tbuckley/cabot-search huggingface dataset:
Frequent Epigenetic Inactivation of <i>Spleen Tyrosine Kinase</i> Gene in Human Hepatocellular Carcinoma
Authors: Yunfei Yuan, Jianping Wang, Jinqing Li, Li Wang, Meixiang Li, Zuli Yang, Changqing Zhang, Jia Le Dai
Journal: Clinical Cancer Research (2006)

Abstract Purpose: The aim of present study was to investigate the methylation and expression status of spleen tyrosine kinase (SYK) in human hepatocellular carcinoma (HCC) and to evaluate this information for its ability to predict disease prognosis. E-cadherin and TIMP-3 methylation was also analyzed here as control because both were associated with poor prognosis in some types of tumors. Experimental Design: We analyzed the methylation status of SYK, E-cadherin, and TIMP-3 in 124 cases of HCC and assessed the correlation of such methylations with clinicopathologic variables and prognosis after tumor resection. Results: We found that SYK, E-cadherin, and TIMP-3 genes were methylated in 27%, 27%, and 42% of HCC neoplastic tissues, respectively. The loss of SYK mRNA or Syk protein expression was highly correlated with SYK gene methylation. The patients with methylated SYK in neoplastic tissues had a significantly lower overall survival rate after hepatectomy than those with unmethylated SYK. No significant difference in overall survival rates, however, was found between groups of patients with methylated and unmethylated E-cadherin or TIMP-3. Patients with negative Syk protein expression had a significantly lower overall survival rate than those with positive Syk protein expression. Multivariate analyses indicated that factors affecting overall survival were tumor-node-metastasis stage, Child-Pugh classification, SYK methylation, or Syk protein status. Conclusions: Our results indicate that SYK methylation and loss of Syk expression in HCC neoplastic tissues are independent biomarkers of poor patient outcome and that determination of SYK methylation or Syk expression status may offer guidance for selecting appropriate treatments.
Blood dendritic cells in systemic lupus erythematosus exhibit altered activation state and chemokine receptor function
Authors: V. Gerl, A. Lischka, D. Panne, P. Grossmann, R. Berthold, B. F. Hoyer, R. Biesen, A. Bruns, T. Alexander, A. Jacobi, T. Dorner, G.-R. Burmester, A. Radbruch, F. Hiepe
Journal: Annals of the Rheumatic Diseases (2009)

<h3>Background</h3> Dendritic cells (DCs) have a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE). Reduced numbers of blood DCs and the accumulation of DCs at inflammatory sites have been observed in SLE. One crucial feature of DCs is their ability to migrate. <h3>Objective</h3> To analyse the maturation/activation state and the migratory capacity of different DC precursor subsets in SLE to further elucidate their role in autoimmunity. <h3>Methods</h3> Plasmacytoid DCs (pDCs), myeloid DCs (mDCs) and monocytes from patients with SLE, healthy volunteers and healthy volunteers immunised with tetanus/diphtheria were examined by flow cytometry for expression of subset-specific antigens (BDCA-2, CD11c, CD14, HLA-DR), activation/maturation markers (CD83, CD86, CD40, BLyS) and chemokine receptors (CCR1, CCR5, CCR7, ChemR23). Additionally, migratory capacity to chemokine receptors was investigated in vitro using the chemokines RANTES, CCL19 and chemerin. <h3>Results</h3> SLE monocytes and mDCs had higher CD86 and B-lymphocyte stimulatory factor (BLyS) expression levels. ChemR23 expression was lower in SLE pDCs and mDCs. Basal and CCL19-specific migration levels were higher in SLE pDCs. Altered DC function in SLE had no correlative changes in chemokine receptor expression, whereas immunisation-induced blood DC migration patterns in healthy donors were accompanied by changes in chemokine receptor expression. <h3>Conclusions</h3> The phenotypic and migratory disturbances observed in SLE blood DCs could result in altered distribution of DCs in peripheral tissues, contributing to dysregulated immune responses and autoimmunity.
Frequency-Dependent Breakdown of Wave Propagation Into Fibrillatory Conduction Across the Pectinate Muscle Network in the Isolated Sheep Right Atrium
Authors: Omer Berenfeld, Alexey V. Zaitsev, Sergey F. Mironov, Arkady M. Pertsov, José Jalife
Journal: Circulation Research (2002)

Atrial fibrillation (AF) may result from stationary reentry in the left atrium (LA), with fibrillatory conduction toward the right atrium (RA). We hypothesize that periodic input to the RA at an exceedingly high frequency results in disorganized wave propagation, compatible with fibrillatory conduction. Simultaneous endocardial and epicardial optical mapping (di-4-ANEPPS) was performed in isolated, coronary-perfused sheep RA. Rhythmic pacing of Bachmann’s bundle allowed well-controlled and realistic conditions for LA-driven RA. Pacing at increasingly higher frequencies (2.0 to 6.0 Hz) led to increasing delays in activation distal to major branching sites of the crista terminalis and pectinate bundles, culminating in spatially distributed intermittent blockade at or above ≈6.5 Hz. At this “breakdown frequency,” the direction of RA propagation became completely variable from beat to beat and thus transformed into fibrillatory conduction. Such frequency-dependent changes were independent of action potential duration. Rather, the spatial boundaries between proximal and distal frequencies correlated well with branch sites of the pectinate musculature. Thus, there exists a breakdown frequency in the sheep RA below which activity is periodic throughout the atrium and above which it is fibrillation-like. The data are consistent with the ideas that during AF, high-frequency activation initiated in the LA undergoes fibrillatory conduction toward the RA, and that sink-to-source effect at branch points of the crista terminalis and pectinate muscles is important in determining the complexity of the arrhythmia.
Antibiotic Prescribing for Acute Respiratory Infections in Direct-to-Consumer Telemedicine Visits
Authors: Lori Uscher-Pines, Andrew Mulcahy, David Cowling, Gerald Hunter, Rachel Burns, Ateev Mehrotra
Journal: JAMA Internal Medicine (2015)

We thank the resident physicians who collected the data in the context of patient care, as well as our attending physicians, who strive to provide patients with the best care.
Glycemia and Its Relationship to Outcomes in the Metformin in Gestational Diabetes Trial
Authors: Janet A. Rowan, Wanzhen Gao, William M. Hague, Harold David McIntyre
Journal: Diabetes Care (2009)

OBJECTIVE To determine how glucose control in women with GDM treated with metformin and/or insulin influenced pregnancy outcomes. RESEARCH DESIGN AND METHODS Women randomly assigned to metformin or insulin treatment in the Metformin in Gestational Diabetes (MiG) trial had baseline glucose tolerance test (OGTT) results and A1C documented, together with all capillary glucose measurements during treatment. In the 724 women who had glucose data for analysis, tertiles of baseline glucose values and A1C and of mean capillary glucose values during treatment were calculated. The relationships between maternal factors, glucose values, and outcomes (including a composite of neonatal complications, preeclampsia, and large-for-gestational-age [LGA] and small-for-gestational-age infants) were examined with bivariable and multivariate models. RESULTS Baseline OGTT did not predict outcomes, but A1C predicted LGA infants (P = 0.003). During treatment, fasting capillary glucose predicted neonatal complications (P &amp;lt; 0.001) and postprandial glucose predicted preeclampsia (P = 0.016) and LGA infants (P = 0.001). Obesity did not influence outcomes, and there was no interaction between glycemic control, randomized treatment, or maternal BMI in predicting outcomes. The lowest risk of complications was seen when fasting capillary glucose was &amp;lt;4.9 mmol/l (mean ± SD 4.6 ± 0.3 mmol/l) compared with 4.9–5.3 mmol/l or higher and when 2-h postprandial glucose was 5.9–6.4 mmol/l (6.2 ± 0.2 mmol/l) or lower. CONCLUSIONS Glucose control in women with gestational diabetes mellitus treated with metformin and/or insulin is strongly related to outcomes. Obesity is not related to outcomes in this group. Targets for fasting and postprandial capillary glucose may need to be lower than currently recommended.
Antitumor Activity of HKI-272, an Orally Active, Irreversible Inhibitor of the HER-2 Tyrosine Kinase
Authors: Sridhar K. Rabindran, Carolyn M. Discafani, Edward C. Rosfjord, Michelle Baxter, M. Brawner Floyd, Jonathan Golas, William A. Hallett, Bernard D. Johnson, Ramaswamy Nilakantan, Elsebe Overbeek, Marvin F. Reich, Ru Shen, Xiaoqing Shi, Hwei-Ru Tsou, Yu-Fen Wang, Allan Wissner
Journal: Cancer Research (2004)

Abstract HER-2 belongs to the ErbB family of receptor tyrosine kinases, which has been implicated in a variety of cancers. Overexpression of HER-2 is seen in 25–30% of breast cancer patients and predicts a poor outcome in patients with primary disease. Trastuzumab (Herceptin), a monoclonal antibody to HER-2, is specifically approved for HER-2-positive breast cancer but is active only in a subset of these tumors. Blocking HER-2 function by a small molecule kinase inhibitor, therefore, represents an attractive alternate strategy to inhibit the growth of HER-2-positive tumors. HKI-272 is a potent inhibitor of HER-2 and is highly active against HER-2-overexpressing human breast cancer cell lines in vitro. It also inhibits the epidermal growth factor receptor (EGFR) kinase and the proliferation of EGFR-dependent cells. HKI-272 reduces HER-2 receptor autophosphorylation in cells at doses consistent with inhibition of cell proliferation and functions as an irreversible binding inhibitor, most likely by targeting a cysteine residue in the ATP-binding pocket of the receptor. In agreement with the predicted effects of HER-2 inactivation, HKI-272 treatment of cells results in inhibition of downstream signal transduction events and cell cycle regulatory pathways. This leads to arrest at the G1-S (Gap 1/DNA synthesis)-phase transition of the cell division cycle, ultimately resulting in decreased cell proliferation. In vivo, HKI-272 is active in HER-2- and EGFR-dependent tumor xenograft models when dosed orally on a once daily schedule. On the basis of its favorable preclinical pharmacological profile, HKI-272 has been selected as a candidate for additional development as an antitumor agent in breast and other HER-2-dependent cancers.
Haptoglobin Phenotype and Gestational Diabetes
Authors: Stefan Mustafa, Thomas Vukovich, Thomas Prikoszovich, Christine Winzer, Barbara Schneider, Harald Esterbauer, Oswald Wagner, Alexandra Kautzky-Willer
Journal: Diabetes Care (2004)

OBJECTIVE—Haptoglobin (Hp), an Hb-binding plasma protein, exists in two major allelic variants. Hp1 has higher Hb binding and antioxidant capacity compared with Hp2. Individuals with Hp1 exhibit a lower incidence of angiopathies. Gestational diabetes mellitus (GDM) is an early manifestation of type 2 diabetes in pregnant women. It is usually confined to the time of gestation, but carries an increased risk to develop type 2 diabetes later in life. RESEARCH DESIGN AND METHODS—From consecutive Caucasian pregnant women (n = 250) referred for oral glucose tolerance testing, the Hp phenotype was determined. Significance of distribution and odds ratios (ORs) associated with Hp phenotype were calculated for women with GDM (n = 110) and women with normal glucose tolerance (n = 140). RESULTS—Frequency of GDM in Hp phenotype classes increased with the number of Hp2 alleles (P &amp;lt; 0.001). ORs for GDM in women heterozygous and homozygous for Hp2 were 2.7 (95% CI 1.06–6.84) and 4.2 (1.67–10.55), respectively. CONCLUSIONS—Hp phenotype is an apparent risk factor for the development of GDM in our study population. This might be due to the low antioxidative potential of Hp2 compared with Hp1.
Dilated Cardiomyopathy and Sudden Death Resulting From Constitutive Activation of Protein Kinase A
Authors: Christopher L. Antos, Norbert Frey, Steven O. Marx, Steven Reiken, Marta Gaburjakova, James A. Richardson, Andrew R. Marks, Eric N. Olson
Journal: Circulation Research (2001)

β-Adrenergic receptor (βAR) signaling, which elevates intracellular cAMP and enhances cardiac contractility, is severely impaired in the failing heart. Protein kinase A (PKA) is activated by cAMP, but the long-term physiological effect of PKA activation on cardiac function is unclear. To investigate the consequences of chronic cardiac PKA activation in the absence of upstream events associated with βAR signaling, we generated transgenic mice that expressed the catalytic subunit of PKA in the heart. These mice developed dilated cardiomyopathy with reduced cardiac contractility, arrhythmias, and susceptibility to sudden death. As seen in human heart failure, these abnormalities correlated with PKA-mediated hyperphosphorylation of the cardiac ryanodine receptor/Ca 2+ -release channel, which enhances Ca 2+ release from the sarcoplasmic reticulum, and phospholamban, which regulates the sarcoplasmic reticulum Ca 2+ -ATPase. These findings demonstrate a specific role for PKA in the pathogenesis of heart failure, independent of more proximal events in βAR signaling, and support the notion that PKA activity is involved in the adverse effects of chronic βAR signaling.
Role of Ca <sup>2+</sup> -Activated K <sup>+</sup> Channels in the Regulation of Membrane Potential and Tone of Smooth Muscle in Human Pial Arteries
Authors: Natalia I. Gokina, Theresa D. Wellman, Rosemary D. Bevan, Carrie L. Walters, Paul L. Penar, John A. Bevan
Journal: Circulation Research (1996)

Smooth muscle cells (SMCs) in 58% of human pial arteries obtained during surgery showed no spontaneous contractions and displayed a stable resting membrane potential (MP) of -54.7 +/- 1.5 mV. Those that exhibited periodic spontaneous contractions associated with periodic depolarization and generation of spontaneous action potentials (APs) had a less negative MP of -43.1 +/- 0.5 mV (42%). Inhibition of calcium-activated potassium (KCa) channels in the silent arteries by charybdotoxin (CTX) and tetraethylammonium ions (TEA) induced dose-dependent depolarization, AP generation, and contraction. TEA and CTX enhanced the spontaneous depolarization and force in arteries that exhibited spontaneous activity. They also prolonged the spontaneous APs up to several times and increased their upstroke amplitude. Both TEA and CTX failed to produce significant depolarization in arteries treated with nifedipine. It is concluded that KCa channels are important regulators of human pial artery SMC resting MP and tone. They are also involved in the control of AP amplitude and duration and the associated contractions. These data suggest that alterations in the activity of SMC KCa channels could be responsible for the appearance of spontaneous activity in human pial arteries in vitro and that impaired function of these channels might be related to vasospastic phenomena in human cerebral circulation.
Calcium Channel Blocker Reduces Airway Remodeling in Severe Asthma. A Proof-of-Concept Study
Authors: Pierre-Olivier Girodet, Gaël Dournes, Matthieu Thumerel, Hugues Begueret, Pierre Dos Santos, Annaig Ozier, Isabelle Dupin, Thomas Trian, Michel Montaudon, François Laurent, Roger Marthan, Patrick Berger
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Rationale: Severe asthma is a major public health issue throughout the world. Increased bronchial smooth muscle (BSM) mass, a characteristic feature of airway remodeling in severe asthma, is associated with resistance to high-intensity treatment and poor prognosis. In vitro, the Ca2+-channel blocker gallopamil decreased the proliferation of BSM cells from patients with severe asthma.Objectives: We conducted a double-blind, randomized, placebo-controlled study to evaluate the effect of gallopamil on airway remodeling in patients with severe asthma.Methods: Subjects received either gallopamil (n = 16) or placebo (n = 15) for 1 year and were monitored for an additional 3-month period. Airway remodeling was analyzed at baseline and after treatment phase using both fiberoptic bronchoscopy and computed tomography scan. The primary end point was the BSM area. Secondary end points included normalized BSM thickness and frequency of asthma exacerbations.Measurements and Main Results: BSM area was reduced in the gallopamil group (baseline vs. end of treatment) but was unchanged in the placebo group. Between-group differences in BSM area were not significantly different in gallopamil versus placebo groups. By contrast, between-group differences in normalized BSM thickness were significantly different between the two groups. The mean number of exacerbations per month was not different during the treatment phase in gallopamil versus placebo group but was significantly lower in patients previously treated with gallopamil during the follow-up period. There were no differences between the groups with respect to overall side effects.Conclusions: Gallopamil treatment for 12 months reduces BSM remodeling and prevents the occurrence of asthma exacerbations.Clinical trial registered with www.clinicaltrials.gov (NCT 00896428).
Myocardial Mural Thickness During the Cardiac Cycle
Authors: ERIC O. FEIGL, DONALD L. FRY
Journal: Circulation Research (1964)

The instantaneous and continuous thickness of the left ventricular wall was measured in ten dogs with a specially designed transducer. The thickness change during the "isovolumic" phase of systole was 11%. The average thickness increased an additional 10% during the ejection period of systole. These average values increased to 20% and 15% respectively with the administration of norepinephrine (approximately 0.001 mg/kg per minute). Transverse and longitudinal epicardial are strains were compared with thickness strain of the myocardium. Assuming the myocardium is incompressible, reasonable agreement was found in the three strains, which lends support to the measurements that were made. It is concluded that changes in the thickness of the myocardial wall during the cardiac cycle may be important in some considerations of the heart's performance.
Antitumor Activity of the Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor Gefitinib (ZD1839, Iressa) in Non–Small Cell Lung Cancer Cell Lines Correlates with Gene Copy Number and EGFR Mutations but not EGFR Protein Levels
Authors: Barbara A. Helfrich, David Raben, Marileila Varella-Garcia, Dan Gustafson, Daniel C. Chan, Lynne Bemis, Chris Coldren, Anna Barón, Chan Zeng, Wilbur A. Franklin, Fred R. Hirsch, Adi Gazdar, John Minna, Paul A. Bunn
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Recognition that the epidermal growth factor receptor (EGFR) was a therapeutic target in non–small cell lung cancer (NSCLC) and other cancers led to development of the small-molecule receptor tyrosine kinase inhibitors gefitinib and erlotinib. Clinical trials established that EGFR tyrosine kinase inhibitors produced objective responses in a minority of NSCLC patients. We examined the sensitivity of 23 NSCLC lines with wild-type or mutated EGFR to gefitinib to determine genes/proteins related to sensitivity, including EGFR and HER2 cell surface expression, phosphorylated EGFR expression, EGFR gene copy number, and EGFR mutational status. Downstream cell cycle and signaling events were compared with growth-inhibitory effects. Experimental Design: We determined gefitinib sensitivity by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays, EGFR expression by fluorescence-activated cell sorting and immunohistochemistry, phosphorylated EGFR by Western blotting, EGFR gene copy number by fluorescence in situ hybridization, and EGFR mutation by sequencing. The cellular effects of gefitinib on cell cycle were determined by flow cytometry and the molecular effects of gefitinib EGFR inhibition on downstream signal proteins by Western blotting. Gefitinib in vivo effects were evaluated in athymic nude mice bearing sensitive and resistant NSCLC xenografts. Results: There was a significant correlation between EGFR gene copy number, EGFR gene mutations, and gefitinib sensitivity. EGFR protein was necessary but not sufficient for predicting sensitivity. Gefitinib-sensitive lines showed a G1 cell cycle arrest and inactivation of downstream signaling proteins; resistant cell lines had no changes. The in vivo effects mirrored the in vitro effects. Conclusions: This panel of NSCLC lines characterized for gefitinib response was used to identify predictive molecular markers of response to gefitinib. Several of these have subsequently been shown to identify NSCLC patients likely to benefit from gefitinib therapy.
An Immunofluorescence Study of Rheumatoid Factor
Authors: J. N. McCormick
Journal: Annals of the Rheumatic Diseases (1963)

The rheumatoid factor group of macroglobulins is a characteristic concomitant of rheumatoid arthritis and can be detected readily in the serum of most rheumatoid patients by a variety of sero- logical techniques employing as reactant either human gamma globulin (Heller, Jacobson,
Chimeric DNA–RNA hammerhead ribozyme targeting PDGF A-chain mRNA specifically inhibits neointima formation in rat carotid artery after balloon injury
Authors: M Kotani
Journal: Cardiovascular Research (2002)

Objective: Restenosis of the coronary artery after percutaneous transluminal coronary angioplasty (PTCA) occurs in 30–50% of patients and remains a major clinical problem. We developed ribozyme that targets platelet-derived growth factor (PDGF) A-chain mRNA as a gene therapy for restenosis after PTCA. Thus, we examined the effects of a chimeric DNA–RNA ribozyme targeting PDGF A-chain mRNA on neointima formation in rat carotid artery after balloon injury and evaluated its specificity for PDGF A-chain mRNA by microarray analysis. Methods: Rat carotid artery was injured with a 2F Fogarty catheter, and PDGF A-chain specific ribozyme was delivered to the injured artery with polyethylenimine. Two weeks after injury, the artery was removed, and the intima/media (I/M) ratio was evaluated. Six hours after injury, mRNA was extracted with oligo dT cellulose, and expression of PDGF A-chain mRNA was evaluated by reverse transcription-polymerase chain reaction. Expression of PDGF-AA protein was evaluated by Western blot analysis. Expression of 970 genes was evaluated by microarray (GeneChip, Affimetrix Inc). Results: FITC-labeled ribozyme was taken up into the midlayer smooth muscle of the carotid artery until 24 h after balloon injury. Two and 5 μg of ribozyme significantly reduced neointima formation by 44 and 55% of control levels, respectively, in a dose-dependent manner. Ribozyme markedly inhibited expression of PDGF A-chain mRNA as well as production of PDGF-AA protein in injured vessels. Microarray analysis revealed that expression of 525 genes was increased after balloon injury. These genes included FLK-1, interleukin-1 receptor, retinoic acid receptor α2 isoform, heat shock protein, MAP kinase kinase, Fas antigen, G6Pase, PI-5-P-kinase, p38 MAP kinase, proliferating cell nuclear antigen, transforming growth factor-β, extracellular signal-related kinase, and fibroblast growth factor receptor. With respect to expression of cytokine and growth factor mRNAs, the best ribozyme specifically inhibited expression of PDGF A-chain mRNA. Conclusions: Our chimeric DNA–RNA hammerhead ribozyme targeting PDGF A-chain mRNA inhibited neointima formation in rat carotid artery after balloon injury with specific inhibition of expression of PDGF A-chain mRNA, suggesting that this ribozyme may be useful for therapy of restenosis of coronary artery after PTCA.