tbuckley/cabot-search huggingface dataset:
Modification of the Cardiovascular Effects of <scp>L</scp> -Dopa in Anesthetized Dogs by Inhibitors of Enzymes Involved in Catecholamine Metabolism
Authors: RONALD D. ROBSON
Journal: Circulation Research (1971)

The influence of various enzyme inhibitors on the cardiovascular effects of L -dopa (methylester) has been studied to determine the sites of action of the drug or a responsible metabolite. L -Dopa, 10 mg/kg, iv, had minor early effects on heart rate and blood pressure in normal dogs, but in animals with inhibition of monoamine oxidase (MAO), it caused tachycardia and severe hypotension of gradual onset. When MAO was inhibited, earlier doses of a dopamine β-oxidase inhibitor (FLA 63) did not significantly modify the effects of L -dopa; prior administration of a decarboxylase inhibitor, NSD 1055 or Ro 4-4602, prevented all but the initial effects; selective extracerebral decarboxylase inhibition with MK 486 ( L -α-hydrazino-α-methyldopa) prevented the tachycardia but not the hypotension. DL - threo -Dihydroxyphenylserine caused an initial rise in blood pressure in dogs with MAO inhibition, had less pressor activity when peripheral decarboxylase was also inhibited, and in both cases did not cause the hypotension characteristic of L -dopa. L -Dopa enhanced pressor responses and especially associated bradycardic responses to norepinephrine in dogs with MAO inhibition. This action was prevented by all decarboxylase inhibitors but not FLA 63. Responses to angiotensin were similarly augmented. Thus, MAO inhibition enabled L -dopa to induce severe hypotension, which appeared to rely on a central conversion to dopamine; the other effects were probably mediated by peripherally formed dopamine.
Oral sodium phenylbutyrate in patients with recurrent malignant gliomas: A dose escalation and pharmacologic study
Authors: Surasak Phuphanich, Sharyn D. Baker, Stuart A. Grossman, Kathryn A. Carson, Mark R. Gilbert, Joy D. Fisher, Michael A. Carducci
Journal: Neuro-Oncology (2005)

We determined the maximum tolerated dose (MTD), toxicity profile, pharmacokinetic parameters, and preliminary efficacy data of oral sodium phenylbutyrate (PB) in patients with recurrent malignant gliomas. Twenty-three patients with supratentorial recurrent malignant gliomas were enrolled on this dose escalation trial. Four dose levels of PB were studied: 9, 18, 27, and 36 g/day. Data were collected to assess toxicity, response, survival, and pharmacokinetics. All PB doses of 9, 18, and 27 g/day were well tolerated. At 36 g/day, two of four patients developed dose-limiting grade 3 fatigue and somnolence. At the MTD of 27 g/day, one of seven patients developed reversible grade 3 somnolence. Median survival from time of study entry was 5.4 months. One patient had a complete response for five years, and no partial responses were noted, which yielded an overall response rate of 5%. Plasma concentrations of 706, 818, 1225, and 1605 muM were achieved with doses of 9, 18, 27, and 36 g/day, respectively. The mean value for PB clearance in this patient population was 22 liters/h, which is significantly higher than the 16 liters/h reported in patients with other malignancies who were not receiving P450 enzyme-inducing anticonvulsant drugs (P = 0.038). This study defines the MTD and recommended phase 2 dose of PB at 27 g/day for heavily pretreated patients with recurrent gliomas. The pharmacology of PB appears to be affected by concomitant administration of P450-inducing anticonvulsants.
The PTPN22 allele encoding an R620W variant interferes with the removal of developing autoreactive B cells in humans
Authors: Laurence Menard, David Saadoun, Isabelle Isnardi, Yen-Shing Ng, Greta Meyers, Christopher Massad, Christina Price, Clara Abraham, Roja Motaghedi, Jane H. Buckner, Peter K. Gregersen, Eric Meffre
Journal: Journal of Clinical Investigation (2011)

Protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene polymorphisms are associated with many autoimmune diseases. The major risk allele encodes an R620W amino acid change that alters B cell receptor (BCR) signaling involved in the regulation of central B cell tolerance. To assess whether this PTPN22 risk allele affects the removal of developing autoreactive B cells, we tested by ELISA the reactivity of recombinant antibodies isolated from single B cells from asymptomatic healthy individuals carrying one or two PTPN22 risk allele(s) encoding the PTPN22 R620W variant. We found that new emigrant/transitional and mature naive B cells from carriers of this PTPN22 risk allele contained high frequencies of autoreactive clones compared with those from non-carriers, revealing defective central and peripheral B cell tolerance checkpoints. Hence, a single PTPN22 risk allele has a dominant effect on altering autoreactive B cell counterselection before any onset of autoimmunity. In addition, gene array experiments analyzing mature naive B cells displaying PTPN22 risk allele(s) revealed that the association strength of PTPN22 for autoimmunity may be due not only to the impaired removal of autoreactive B cells but also to the upregulation of genes such as CD40, TRAF1, and IRF5, which encode proteins that promote B cell activation and have been identified as susceptibility genes associated with autoimmune diseases. These data demonstrate that early B cell tolerance defects in autoimmunity can result from specific polymorphisms and precede the onset of disease.
Immune reconstitution after allogeneic marrow transplantation compared with blood stem cell transplantation
Authors: Jan Storek, Monja A. Dawson, Barry Storer, Terry Stevens-Ayers, David G. Maloney, Kieren A. Marr, Robert P. Witherspoon, William Bensinger, Mary E. D. Flowers, Paul Martin, Rainer Storb, Frederick R. Appelbaum, Michael Boeckh
Journal: Blood (2001)
Chronic Infusion of Bradykinin Delays the Progression of Heart Failure and Preserves Vascular Endothelium-Mediated Vasodilation in Conscious Dogs
Authors: Daniel Tonduangu, Luc Hittinger, Bijan Ghaleh, Philippe Le Corvoisier, Lucien Sambin, Stéphane Champagne, Thierry Badoual, Fanny Vincent, Alain Berdeaux, Bertrand Crozatier, Jin Bo Su
Journal: Circulation (2003)

This study examined the effects of chronic bradykinin infusion on hemodynamics and myocardial and endothelial functions during the development of heart failure.Sixteen instrumented dogs were randomized to receive through the left atria either vehicle or bradykinin (1 microg/min) during ventricular pacing (250 bpm, 5 weeks). Hemodynamic and left ventricular (LV) parameters and the vasodilator responses to intravenous acetylcholine (0.3 to 3 microg/kg) and nitroglycerin (1 to 10 microg/kg) were examined in the control and after 3 and 5 weeks of pacing. The expression of endothelial NOS in femoral, carotid, and renal arteries was determined by Western blot analysis. After 3 weeks of pacing, changes in LV diastolic and systolic parameters were significantly lower in bradykinin-treated than vehicle-treated dogs (LV end-diastolic pressure, +10+/-3 versus +19+/-2 mm Hg; time constant of LV isovolumic relaxation, +11+/-2 versus +17+/-1 ms; LV wall thickening, -33+/-18% versus -75+/-9%; and cardiac output, -16+/-6% versus -32+/-6%; all P<0.05). Compared with vehicle-treated dogs, bradykinin-treated dogs had a reduced rightward shift of the diastolic LV pressure-diameter relation and a reduced diastolic LV wall stress. Similar trends were observed after 5 weeks. The vasodilator response to nitroglycerin was preserved in both groups. The response to acetylcholine was blunted in vehicle-treated but preserved in bradykinin-treated dogs. Vascular endothelial NOS expression decreased in vehicle-treated but was preserved in bradykinin-treated dogs.In conscious dogs, chronic bradykinin infusion delays the heart failure progression by preserving LV diastolic and systolic functions and by preserving vascular endothelial function.
Identification of microRNA-135b in Stool as a Potential Noninvasive Biomarker for Colorectal Cancer and Adenoma
Authors: Chung Wah Wu, Siew Chien Ng, Yujuan Dong, Linwei Tian, Simon Siu Man Ng, Wing Wa Leung, Wai Tak Law, Tung On Yau, Francis Ka Leung Chan, Joseph Jao Yiu Sung, Jun Yu
Journal: Clinical Cancer Research (2014)

Detecting microRNA (miRNA) in stool is a novel approach for colorectal cancer (CRC) screening. This study aimed to identify stool-based miRNA as noninvasive biomarkers for detection of CRC and adenoma.A miRNA expression array covering 667 human miRNAs was performed on five pairs of CRC and two pairs of advanced adenoma tissues. The most upregulated miRNAs were validated in 40 pairs of CRC tissues, 16 pairs of advanced adenoma tissues, and 424 stool samples, including 104 CRCs, 169 adenomas, 42 inflammatory bowel diseases (IBD), and 109 healthy controls. miRNA levels were followed-up after removal of lesions.In an array analysis, miR-31 and miR-135b were the most upregulated miRNAs in CRC and advanced adenoma as compared with their adjacent normal tissues (>13-fold increase). In stool samples, level of miR-135b was significantly higher in subjects with CRC (P < 0.0001) or adenomas (P < 0.0001), but not in patients with IBD compared with controls. miR-135b showed a significant increasing trend across the adenoma to cancer sequence (P < 0.0001). Levels of miR-31 were not significantly different among groups. The sensitivity of stool mR-135b was 78% for CRC, 73% for advanced adenoma, and 65% for any adenoma, respectively, with a specificity of 68%. No significant difference in the miR-135b level was found between proximal and distal colorectal lesions. Stool miR-135b dropped significantly upon removal of CRC or advanced adenoma (P < 0.0001).Stool-based miR-135b can be used as a noninvasive biomarker for the detection of CRC and advanced adenoma. Clin Cancer Res; 20(11); 2994-3002. ©2014 AACR.
Slow-Channel Depolarization: Mechanism and Control of Arrhythmias
Authors: J C Bailey, V Elharrar, D P Zipes
Journal: Annual Review of Medicine (1978)

The secondary inward current that flows through the slow channel is probably carried primarily by calcium ions. This current is responsible, in part, for the plateau phase of the cardiac action potential. Inward calcium current through the slow channel is essential to excitation-contraction coupling, and enhancement of this current exerts a positive inotropic effect. Transmembrane electrical potentials generated as a consequence of this slow inward current, so-called slow-channel depolarizations or slow responses, have been useful models in recent studies of cardiac autonomic interactions. The significance of the slow response in ventricular arrhythmias remains controversial and awaits more definitive experiments. The role of slow-channel depolarization as a basis for SA and AV nodal electrical activity is suggested by the electrophysiological similarities between these tissues and slow responses produced in vitro. This hypothesis is supported by the responses of these nodal tissues to interventions that augment of impede the slow inward current. More direct evidence in support of this notion may not be obtainable in the near future, since the critical voltage-clamp studies of ionic currents in SA and AV nodes are not technically feasible at this time.
Transcriptional control of viral gene therapy by cisplatin
Authors: James O. Park, Carlos A. Lopez, Vinay K. Gupta, Charles K. Brown, Helena J. Mauceri, Thomas E. Darga, Abdullah Manan, Samuel Hellman, Mitchell C. Posner, Donald W. Kufe, Ralph R. Weichselbaum
Journal: Journal of Clinical Investigation (2002)

Ionizing radiation (IR) and radical oxygen intermediates (ROIs) activate the early growth response-1 (Egr1) promoter through specific cis-acting sequences termed CArG elements. Ad.Egr.TNF.11D, a replication-deficient adenoviral vector containing CArG elements cloned upstream of the cDNA for human recombinant TNF-alpha was used to treat human esophageal adenocarcinoma and rat colon adenocarcinoma cells in culture and as xenografts in athymic nude mice. Cisplatin, a commonly used chemotherapeutic agent, causes tumor cell death by producing DNA damage and generating ROIs. The present studies demonstrate induction of TNF-alpha production in tumor cells and xenografts treated with the combination of Ad.Egr.TNF.11D and cisplatin. The results show that the Egr1 promoter is induced by cisplatin and that this induction is mediated in part through the CArG elements. These studies also demonstrate an enhanced antitumor response without an increase in toxicity following treatment with Ad.Egr.TNF.11D and cisplatin, compared with either agent alone. Chemo-inducible cancer gene therapy thus provides a means to control transgene expression while enhancing the effectiveness of commonly used chemotherapeutic agents.
MADS-complexes regulate transcriptome dynamics during pollen maturation
Authors: Wim Verelst, David Twell, Stefan de Folter, Richard Immink, Heinz Saedler, Thomas Münster
Journal: Genome biology (2007)

Differentiation processes are responsible for the diversity and functional specialization of the cell types that compose an organism. The outcome of these processes can be studied at molecular, physiologic, and biochemical levels by comparing different cell types, but the complexity and dynamics of the regulatory processes that specify the differentiation are largely unexplored.Here we identified the pollen-specific MIKC* class of MADS-domain transcription factors as major regulators of transcriptome dynamics during male reproductive cell development in Arabidopsis thaliana. Pollen transcript profiling of mutants deficient in different MIKC* protein complexes revealed that they control a transcriptional switch that directs pollen maturation and that is essential for pollen competitive ability. We resolved the functional redundancy among the MIKC* proteins and uncovered part of the underlying network by identifying the non-MIKC* MADS-box genes AGL18 and AGL29 as downstream regulators of a subset of the MIKC* MADS-controlled genes.Our results provide a first, unique, and compelling insight into the complexity of a transcription factor network that directs cellular differentiation during pollen maturation, a process that is essential for male reproductive fitness in flowering plants.
Comparing driving simulator parameters between obstructive sleep apnoea syndrome (OSAS) patients and controls in an office based advanced driving simulator (MiniSim)
Authors: Akshay Dwarakanath, Dipansu Ghosh, Samantha Jamson, Mark Elliott
Journal: European Respiratory Journal (2013)

Introduction-  Untreated OSAS patients are at increased risk of traffic accidents. We have previously shown that controls perform better on the MiniSim than patients (failure rate-12% v/s 24%, p-0.03, OR-2.2). Task failure in patients can be identified based on standard deviation of lane position at epoch-3 (SDLP-3) and veer reaction time (Veer- RT). These parameters were further explored in controls.  Methods-  178 (52+/-11 yrs, ESS 13+/-7, ODI 32+/-24) untreated OSAS patients and 96 controls (50+/-15 yrs, ESS 3+/- 2) performed a 90km motorway driving simulation. Outcome pass, indeterminate or fail, based on preset criteria, was compared between patients and controls.  Results-  SDLP-3 and Veer-RT were worse in the fail group. A hierarchical pattern of worsening parameters was noted both in controls and patients. On multiple comparison there was a significant difference in SDLP-3 and Veer-RT in the pass and fail group, both in controls and in untreated OSAS patients.  Conclusion-  SDLP-3 and Veer-RT during simulated driving on an advanced simulator are objective markers of poor driving both in controls and in untreated OSAS patients.
Does Idiopathic Hypercalciuria Trigger Calcium-Sensing Receptor–Mediated Protection from Urinary Supersaturation?
Authors: Elaine M. Worcester, Fredric L. Coe
Journal: Journal of the American Society of Nephrology (2009)

Kidney stone formation is common, affecting 5 to 6% of the American adult population, and highly recurrent. Approximately 70% of stones are composed predominantly of calcium oxalate (CaOx) with small amounts of calcium phosphate (CaP); another 10% are largely CaP. The physicochemical requirement for stone formation is supersaturation of urine with respect to the stone minerals. In the case of calcium stones, supersaturation is driven by urine calcium concentration, which is a function of calcium excretion and urine volume. For CaP, supersaturation is also controlled by urine pH, because solubility of this salt decreases as urine pH rises; CaP stones are seen largely in patients with urine pH >6.

Biopsies of renal medullary papillae of stone formers, taken during percutaneous nephrolithotomy, demonstrate that stone formers are also characterized by specific patterns of mineral deposition in tissue. Common idiopathic CaOx stone formers have interstitial deposits of CaP in the medullary interstitium, so-called Randall's plaques, which begin in the thin loops of Henle and extend downward toward the base of the papilla, where they can be seen beneath the urothelium.1 CaOx stones form as overgrowths on plaque, attached to the papillae.2 When the amount of plaque covering the papillary surface was quantified, it varied directly with urine calcium excretion and inversely with urine volume and pH.3 The factors that control urinary supersaturation also affect plaque formation, which seems to be critical to the initiation of most calcium stones.

Medullary biopsy of patients with CaP stones have a different appearance. CaP deposits are found in the inner medullary collecting ducts and the terminal ducts of Bellini, associated with fibrosis and papillary deformity,4 and interstitial plaque abundance is low. The process of stone formation is less clear …
984 ELEVATED MARKERS OF APOPTOTIC CELL DEATH INDICATING NASH IN PATIENTS WITH POLYCYSTIC OVARY SYNDROME
Authors: S. Tan, L.P. Bechmann, S. Benson, S. Eichner, H. Lahner, T. Dietz, G. Gerken, K. Mann, A.E. Canbay
Journal: Journal of Hepatology (2009)
Postinfarction Gene Therapy Against Transforming Growth Factor-β Signal Modulates Infarct Tissue Dynamics and Attenuates Left Ventricular Remodeling and Heart Failure
Authors: Hideshi Okada, Genzou Takemura, Ken-ichiro Kosai, Yiwen Li, Tomoyuki Takahashi, Masayasu Esaki, Kentaro Yuge, Shusaku Miyata, Rumi Maruyama, Atsushi Mikami, Shinya Minatoguchi, Takako Fujiwara, Hisayoshi Fujiwara
Journal: Circulation (2005)

Fibrosis and progressive failure are prominent pathophysiological features of hearts after myocardial infarction (MI). We examined the effects of inhibiting transforming growth factor-beta (TGF-beta) signaling on post-MI cardiac fibrosis and ventricular remodeling and function.MI was induced in mice by left coronary artery ligation. An adenovirus harboring soluble TGF-beta type II receptor (Ad.CAG-sTbetaRII), a competitive inhibitor of TGF-beta, was then injected into the hindlimb muscles on day 3 after MI (control, Ad.CAG-LacZ). Post-MI survival was significantly improved among sTbetaRII-treated mice (96% versus control at 71%), which also showed a significant attenuation of ventricular dilatation and improved function 4 weeks after MI. At the same time, histological analysis showed reduced fibrous tissue formation. Although MI size did not differ in the 2 groups, MI thickness was greater and circumference was smaller in the sTbetaRII-treated group; within the infarcted area, alpha-smooth muscle actin-positive cells were abundant, which might have contributed to infarct contraction. Apoptosis among myofibroblasts in granulation tissue during the subacute stage (10 days after MI) was less frequent in the sTbetaRII-treated group, and sTbetaRII directly inhibited Fas-induced apoptosis in cultured myofibroblasts. Finally, treatment of MI-bearing mice with sTbetaRII was ineffective if started during the chronic stage (4 weeks after MI).Postinfarction gene therapy aimed at suppressing TGF-beta signaling mitigates cardiac remodeling by affecting cardiac fibrosis and infarct tissue dynamics (apoptosis inhibition and infarct contraction). This suggests that such therapy may represent a new approach to the treatment of post-MI heart failure, applicable during the subacute stage.
Computational Models Reduce Complexity and Accelerate Insight Into Cardiac Signaling Networks
Authors: Jason H. Yang, Jeffrey J. Saucerman
Journal: Circulation Research (2011)

Cardiac signaling networks exhibit considerable complexity in size and connectivity. The intrinsic complexity of these networks complicates the interpretation of experimental findings. This motivates new methods for investigating the mechanisms regulating cardiac signaling networks and the consequences these networks have on cardiac physiology and disease. Next-generation experimental techniques are also generating a wealth of genomic and proteomic data that can be difficult to analyze or interpret. Computational models are poised to play a key role in addressing these challenges. Computational models have a long history in contributing to the understanding of cardiac physiology and are useful for identifying biological mechanisms, inferring multiscale consequences to cell signaling activities and reducing the complexity of large data sets. Models also integrate well with experimental studies to explain experimental observations and generate new hypotheses. Here, we review the contributions computational modeling approaches have made to the analysis of cardiac signaling networks and forecast opportunities for computational models to accelerate cardiac signaling research.
Failure of salmeterol to inhibit circulating white cell responses and bronchoconstriction induced by platelet activating factor.
Authors: J Spring, S R Johnston, J Seale, P W Ind
Journal: Thorax (1992)

BACKGROUND: Platelet activating factor (PAF) is a potent mediator of inflammation. Inhalation of PAF causes acute bronchoconstriction and a transient fall in white blood cell count in humans. Salmeterol inhibits pulmonary inflammation induced by PAF in guinea pigs. METHODS: The effect of salmeterol on effects induced by PAF was investigated in eight normal subjects who inhaled salmeterol (50 micrograms) twice daily or a matched placebo for one week before challenge with PAF. Blood samples were taken from a forearm catheter for total white cell and neutrophil counts before and for 30 minutes after administration of PAF (48 micrograms) through a Mefar dosimeter. Blood films were stained for unsegmented neutrophils before and after treatment with PAF on a placebo day. RESULTS: Mean baseline total white cell counts and neutrophil counts did not differ on the two days. Mean baseline sGaw was significantly higher after inhaled salmeterol (1.84 (95% C1 1.45-2.23) s-1kPa-1) than after placebo (1.53 (1.24-1.82)). After placebo mean total white cell counts, neutrophil counts, and sGaw were reduced to 60 (43-78)%, 39 (14-64)%, and 82 (71-93)% of baseline respectively five minutes after inhaled PAF. After salmeterol treatment mean reductions five minutes after inhaled PAF were 59 (45-73)%, 40 (19-61)%, and 82 (71-93)% of baseline respectively. At 30 minutes after treatment with PAF the neutrophil count rebounded to 143 (82-204)% of baseline after placebo and to 127 (93-161)% after inhaled salmeterol. There was no significant difference in the percentage of immature neutrophils before and after treatment with PAF (2.0 (0.5-2.6)% compared with 3.9 (2.2-5.6)%. CONCLUSIONS: Treatment with salmeterol did not inhibit reduction in total white cell count or neutrophil count, rebound neutrophilia, acute bronchoconstriction, or transient flushing after inhalation of PAF. These results conflict with the inhibitory effect of salmeterol on lung inflammation in guinea pigs but are consistent with the lack of effect of salbutamol in humans. Salmeterol does not have an anti-PAF effect in vivo in humans.