge of human muscle sympathetic nerve activity (SNA) as measured by microneurography, whether muscle SNA parallels renal and cardiac SNAs remains unknown. Method and Results— In experiment 1, muscle (microneurography, tibial nerve), renal, and cardiac SNAs were recorded in anesthetized rabbits (n=6) while arterial pressure was changed by intravenous bolus injections of nitroprusside (3 μg/kg) followed by phenylephrine (3 μg/kg). In experiment 2, the carotid sinus region was vascularly isolated in anesthetized, vagotomized, and aorta-denervated rabbits (n=10). The 3 SNAs were recorded while intracarotid sinus pressure was increased stepwise from 40 to 160 mm Hg in 20-mm Hg increments maintained for 60 seconds each. Muscle SNA averaged over 1 minute was well correlated with renal (r=0.96±0.01, mean±SE) and cardiac (r=0.96±0.01) SNAs in experiment 1 (baroreflex closed-loop condition) and also with renal (r=0.97±0.01) and cardiac (r=0.97±0.01) SNAs in experiment 2 (ba...
Function of Potential Bypass Tracts for Atrioventricular Conduction
Authors: Toyomisano, Fumiosuzuki, Hiromichitsuchihashi
Journal: Circulation (1970)

Function of potential bypass tracts for the atrioventricular conduction was examined in isolated rabbit hearts using microelectrodes, a suction electrode, and bipolar electrocardiographic leads. After the normal A-V conduction was blocked by acetylcholine, conduction to the ventricle occurred with a much shorter A-V conduction time and without significant QRS change, when a point at the root of the inferior vena cava was stimulated. By analyzing the site of delay, this route was presumed to go from the right atrium to the lower portion of the His bundle bypassing the A-V node. When a point inferior to this point was stimulated, marked shortening of conduction time and marked QRS change occurred. This second tract seemed to exist between the right atrium and ventricle bypassing the specialized system. The third tract was found when an anterior point on the right atrium was stimulated. The conduction was markedly prolonged without changing the QRS. This route seemed to enter some point of the A-V node, indu...
Infections, Immunity, and Atherosclerosis
Authors: ManuelMayr, StefanKiechl, JohannWilleit, GeorgWick, QingboXu
Journal: Circulation (2000)

Background—Atherogenesis involves inflammatory processes in which infections are incriminated as possible contributors. Methods and Results—We evaluated cardiovascular risk factors as well as seropositivity to Chlamydia pneumoniae, Helicobacter pylori, and cytomegalovirus in a population-based study. A significant association between prevalence and severity of atherosclerosis in carotid and femoral arteries and IgA antibodies to C pneumoniae was demonstrated that was not substantially altered after adjustment for established risk factors. For anti–H pylori IgG antibodies, significant correlations to vascular disease were restricted to low social status and lesions in carotid arteries. In addition, the study design allowed us to monitor lesion progression over time. In this prospective analysis, C pneumoniae seropositivity emerged as a significant risk predictor. Antibody titers against cytomegalovirus were not a marker for prevalence or incidence of atherosclerosis in this population. Further infection pa...