tbuckley/cabot-search huggingface dataset:
Protein Kinase N Promotes Stress-Induced Cardiac Dysfunction Through Phosphorylation of Myocardin-Related Transcription Factor A and Disruption of Its Interaction With Actin
Authors: Teruhiro Sakaguchi, Mikito Takefuji, Nina Wettschureck, Tomonari Hamaguchi, Mutsuki Amano, Katsuhiro Kato, Takuma Tsuda, Shunsuke Eguchi, Sohta Ishihama, Yu Mori, Yoshimitsu Yura, Tatsuya Yoshida, Kazumasa Unno, Takahiro Okumura, Hideki Ishii, Yuuki Shimizu, Yasuko K. Bando, Koji Ohashi, Noriyuki Ouchi, Atsushi Enomoto, Stefan Offermanns, Kozo Kaibuchi, Toyoaki Murohara
Journal: Circulation (2019)

Heart failure is a complex syndrome that results from structural or functional impairment of ventricular filling or blood ejection. Protein phosphorylation is a major and essential intracellular mechanism that mediates various cellular processes in cardiomyocytes in response to extracellular and intracellular signals. The RHOA-associated protein kinase (ROCK/Rho-kinase), an effector regulated by the small GTPase RHOA, causes pathological phosphorylation of proteins, resulting in cardiovascular diseases. RHOA also activates protein kinase N (PKN); however, the role of PKN in cardiovascular diseases remains unclear.To explore the role of PKNs in heart failure, we generated tamoxifen-inducible, cardiomyocyte-specific PKN1- and PKN2-knockout mice by intercrossing the αMHC-CreERT2 line with Pkn1flox/flox and Pkn2flox/flox mice and applied a mouse model of transverse aortic constriction- and angiotensin II-induced heart failure. To identify a novel substrate of PKNs, we incubated GST-tagged myocardin-related transcription factor A (MRTFA) with recombinant GST-PKN-catalytic domain or GST-ROCK-catalytic domain in the presence of radiolabeled ATP and detected radioactive GST-MRTFA as phosphorylated MRTFA.We demonstrated that RHOA activates 2 members of the PKN family of proteins, PKN1 and PKN2, in cardiomyocytes of mice with cardiac dysfunction. Cardiomyocyte-specific deletion of the genes encoding Pkn1 and Pkn2 (cmc-PKN1/2 DKO) did not affect basal heart function but protected mice from pressure overload- and angiotensin II-induced cardiac dysfunction. Furthermore, we identified MRTFA as a novel substrate of PKN1 and PKN2 and found that MRTFA phosphorylation by PKN was considerably more effective than that by ROCK in vitro. We confirmed that endogenous MRTFA phosphorylation in the heart was induced by pressure overload- and angiotensin II-induced cardiac dysfunction in wild-type mice, whereas cmc-PKN1/2 DKO mice suppressed transverse aortic constriction- and angiotensin II-induced phosphorylation of MRTFA. Although RHOA-mediated actin polymerization accelerated MRTFA-induced gene transcription, PKN1 and PKN2 inhibited the interaction of MRTFA with globular actin by phosphorylating MRTFA, causing increased serum response factor-mediated expression of cardiac hypertrophy- and fibrosis-associated genes.Our results indicate that PKN1 and PKN2 activation causes cardiac dysfunction and is involved in the transition to heart failure, thus providing unique targets for therapeutic intervention for heart failure.
Phase I Study of An Investigational Aurora A Kinase Inhibitor MLN8237 In Patients with Advanced Hematologic Malignancies.
Authors: Swaminathan Padmanabhan, Thomas C. Shea, Julie M. Vose, Craig B. Reeder, Jesus G Berdeja, Kevin T. McDonagh, Andre Goy, Kevin R Kelly, Xiaofei Zhou, Hua Liu, Howard Fingert, Nathan Fowler
Journal: Blood (2010)
SAT0713-HPR DYNAMIC JOINT STABILITY MEASURED AS GAIT SYMMETRY IN PEOPLE WITH SYMPTOMATIC KNEE OSTEOARTHRITIS
Authors: Emma Haglund, Anita Sant’anna, Maria Andersson, Ann Bremander, Katarina Aili
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Modern strategies for knee osteoarthritis (OA) treatment and prevention includes early detection and analyses about pain, gait and lower extremity muscle function including both strength and stability. The very first sign of knee OA is pain or perceived knee instability, often experienced during weight bearing activities e.g. walking. Increased muscle strength will provide dynamic joint stability, reduce pain, and disability. Specific measures of gait symmetry (GS) can be assessed objectively by using accelerometers, which potentially is a feasible method when evaluating early symptoms of symptomatic knee OA. <h3>Objectives:</h3> The aim was to study if symptoms of early knee pain affected gait symmetry, and the association between lower extremity muscles function and gait symmetry in patients with symptomatic knee OA. <h3>Methods:</h3> Thirty-five participants (mean age 52 SD 9 years, 66% women) with uni- or bilateral symptomatic knee OA, and without signs of an inflammatory rheumatic disease or knee trauma were included. Pain was assessed by a numeric rating scale (NRS, range 0-10 best to worse), tests of lower extremity muscle function with the maximum number of one leg rises. Dynamic stability was measured as GS by using wearable inertial sensors (PXNordic senseneering platform), during the 6 min walking test to obtain spatio-temporal gait parameters. GS was computed based on stride time (temporal symmetry, TS) and stride length (spatial symmetry, SS). Stride length was normalized by height. Kruskal-Wallis and Spearman's correlation coefficient were used for analyses. <h3>Results:</h3> Reports of knee pain did not differ between gender (women 4.7, SD 2.4 vs. men 3.9, SD 2.4, p= 0.362), neither did one leg rises or gait symmetry. Participants who reported unilateral knee pain (left/right side n=9/13), had a shorter stride length on the painful side. The mean difference in stride length was 0.7% of the subject's height (SD 1.3). Participants with unilateral pain also presented less SS gait than those who reported bilateral pain (p=0.005). The higher number of one-leg rises performed, the better TS was observed. We found a significant relationship between TS and one-leg rise for the right r<sub>s</sub>=-0.39, p=0.006, and left r<sub>s</sub>=-0.40, p=0.004 left side). No significant relationship was observed between SS and one-leg rises. <h3>Conclusion:</h3> Our results is in line with earlier findings stating that knee pain affects GS negatively and that lower extremity muscle function is an important feature for symmetry and dynamic joint stability in patients with symptomatic knee OA. We also found that pain in one leg was related to impaired GS. Bilateral knee pain was however more symmetrical and will need healthy controls for comparison to better understand the negative impact of symptomatic knee OA. <h3> Disclosure of Interests:</h3> None declared
Detection of microRNAs as biomarker for anti-EGFR antibody resistance in colon cancer patients
Authors: J.C. Hahne, A. Lampis, M. Ghidini, M. Ratti, M. Salati, C. Senti, R. Passalacqua, L. Cascione, C. Braconi, O.J. Sansom, M. Fassan, N. Valeri
Journal: Annals of Oncology (2019)
The molecular bases of delta/alpha beta T cell-mediated antigen recognition
Authors: D.G. Pellicci, A.P. Uldrich, J. Le Nours, F. Ross, E. Chabrol, S.B.G. Eckle, R. de Boer, R.T. Lim, K. McPherson, G. Besra, A.R. Howell, L. Moretta, J. McCluskey, M.H.M. Heemskerk, S. Gras, J. Rossjohn, D.I. Godfrey
Journal: The Journal of Experimental Medicine (2014)

αβ and γδ T cells are disparate T cell lineages that can respond to distinct antigens (Ags) via the use of the αβ and γδ T cell Ag receptors (TCRs), respectively. Here we characterize a population of human T cells, which we term δ/αβ T cells, expressing TCRs comprised of a TCR-δ variable gene (Vδ1) fused to joining α and constant α domains, paired with an array of TCR-β chains. We demonstrate that these cells, which represent ∼50% of all Vδ1(+) human T cells, can recognize peptide- and lipid-based Ags presented by human leukocyte antigen (HLA) and CD1d, respectively. Similar to type I natural killer T (NKT) cells, CD1d-lipid Ag-reactive δ/αβ T cells recognized α-galactosylceramide (α-GalCer); however, their fine specificity for other lipid Ags presented by CD1d, such as α-glucosylceramide, was distinct from type I NKT cells. Thus, δ/αβTCRs contribute new patterns of Ag specificity to the human immune system. Furthermore, we provide the molecular bases of how δ/αβTCRs bind to their targets, with the Vδ1-encoded region providing a major contribution to δ/αβTCR binding. Our findings highlight how components from αβ and γδTCR gene loci can recombine to confer Ag specificity, thus expanding our understanding of T cell biology and TCR diversity.
"M3-M6" Molecular Response Evolution As Early Predictor of Outcome Considering Generic Vs Branded TKIs for Chronic Myeloid Leukemia (CML): An Argentine Multicentric Study
Authors: Isabel Amanda Giere, María Jose Mela Osorio, Federico Andrés Klosowski, Mariana Debus, Federico Sackmann, Miguel A Pavlovsky, Isolda Fernandez, Elena Beatriz Moiraghi, Ana Inés Varela, Mariel Ana Perez, Julio M. Pose Cabarcos, Georgina Bendek, Romina Mariano, Silvina Palmer, Alicia Enrico, Isabel Cristina Annetta, Andres L. Brodsky, Dante Intile, Carolina Pavlovsky
Journal: Blood (2016)
Abstract P245: Amount and Frequency of Alcohol Consumption and the Risk of Incident Pulmonary Embolism in the Nurses’ Health Study
Authors: Laura B Harrington, Marta Crous-Bou, Jae H Kang, Sara Lindström, Kenneth J Mukamal, Eric B Rimm, Christopher Kabrhel, Majken K Jensen
Journal: Circulation (2017)

Introduction: Moderate alcohol consumption has been associated with differences in hemostatic factor levels that may lead to a lower thrombotic risk, but the association between alcohol consumption and the risk of incident pulmonary embolism (PE) has been inconsistent. Hypotheses: Moderate alcohol consumption is associated with a lower PE risk than lower or higher quantities, and more frequent alcohol consumption is associated with a lower PE risk than less frequent alcohol consumption. Methods: Nurses’ Health Study participants free of venous thromboembolism in 1984 (n=79,914) reported alcohol consumption every two-four years between 1984 and 2012 and number of drinking days per week on five questionnaires between 1986 and 2004. PE were initially identified by self-report and were confirmed for the subset of patients without a previous cancer using a combination of medical record review and participant reconfirmation. Cox Proportional Hazards models estimated multivariable-adjusted hazard ratios for PE associated with average amount of alcohol consumed and, separately, drinking days per week. Secondary analyses estimated the risk of medical-record confirmed idiopathic PE, events which were not associated with surgery, trauma, or cancer. Results: We identified 1,112 total incident PE events, including 360 idiopathic PE events, during 28 years of follow-up. In multivariable-adjusted analyses, we found no strong evidence of an association between the amount of alcohol consumed per day and the risk of any PE (quadratic p-trend=0.3) or idiopathic PE (quadratic p-trend=0.4) or between the frequency of alcohol consumption and the risk of any PE (linear p-trend=0.5) or idiopathic PE (linear p-trend=0.8) (Table). Conclusions: Among this population of women with relatively low average amounts of alcohol consumption, we found no substantial evidence of an association between the amount or frequency of alcohol consumption and the risk of PE.
Factors associated with disease progression in patients treated with trametinib in combination with dabrafenib for unresectable advanced BRAFV600-mutant melanoma: An open label, non randomized study
Authors: P. Saiag, C. Robert, J.J. Grob, L. Mortier, O. Dereure, C. Lebbe, S. Mansard, F. Grange, E.-M. Neidhardt, T. Lesimple, L. Machet, C. Bedane, H. Maillard, S. Dalac-Rat, C. Nardin, A. Szenik, A. Denden, C. Dutriaux
Journal: Annals of Oncology (2019)
Primary analysis results of randomized controlled trial evaluating reactive topical corticosteroid strategies for the facial acneiform rash by EGFR inhibitors (EGFRIs) in patients (pts) with RAS wild-type (wt) metastatic colorectal cancer (mCRC): FAEISS study
Authors: N. Yamazaki, K. Kikuchi, K. Nozawa, H. Fukuda, T. Shibata, T. Hamaguchi, A. Takashima, H. Shoji, N. Boku, S. Takatsuka, T. Takenouchi, T. Nishina, K. Hino, S. Yoshikawa, K. Yamazaki, M. Takahashi, A. Hasegawa, H. Bando, T. Masuishi, Y. Kiyohara
Journal: Annals of Oncology (2019)
The effects of progressive muscle relaxation and mindfulness meditation on fatigue, coping styles, and quality of life in breast cancer patients receiving adjuvant paclitaxel regimen: An assessor blinded, three-arm randomized controlled trial
Authors: Z. Gok Metin, N. Izgu, C. Karadas, L. Ozdemir, U. Demirci
Journal: Annals of Oncology (2019)
Abstract 15939: Development of a Drug-specific Long QT-JT Index for Prediction of Drug-induced QT Prolongation
Authors: Lauren E Steffen, Calvin H Knowlton, Jacques Turgeon
Journal: Circulation (2016)

Drug-induced Long QT Syndrome (LQTS) is a potential side effect of over 120 medications and is responsible for at least six medications being withdrawn by the FDA since 1997. Drug-induced LQTS may predispose patients to a potentially lethal polymorphic ventricular tachycardia, namely torsade de pointes (TdP). Current models for estimation of drug-induced LQTS risk are mostly based on their propensity and potency for block of the rapid component of the delayed rectifier (IKr/hERG). We assessed the hypothesis that a comprehensive index taking into account a medication’s molecular and metabolic properties would give an accurate depiction of clinical risk. In order to do so, we have developed a quantitative drug index taking into account IC50 for block of IKr (hERG), block of IKs (KvLQT1), block of ICa (Cav1.2), block of INa (Nav1.5), percent protein binding, Cmax at a test dose, maximum daily dose, inhibition of hERG trafficking (phosphorylation), and a drug-drug interaction coefficient (DDIC) allowing calcu...
Integration of genomic and proteomic data to identify MYCN-regulated genes, proteins, and interaction networks in neuroblastoma cells.
Authors: Kolbrun Kristjansdottir, Kelly M. Bontempo, Kelly E. Regan, Saira Khan, Samuel Louis Volchenboum
Journal: Journal of Clinical Oncology (2012)

9584 Background: Neuroblastoma is the most common extracranial solid tumor found in children. The most common marker prognostic of poor outcome is amplification of the MYCN oncogene, yet the biological programs by which MYCN affects its aggressive phenotype are largely unknown. In order to identify biological pathways affected by MYCN amplification, we performed global analysis of genes and proteins in the Tet 21/N neuroblastoma cell line. Methods: MYCN expression in Tet21/N cells is regulated by tetracycline. Gene arrays were performed on MYCN-high and MYCN-low Tet21/N cells and SH-EP parental cells using Affymetrix GeneChip Human Exon 1.0 ST. For proteomic analysis, the cells were labeled with stable isotopes for relative quantitation, enriched for phosphoproteins to enhance detection of signaling proteins, and analyzed by GeLC-MS/MS analysis. Integrative pathway analysis was performed on the genomic and proteomic datasets using DAVE and GeneGo. Results: Integrating genomic and proteomic data in MYCN-high and MYCN-low expressing cells identified 88 proteins and 300 genes that change in abundance. We compare these results with previous studies and find both novel and previously identified genes and proteins. Integrating proteomic and genomic data identified over 50 gene products that are present in both analyses and are altered in abundance in response to modulating MYCN expression. The majority of these have discordant abundance changes, with protein levels more frequently altered with no change in gene expression. We have validated changes in protein levels using Western blots including NPM1 and MATR3. We present interaction networks and pathways that correlate with MYCN expression. Conclusions: We showed a significant discordance between gene and protein expression, underscoring the need for integrative genomic and proteomic analysis to describe complex systems. Our analysis identified previously reported and novel genes and proteins and networks regulated by MYCN expression that may provide new insights into the biology of MYCN-amplified tumors.
Leuprorelin (LEUP) combined with Letrozole (LET) with/without everolimus (EVE) in ovarian suppressed premenopausal women with hormone receptor (HR) positive, HER2-negative metastatic breast cancer (MBC): Primary analysis of LEO Trial (NCT02344550)
Authors: J. Jeong, J.E. Kim, J.-H. Ahn, K.H. Jung, S.-J. Koh, J. Cheon, J. Sohn, G.M. Kim, K.S. Lee, I.H. Park, S.H. Sim, S.-B. Kim
Journal: Annals of Oncology (2019)
Mechanism for γ-Globin Induction by SCF Is Via PKCα/ERK1/2/Nrf2 Dependent Signal Pathway To Regulate Down-Stream Transcriptional Regulators NF-Y and COUP-TFII.
Authors: Wulin Aerbajinai, Jianqiong Zhu, Peter Gao, Kyung Chin, Griffin P. Rodgers
Journal: Blood (2007)
Accessibility and affordability to trastuzumab for breast cancer patients: Voices of the global oncology community from ONCOLLEGE 001 survey, part 2
Authors: S.C. Altuna, D. Trapani, C. Lengyel, B. Habeeb, S. Hussain, S. Mazher, E. Elfaham, A. Petrillo, K. El Bairi, S.Z. Khan
Journal: Annals of Oncology (2019)
Nanoparticle Doped PEDOT for Enhanced Electrode Coatings and Drug Delivery
Authors: Kevin M. Woeppel, Xin Sally Zheng, Zachary M. Schulte, Nathaniel L. Rosi, Xinyan Tracy Cui
Journal: Advanced Healthcare Materials (2019)

Abstract In order to address material limitations of biologically interfacing electrodes, modified silica nanoparticles are utilized as dopants for conducting polymers. Silica precursors are selected to form a thiol modified particle (TNP), following which the particles are oxidized to sulfonate modified nanoparticles (SNPs). The selective inclusion of hexadecyl trimethylammonium bromide allows for synthesis of both porous and nonporous SNPs. Nonporous nanoparticle doped polyethylenedioxythiophene (PEDOT) films possess low interfacial impedance, high charge injection (4.8 mC cm −2 ), and improved stability under stimulation compared to PEDOT/poly(styrenesulfonate). Porous SNP dopants can serve as drug reservoirs and greatly enhance the capability of conducting polymer‐based, electrically controlled drug release technology. Using the SNP dopants, drug loading and release is increased up to 16.8 times, in addition to greatly expanding the range of drug candidates to include both cationic and electroactive compounds, all while maintaining their bioactivity. Finally, the PEDOT/SNP composite is capable of precisely modulating neural activity in vivo by timed release of a glutamate receptor antagonist from coated microelectrode sites. Together, this work demonstrates the feasibility and potential of doping conducting polymers with engineered nanoparticles, creating countless options to produce composite materials for enhanced electrical stimulation, neural recording, chemical sensing, and on demand drug delivery.
Detection of ultra rare somatic mutations in the p53 gene by Bi-PAP-A, a tool for detection of minimal residual disease in solid tumors
Authors: Steve S. Sommer, Jinxiu Shi, Qiang Liu
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

4206 

Ultra selective detection of somatic mutations can facilitate: i) early cancer detection; ii) monitoring of cancer chemotherapy; and iii) assessment of environmental mutagen exposure. Bi-PAP-A (Bi-directional Pyrophosphorolysis Activated Polymerization Allele-specific Amplification) can detect mutations at 1 part per billion of the wild type. The selectivity of Bi-PAP-A derives from the serial coupling of pyrophosporolysis and DNA polymerization. Bi-PAP-A assays were developed for detection of rare cancer cells in the blood. After removal of a tumor, recurrence can be monitored by following the frequency over time in blood of any point somatic mutation found within the tumor. Bi-PAP-A assays were developed for eight somatic mutations in the p53 gene. Four of them were hotspots of mutation in tumors. The selectivity of each assay was tested using mutated and wild type human genomic DNA extracted from blood samples. The Bi-PAP-A assays detected one to two molecules of mutated template in 10exp6 to 10exp8 copies of the wild type, except for C:G-T:A transitions in which the specificity was 10exp5, presumably because of deamination of C to U during the sample preparation and amplification. Inter-individual variation in somatic mutation frequency is dramatic which may have implications for human carcinogensis. Bi-PAP-A is a convenient and general method that has the desirable properties of allele-specific PCR with enhancement of selectivity by a million fold.
Global and sex-specific epigenome-wide association studies for the identification of the main methylated loci related to smoking in a mediterranean population
Authors: J.B. Ramirez Sabio, O. Coltell, E.M. Asensio, C. Ortega-Azorín, O. Portoles, I. Gonzalez-Monje, D. Corella, J.V. Sorlí
Journal: Annals of Oncology (2019)
Nanotechnology: A reality for diagnosis of HCV infectious disease
Authors: Sonia Arca-Lafuente, Paula Martínez-Román, Irene Mate-Cano, Ricardo Madrid, Verónica Briz
Journal: Journal of Infection (2019)

Hepatitis C virus (HCV) is the primary etiologic agent of liver cirrhosis or hepatocellular carcinoma. HCV elevated infection rates are mostly due to the lack of an accurate and accessible screening and diagnosis, especially in low- and middle-income countries. Conventional HCV diagnostic algorithm consists of a serological test followed by a nucleic acid test. This sequence of tests is time consuming and not affordable for low-resource settings. Nanotechnology have introduced new promising tests for the diagnose of infectious diseases. Based on the employment of nanoparticles and other nanomaterials which lead to highly sensitive and specific nanoscale tests, most of them target pathogen genome. Implementation of nanoscale tests, which are affordable, portable and easy to use by non-specialized personal, would improve HCV diagnosis algorithm. In this review, we have summed up the current emerging nanotechnology tools, which will improve actual screening and treatment programs, and help to reach HCV elimination proposal.
Bioremediation of a Common Product of Food Processing by a Human Gut Bacterium
Authors: Ashley R. Wolf, Darryl A. Wesener, Jiye Cheng, Alexandra N. Houston-Ludlam, Zachary W. Beller, Matthew C. Hibberd, Richard J. Giannone, Samantha L. Peters, Robert L. Hettich, Semen A. Leyn, Dmitry A. Rodionov, Andrei L. Osterman, Jeffrey I. Gordon
Journal: Cell Host & Microbe (2019)
Enhanced access to EGFR molecular testing in NSCLC using a cell-free DNA tube for liquid biopsy
Authors: T.E. May, S.A. Scudder, S.J. Joshi, M. Kohlmann, N. Shrestha, N. Lee, J.A. Højbjerg, J. Lai, A.T. Madsen, M.S. Clement, P. Meldgaard, M. Tsourounis, B. Sørensen, A. Kohlmann, P. O’Donnell, H. Halait
Journal: Annals of Oncology (2019)
Overall and progression-free survival according to MSKCC scores in 1st line sunitinib treatment of metastatic renal cell carcinoma (mRCC)
Authors: J. Finek, A. Poprach, B. Melichar, J. Kopecky, M. Zemanova, T. Buchler, K. Kopeckova, T. Mlcoch, T. Dolezal, O. Fiala
Journal: Annals of Oncology (2019)
Predicting chemotherapy toxicity in elderly patients with advanced non-small cell lung cancer: A prospective multicenter study of the National Hospital Organization in Japan
Authors: M. Kanazu, M. Shimokawa, R. Saito, M. Mori, A. Tamura, Y. Okano, Y. Fujita, T. Endo, M. Motegi, S. Takata, T. Kita, N. Sukoh, M. Takenoyama, S. Atagi
Journal: Annals of Oncology (2019)