tbuckley/cabot-search huggingface dataset:
Mercuric Conjugates of Cysteine Are Transported by the Amino Acid Transporter System b0,+
Authors: Christy C. Bridges, Christian Bauch, Franc[COMBINING CEDILLA]ois Verrey, Rudolfs K. Zalups
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. Humans and other mammals continue to be exposed to various forms of mercury in the environment. The kidneys, specifically the epithelial cells lining the proximal tubules, are the primary targets where mercuric ions accumulate and exert their toxic effects. Although the actual mechanisms involved in the transport of mercuric ions along the proximal tubule have not been defined, current evidence implicates mercuric conjugates of cysteine, primarily 2-amino-3-(2-amino-2-carboxyethylsulfanylmercuricsulfanyl)propionic acid (Cys-S-Hg-S-Cys), as the most likely transportable species of inorganic mercury (Hg2+). Because Cys-S-Hg-S-Cys and the amino acid cystine (Cys-S-S-Cys) are structurally similar, it was hypothesized that Cys-S-Hg-S-Cys might act as a molecular mimic of cystine at one or more of the amino acid transporters involved in the luminal absorption of this amino acid. One such candidate is the Na+-independent heterodimeric transporter system b0,+. Therefore, the transport of Cys-S-Hg-S-Cys and cystine was studied in MDCK II cells that were or were not stably transfected with b0,+AT-rBAT. Transport of Cys-S-Hg-S-Cys and cystine across the luminal plasma membrane was similar in the transfected cells, indicating that Cys-S-Hg-S-Cys can behave as a molecular mimic of cystine at the site of system b0,+. Moreover, only the b0,+AT-rBAT transfectants became selectively intoxicated during exposure to Cys-S-Hg-S-Cys. These findings indicate that system b0,+ likely contributes to the nephropathy induced by Hg2+in vivo. These data represent the first direct molecular evidence for the participation of a specific transporter in the luminal uptake of a large divalent metal cation in proximal tubular cells.
Allele-specific copy number analysis of tumor samples with aneuploidy and tumor heterogeneity
Authors: Markus Rasmussen, Magnus Sundström, Hanna Kultima, Johan Botling, Patrick Micke, Helgi Birgisson, Bengt Glimelius, Anders Isaksson
Journal: Genome biology (2011)

We describe a bioinformatic tool, Tumor Aberration Prediction Suite (TAPS), for the identification of allele-specific copy numbers in tumor samples using data from Affymetrix SNP arrays. It includes detailed visualization of genomic segment characteristics and iterative pattern recognition for copy number identification, and does not require patient-matched normal samples. TAPS can be used to identify chromosomal aberrations with high sensitivity even when the proportion of tumor cells is as low as 30%. Analysis of cancer samples indicates that TAPS is well suited to investigate samples with aneuploidy and tumor heterogeneity, which is commonly found in many types of solid tumors.
Regulation of high-affinity IgE receptor-mediated mast cell activation by murine low-affinity IgG receptors.
Authors: M Daëron, O Malbec, S Latour, M Arock, W H Fridman
Journal: Journal of Clinical Investigation (1995)

Allergic symptoms result from the release of granular and lipidic mediators and of cytokines by inflammatory cells. The whole process is initiated by the aggregation of mast cell and basophil high-affinity IgE receptors (Fc epsilon RI) by IgE and antigen. We report here that IgE-induced release of mediator and cytokine can be inhibited by cross-linking Fc epsilon RI to low-affinity IgG receptors (Fc gamma RII) which are constitutively expressed on mast cells and basophils. Using a model of stable transfectants in RBL-2H3 cells expressing endogeneous rat Fc epsilon RI and recombinant murine Fc gamma RII, we showed that inhibition requires that Fc epsilon RI be crosslinked to Fc gamma RII by the same multivalent ligand. Inhibition of cross-linked receptors left non-cross-linked Fc epsilon RI capable of triggering mediator release and was reversible upon disengagement. Both isoforms of wild-type Fc gamma RII were equally capable of inhibiting Fc epsilon RI-mediated mast cell activation provided they had an intact intracytoplasmic domain. Our results demonstrate that mast cell secretory responses triggered by high-affinity receptors for IgE may be controlled by low-affinity receptors for IgG. This regulation of Fc epsilon RI-mediated mast cell activation is of potential interest in mast cell physiology and in allergic pathology.
Hazelnut allergy: A double-blind, placebo-controlled food challenge multicenter study
Authors: Claudio Ortolani, Barbara K. Ballmer-Weber, Kirsten Skamstrup Hansen, Marco Ispano, Brunello Wüthrich, Carsten Bindslev-Jensen, Raffaella Ansaloni, Luciana Vannucci, Valerio Pravettoni, Joseph Scibilia, Lars K. Poulsen, Elide A. Pastorello
Journal: Journal of Allergy and Clinical Immunology (2000)
Topoisomerase I, IIα and IIβ mRNA expression in peripheral blood mononuclear cells of patients with solid tumor: preliminary results
Authors: G. Cartei, A. Trestin, E. Colombrino, M. Nadai, S.N. Richter, L. Barzon, G. Palù, M. Palumbo
Journal: Annals of Oncology (2006)
Inhibition of MAPK Kinase Signaling Pathways Suppressed Renal Cell Carcinoma Growth and Angiogenesis <i>In vivo</i>
Authors: Dan Huang, Yan Ding, Wang-Mei Luo, Stephanie Bender, Chao-Nan Qian, Eric Kort, Zhong-Fa Zhang, Kristin VandenBeldt, Nicholas S. Duesbery, James H. Resau, Bin Tean Teh
Journal: Cancer Research (2008)

Abstract The mitogen-activated protein kinase (MAPK) signaling pathways play essential roles in cell proliferation and differentiation. Recent studies also show the activation of MAPK signaling pathways in tumorigenesis, metastasis, and angiogenesis of multiple human malignancies, including renal cell carcinoma (RCC). To assess the role of this pathway in regulating the proliferation and survival of RCC cells, we first examined the expression of MAPK kinase (MKK) and MAPK in clear cell RCC and confirmed the overexpression of MKK1 and extracellular signal-regulated kinase 2 (ERK2) in these tumors. We then tested the effects of pharmacologic inhibition of MKK on human RCC cell lines, both in vitro and in vivo, using anthrax lethal toxin (LeTx), which cleaves and inactivates several MKKs. Western blotting showed that the phosphorylation levels of ERK, c-Jun-NH2 kinase, and p38 MAPK decreased after 72 h of LeTx treatment. Exposure to LeTx for 72 h reduced cell proliferation by 20% without significant effects on cell cycle distribution and apoptosis. Anchorage-independent growth of RCC cells was dramatically inhibited by LeTx. In vivo studies showed that tumor growth of RCC xenografts could be suppressed by LeTx. Extensive necrosis and decreased tumor neovascularization were observed after LeTx treatment. LeTx also showed direct inhibition of proliferation of endothelial cells in vitro. Our results suggest that suppression of one or more MAPK signaling pathways may inhibit RCC growth through the disruption of tumor vasculature. [Cancer Res 2008;68(1):81–8]
Serum gastrin in duodenal ulcer: Part III Influence of vagotomy and pylorectomy
Authors: M. G. Korman, J. Hansky, P. R. Scott
Journal: Gut (1972)

Following truncal vagotomy and anterior pylorectomy for duodenal ulcer, fasting serum gastrin levels were higher at 84 +/- 7.9 pg per ml than in unoperated patients with duodenal ulcer (16 +/- 1.5 pg per ml). In response to a standard protein meal, the peak serum gastrin achieved in the vagotomized group was 259 +/- 37.8 pg per ml at 75 minutes after ingestion, a much higher response than that obtained with a standard meal plus prior atropinization in the unoperated duodenal ulcer patients.These results suggest that truncal vagotomy allows release of gastrin which was previously inhibited with the vagi intact and the temporal characteristics of the response indicate that some of this gastrin is derived from an extragastric source. The results also exemplify the dependence of gastrin estimations as measured by this immunoassay on the acidity of the contents bathing the gastric antrum.
Beta-adrenergic function in airways of healthy and asthmatic subjects.
Authors: P Gayrard, J Orehek, C Grimaud, J Charpin
Journal: Thorax (1975)

We measured the short-term effects of beta-adrenergic blockade with propranolol (0.2 mg/kg iv), followed by stimulation with salbutamol (200 mug inhaled), on specific airway conductance (SGaw) heart rate, and systemic blood pressure (BP) in 11 healthy subjects, and 11 symptom-free asthmatics with normal lung function values. Propranolol induced a significant bronchoconstrictor effect in both groups, stronger in asthmatics than in normals: mean SGaw decreased 34.6 +/- 25% against 9.4 +/- 9% (p less than 0.01). Six of the 11 asthmatics exhibited a more pronounced bronchoconstriction than the most responsive healthy subject. Large individual variations were seen in both groups although they were greater in the asthmatics. A similar rise in SGaw was produced by salbutamol in both groups. The decrease of heart rate provoked by propranolol was similar in the two groups, averaging 18.6%, with no further change after salbutamol. The blood pressure was slightly decreased by propranolol in both groups. The results indicate that normal subjects have a weak and variable bronchodilator beta-adrenergic activity. In most asthmatics beta-adrenergic tone appeared more pronounced. The individual differences in response to propranolol observed in both groups suggest that asthmatic patients differ quantitatively rather than qualitatively from healthy subjects with respect to beta-adrenergic receptor function. There was no association between clinical findings and the degree of bronchomotor effect of propranolol in the patients with asthma. This study does not support the view that airways of asthmatic patients have a decreased beta-adrengeric receptor function.
Contribution of lead from calcium supplements to blood lead.
Authors: B L Gulson, K J Mizon, J M Palmer, M J Korsch, A J Taylor
Journal: Environmental Health Perspectives (2001)

We conducted a case-control study to determine the contribution of lead to blood from consumption of calcium supplements approximating the recommended daily intakes over a 6-month period. Subjects were males and females ages 21 to 47 years (geometric mean 32 years) with a geometric mean blood lead concentration of 2.5 microg/dL. They were subdivided into three groups. One treatment group (n = 8) was administered a complex calcium supplement (carbonate/phosphate/citrate) and the other treatment group (n = 7) calcium carbonate. The control group (n = 6) received no supplement. The lead isotopic compositions of the supplements were completely different from those of the blood of the subjects, allowing us easily to estimate contribution from the supplements. The daily lead dose from the supplements at 100% compliance was about 3 microg Pb. Three blood samples were taken at 2-month intervals before treatment to provide background values, and three were taken during treatment. Subjects in the treatment group were thus their own controls. Lead isotopic compositions for the complex supplement showed minimal change during treatment compared with pretreatment. Lead isotopic compositions in blood for the calcium carbonate supplement showed increases of up to 0.5% in the (206)Pb/(204)Pb ratio, and for all isotope ratios there was a statistically significant difference between baseline and treatment (p < 0.005). The change from baseline to treatment for the calcium carbonate supplement differed from that for both the control group and the group administered the complex supplement. Blood lead concentrations, however, showed minimal changes. Variations in blood lead levels over time did not differ significantly between groups. Our results are consistent with earlier investigations using radioactive and stable lead tracers, which showed minimal gastrointestinal absorption of lead in the presence of calcium (+/- phosphorus) in adults. Even though there is no discernible increase in blood lead concentration during treatment, there are significant changes in the isotopic composition of lead in blood arising from the calcium carbonate supplement, indicating a limited input of lead from diet into the blood. Because calcium carbonate is overwhelmingly the most popular calcium supplement, the changes we have observed merit further investigation. In addition, this type of study, combined with a duplicate diet, needs to be repeated for children, whose fractional absorption of lead is considerably higher than that of adults.
Pre-race drop-out from the Glasgow Marathon.
Authors: K P Fletcher, D Eadie
Journal: British Journal of Sports Medicine (1986)

A high drop-out rate prior to the running of a Marathon reduces its value as a spectacle and needlessly causes rejection and antagonism amongst potential runners. This research investigates reasons for pre-race drop-out in the 1983 Glasgow Marathon, and finds that a major cause was injury or illness during training, with a motivational difference existing between runners and non-runners.
Disruption of PPARγ/β-catenin–mediated regulation of apelin impairs BMP-induced mouse and human pulmonary arterial EC survival
Authors: Tero-Pekka Alastalo, Molong Li, Vinicio de Jesus Perez, David Pham, Hirofumi Sawada, Jordon K. Wang, Minna Koskenvuo, Lingli Wang, Bruce A. Freeman, Howard Y. Chang, Marlene Rabinovitch
Journal: Journal of Clinical Investigation (2011)

Reduced bone morphogenetic protein receptor 2 (BMPR2) expression in patients with pulmonary arterial hypertension (PAH) can impair pulmonary arterial EC (PAEC) function. This can adversely affect EC survival and promote SMC proliferation. We hypothesized that interventions to normalize expression of genes that are targets of BMPR2 signaling could restore PAEC function and prevent or reverse PAH. Here we have characterized, in human PAECs, a BMPR2-mediated transcriptional complex between PPARγ and β-catenin and shown that disruption of this complex impaired BMP-mediated PAEC survival. Using whole genome-wide ChIP-Chip promoter analysis and gene expression microarrays, we delineated PPARγ/β-catenin-dependent transcription of target genes including APLN, which encodes apelin. We documented reduced PAEC expression of apelin in PAH patients versus controls. In cell culture experiments, we showed that apelin-deficient PAECs were prone to apoptosis and promoted pulmonary arterial SMC (PASMC) proliferation. Conversely, we established that apelin, like BMPR2 ligands, suppressed proliferation and induced apoptosis of PASMCs. Consistent with these functions, administration of apelin reversed PAH in mice with reduced production of apelin resulting from deletion of PPARγ in ECs. Taken together, our findings suggest that apelin could be effective in treating PAH by rescuing BMPR2 and PAEC dysfunction.
Abciximab in Patients With Acute Coronary Syndromes Undergoing Percutaneous Coronary Intervention After Clopidogrel Pretreatment&lt;SUBTITLE&gt;The ISAR-REACT 2 Randomized Trial&lt;/SUBTITLE&gt;
Authors: Adnan Kastrati
Journal: JAMA (2006)

No specifically designed studies have addressed the role of the glycoprotein IIb/IIIa inhibitor abciximab in patients with non-ST-segment elevation acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI) after pretreatment with 600 mg of clopidogrel.To assess whether abciximab is associated with clinical benefit in high-risk patients with ACS undergoing PCI after pretreatment with 600 mg of clopidogrel.International, multicenter, randomized, double-blind, placebo-controlled study conducted from March 2003 through December 2005, enrolling 2022 patients (mean age, 66 years) with non-ST-segment elevation ACS undergoing PCI.Patients were assigned to receive either abciximab (0.25 mg/kg of body weight bolus, followed by a 0.125-microg/kg per minute [maximum, 10 microg/min] infusion for 12 hours, plus heparin, 70 U/kg of body weight) or placebo (placebo bolus and infusion of 12 hours, plus heparin bolus, 140 U/kg). All patients received clopidogrel, 600 mg, at least 2 hours prior to the procedure, as well as 500 mg of oral or intravenous aspirin.The primary end point was a composite of death, myocardial infarction, or urgent target vessel revascularization occurring within 30 days after randomization; secondary end points were rates of in-hospital major and minor bleeding.Of 2022 patients enrolled, 1012 were assigned to abciximab and 1010 to placebo. The primary end point was reached in 90 patients (8.9%) assigned to abciximab vs 120 patients (11.9%) assigned to placebo, a 25% reduction in risk with abciximab (relative risk [RR], 0.75; 95% CI, 0.58-0.97; P = .03). Among patients without an elevated troponin level, there was no difference in the incidence of primary end point events between the abciximab group (23/499 patients [4.6%]) and the placebo group (22/474 patients [4.6%]) (RR, 0.99; 95% CI, 0.56-1.76; P = .98), whereas among patients with an elevated troponin level, the incidence of events was significantly lower in the abciximab group (67/513 patients [13.1%]) compared with the placebo group (98/536 patients [18.3%]), which corresponds to an RR of 0.71 (95% CI, 0.54-0.95; P = .02) (P = .07 for interaction). There were no significant differences between the 2 groups regarding the risk of major and minor bleeding as well as need for transfusion.Abciximab reduces the risk of adverse events in patients with non-ST-segment elevation ACS undergoing PCI after pretreatment with 600 mg of clopidogrel. The benefits provided by abciximab appear to be confined to patients presenting with an elevated troponin level.ClinicalTrials.gov Identifier: NCT00133003.
Endothelial dysfunction and arterial rigidity in patients with bronchial asthma out of an exacerbation
Authors: Angelina Kraposhina, Elena Sobko, Svetlana Chubarova, Irina Demko, Alla Salmina, Irina Soloveva
Journal: European Respiratory Journal (2013)

Objective: to study interrelation of endothelial dysfunction and arterial rigidity in patients with the bronchial asthma(BA). Indicators of arterial rigidity of an aorta estimated by means of an indirect arteriography. Vasomotor function of an endothelium investigated on the ultrasonic device VividTM-S6. Assessment of neutrophil elastase(NE) in peripheral blood plasma was performed by ELISA. 126 patients with BA out of a disease exacerbation have been surveyed. The 1st group included 29 patients with mild BA, the 2nd group-32 persons with middle BA, the 3rd group-40 people with severe non-steroid BA. 25 patients are included in the 4th group with steroid BA. The group of control-27 healthy volunteers.  Elevation of NE levels in the peripheral blood was associated with increased severity of the disease. The highest rates were registered in the 4th group–451.7[208.6;676.2]. Changes in vessel tone regulating function of endothelium in assay with a reactive hyperemia in the form of depression of endotelium-dependent vasodilatation(EDV) was lower by 10%, and changes as well as alterations of mechanical properties of aorta become to be more prominent along with disease progression. The highest values of PWVao were found in the group of patients with steroid BA. Correlations between the levels of NE in the peripheral blood and EDV(r=-0.62) were revealed. Also, interrelations between the following parameters have been confirmed: PWVao and EDV(r=-0.53); EDV and AIx(r=-0.47). Results of multiple linear regression showed that the most significant predictors in development of the increased arterial rigidity are the age and duration of BA(their contribution is 45%), and decrease of EDV(21%).
Thioredoxin Reductase as a Potential Molecular Target for Anticancer Agents That Induce Oxidative Stress
Authors: DeeDee K. Smart, Karen L. Ortiz, David Mattson, C. Matthew Bradbury, Kheem S. Bisht, Leah K. Sieck, Martin W. Brechbiel, David Gius
Journal: Cancer Research (2004)

Abstract Redox-sensitive signaling factors regulate multiple cellular processes, including proliferation, cell cycle, and prosurvival signaling cascades, suggesting their potential as molecular targets for anticancer agents. It is logical to set constraints that a molecular target should meet at least one of the following criteria: (1) inhibition of prosurvival signaling pathways; (2) inhibition of cell cycle progression; or (3) enhancement of the cytotoxic effects of anticancer agents. Therefore, we hypothesized that thioredoxin reductase 1 (TR), a component of several redox-regulated pathways, might represent a potential molecular target candidate in response to agents that induce oxidative stress. To address this issue, permanent cell lines overexpressing either the wild-type (pCXN2-myc-TR-wt) or a Cys-Ser mutant (pCXN2-myc-mTR) TR gene were used, as were parental HeLa cells treated with 1-methyl-1-propyl-2-imidazolyl disulfide (IV-2), a pharmacologic inhibitor of TR. Cells were exposed to the oxidative stressors, H2O2 and ionizing radiation (IR), and analyzed for changes in signal transduction, cell cycle, and cytotoxicity. Analysis of HeLa cells overexpressing the pCXN2-myc-TR-wt gene showed increased basal activity of nuclear factor κB (NFκB) and activator protein (AP-1), whereas HeLa cells expressing a pCXN2-myc-mTR gene and HeLa cells treated with IV-2 were unable to induce NFκB or AP-1 activity following H2O2 or IR exposure. Fluorescence-activated cell sorting analysis showed a marked accumulation of pCXN2-myc-mTR cells in the late G1 phase, whereas pCXN2-myc-TR-wt cells showed a decreased G1 subpopulation. Chemical inhibition of TR with IV-2 also completely inhibited cellular proliferation at concentrations between 10 and 25 μmol/L, resulting in a G1 phase cell cycle arrest consistent with the results from cells expressing the pCXN2-myc-mTR gene. Following exposure to H2O2 and IR, pCXN2-myc-mTR– and IV-2–treated cells were significantly more sensitive to oxidative stress-induced cytotoxicity as measured by clonogenic survival assays. Finally, IV-2–treated cells showed increased tumor cell death when treated with H2O2 and IR. These results identify TR as a potential target to enhance the cytotoxic effects of agents that induce oxidative stress, including IR.
Anti-cell surface pemphigus autoantibody stimulates plasminogen activator activity of human epidermal cells. A mechanism for the loss of epidermal cohesion and blister formation.
Authors: K Hashimoto, K M Shafran, P S Webber, G S Lazarus, K H Singer
Journal: The Journal of Experimental Medicine (1983)

Binding of anti-cell surface pemphigus autoantibodies to cultured human epidermal cells stimulates synthesis and secretion of plasminogen activator (PA). Increases in PA activity were detected within 6 h of the addition of IgG and stimulation was dependent upon IgG concentration. Stimulation of PA activity was inhibited by cycloheximide, which indicates that synthesis of protein was necessary. Pharmacological doses of dexamethasone also prevented IgG-induced stimulation of PA. Electrophoretic profiles of PA secreted by cultured human epidermal cells in the presence or absence of pemphigus IgG were similar. The majority of the PA activity comigrated with the higher-molecular-weight species of human urokinase (approximately 55,000). Explants of normal human skin incubated with pemphigus vulgaris IgG displayed loss of epidermal cohesion similar to that observed in patient biopsies. The histologic changes were potentiated by the inclusion of human plasminogen. Loss of epidermal cohesion in normal skin explants incubated with pemphigus foliaceous IgG was dependent upon the addition of plasminogen and was inhibited by aprotinin or lima bean trypsin inhibitor, which indicated that plasmin is the active enzyme in producing acantholysis. These data support the hypothesis that stimulation of PA by the anti-cell surface autoantibodies of pemphigus results in a localized increase in plasmin, which through proteolysis produces the loss of epidermal cohesion characteristic of pemphigus.