tbuckley/cabot-search huggingface dataset:
Effect of protein kinase A on calcium sensitivity of force and its sarcomere length dependence in human cardiomyocytes
Authors: J. Van Der Velden, J. W. De Jong, V. J. Owen, P. B.J. Burton, G. J.M. Stienen
Journal: Cardiovascular Research (2000)

We investigated whether the Frank-Starling mechanism is absent or preserved in end-stage failing human myocardium and if phosphorylation of contractile proteins modulates its magnitude through the sarcomere length-dependence of calcium sensitivity of isometric force development.The effect of phosphorylation of troponin I and C-protein by the catalytic subunit of protein kinase A (3 microg/ml; 40 min at 20 degrees C) was studied in single Triton-skinned human cardiomyocytes isolated from donor and end-stage failing left ventricular myocardium at sarcomere lengths measured at rest of 1.8, 2.0 and 2.2 microm. Isometric force development was studied at various free-calcium concentrations before and after protein kinase A incubation at 15 degrees C (pH 7.1).Maximal isometric tension at 2.2 microm amounted to 39.6+/-10.4 and 33.7+/-3.5 kN/m2 in donor and end-stage failing cardiomyocytes, respectively. The midpoints of the calcium sensitivity curves (pCa50) of donor and end-stage failing hearts differed markedly at all sarcomere lengths (mean delta pCa50=0.22). A reduction in sarcomere length from 2.2 to 1.8 microm caused reductions in maximum isometric force to 64% and 65% and in pCa50 by 0.10 and 0.08 pCa units in donor and failing cardiomyocytes, respectively. In donor tissue, the effect of protein kinase A treatment was rather small, while in end-stage failing myocardium it was much larger (delta pCa50=0.24) irrespective of sarcomere length.The data obtained indicate that the Frank-Starling mechanism is preserved in end-stage failing myocardium and suggest that sarcomere length dependence of calcium sensitivity and the effects of phosphorylation of troponin I and C-protein are independent.
Ro/SSA autoantibodies directly bind cardiomyocytes, disturb calcium homeostasis, and mediate congenital heart block
Authors: Stina Salomonsson, Sven-Erik Sonesson, Lars Ottosson, Saad Muhallab, Tomas Olsson, Maria Sunnerhagen, Vijay K. Kuchroo, Peter Thorén, Eric Herlenius, Marie Wahren-Herlenius
Journal: The Journal of Experimental Medicine (2005)

Congenital heart block develops in fetuses after placental transfer of Ro/SSA autoantibodies from rheumatic mothers. The condition is often fatal and the majority of live-born children require a pacemaker at an early age. The specific antibody that induces the heart block and the mechanism by which it mediates the pathogenic effect have not been elucidated. In this study, we define the cellular mechanism leading to the disease and show that maternal autoantibodies directed to a specific epitope within the leucine zipper amino acid sequence 200–239 (p200) of the Ro52 protein correlate with prolongation of fetal atrioventricular (AV) time and heart block. This finding was further confirmed experimentally in that pups born to rats immunized with p200 peptide developed AV block. p200-specific autoantibodies cloned from patients bound cultured cardiomyocytes and severely affected Ca2+ oscillations, leading to accumulating levels and overload of intracellular Ca2+ levels with subsequent loss of contractility and ultimately apoptosis. These findings suggest that passive transfer of maternal p200 autoantibodies causes congenital heart block by dysregulating Ca2+ homeostasis and inducing death in affected cells.
Impact of HIV-1 Subtype and Antiretroviral Therapy on Protease and Reverse Transcriptase Genotype: Results of a Global Collaboration
Authors: Rami Kantor, David A Katzenstein, Brad Efron, Ana Patricia Carvalho, Brian Wynhoven, Patricia Cane, John Clarke, Sunee Sirivichayakul, Marcelo A Soares, Joke Snoeck, Candice Pillay, Hagit Rudich, Rosangela Rodrigues, Africa Holguin, Koya Ariyoshi, Maria Belen Bouzas, Pedro Cahn, Wataru Sugiura, Vincent Soriano, Luis F Brigido, Zehava Grossman, Lynn Morris, Anne-Mieke Vandamme, Amilcar Tanuri, Praphan Phanuphak, Jonathan N Weber, Deenan Pillay, P. Richard Harrigan, Ricardo Camacho, Jonathan M Schapiro, Robert W Shafer
Journal: PLoS Medicine (2005)

Background The genetic differences among HIV-1 subtypes may be critical to clinical management and drug resistance surveillance as antiretroviral treatment is expanded to regions of the world where diverse non-subtype-B viruses predominate. Methods and Findings To assess the impact of HIV-1 subtype and antiretroviral treatment on the distribution of mutations in protease and reverse transcriptase, a binomial response model using subtype and treatment as explanatory variables was used to analyze a large compiled dataset of non-subtype-B HIV-1 sequences. Non-subtype-B sequences from 3,686 persons with well characterized antiretroviral treatment histories were analyzed in comparison to subtype B sequences from 4,769 persons. The non-subtype-B sequences included 461 with subtype A, 1,185 with C, 331 with D, 245 with F, 293 with G, 513 with CRF01_AE, and 618 with CRF02_AG. Each of the 55 known subtype B drug-resistance mutations occurred in at least one non-B isolate, and 44 (80%) of these mutations were significantly associated with antiretroviral treatment in at least one non-B subtype. Conversely, of 67 mutations found to be associated with antiretroviral therapy in at least one non-B subtype, 61 were also associated with antiretroviral therapy in subtype B isolates. Conclusion Global surveillance and genotypic assessment of drug resistance should focus primarily on the known subtype B drug-resistance mutations.
The bias flow nitrogen washout technique for measuring the functional residual capacity in infants
Authors: M.G. Morris, P. Gustafsson, R. Tepper, M. Gappa, J. Stocks
Journal: European Respiratory Journal (2001)

The functional residual capacity (FRC) is the most commonly measured static lung volume in infants. It is important for interpreting volume-dependent pulmonary mechanics, e.g. airway resistance, and defining normal lung growth. The bias flow nitrogen washout technique is widely used for measuring FRC because the dead space and circuit resistance are low, making it suitable for small or sick infants. Moreover, data acquisition and calculation are easily programmed for a personal computer. The aim of this paper is to provide recommendations pertaining to equipment requirements, study procedures and reporting of data for functional residual capacity measurements. While measuring the functional residual capacity is regarded as physiologically and clinically important, the accuracy of the measurement is undoubtedly equally important. Hence, the paper also emphasizes factors influencing the accuracy of functional residual capacity measurements independent of equipment requirements. These recommendations represent the “State of the Art” in 2000.
Variation in the Renin Angiotensin System throughout the Normal Menstrual Cycle
Authors: Mala Chidambaram, John A. Duncan, Vesta S. Lai, Daniel C. Cattran, John S. Floras, James W. Scholey, Judith A. Miller
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. It has been demonstrated elsewhere that circulating renin angiotensin system (RAS) components peak when plasma estrogen levels are highest, during the luteal phase of the normal menstrual cycle. This phenomenon has been attributed to "activation" of the RAS. The end-organ vasoconstrictive response to this phenomenon has not been well established. In two related experiments, the RAS was studied in healthy, premenopausal women during predefined phases of the normal menstrual cycle. In the first experiment, the circulating components of the RAS and the systemic hemodynamic response to incremental lower body negative pressure (LBNP) during the follicular and luteal phases of the menstrual cycle were examined. Response variables included mean arterial pressure (MAP), renin, plasma renin activity (PRA), angiotensin II (AngII), and aldosterone. Baseline levels of renin, PRA, and aldosterone were significantly higher in the luteal phase. In response to LBNP, there were significant increases in all variables in both phases; however, the humoral response to this stimulus was significantly augmented in the luteal phase compared with the follicular phase. Despite these elevations in circulating components of the RAS during the luteal phase, subjects were unable to maintain MAP in response to LBNP, exhibiting a dramatic depressor response that did not occur during the follicular phase. In the second experiment, renal and peripheral hemodynamic function at baseline, and in response to AngII blockade with losartan, were examined in women during these high and low estrogen phases of the menstrual cycle. The renal and peripheral hemodynamic responses were similar in the luteal phase and the follicular phase. These results demonstrate that, despite an increase in circulating RAS components during the luteal phase of the menstrual cycle, the system is blunted rather than "activated," at least at a tissue level. Further studies are needed to clarify this mechanism.
Polymorphisms in all three ORMDL genes are associated with asthma and their mRNA expression is increased in asthmatics
Authors: Antoaneta Toncheva, Daniel Potaczek, Michaela Schedel, Sven Michel, Natalie Krajnov, Vincent Gaertner, Thomas Illig, Andre Franke, Carla Winkler, Jens Hohlfeld, Christian Vogelberg, Andrea von Berg, Albrecht Bufe, Andrea Heinzmann, Otto Laub, Ernst Rietschel, Burkhard Simma, Jon Genuneit, Michael Kabesch
Journal: European Respiratory Journal (2014)

Background:  The first and well replicated childhood asthma susceptibility locus identified by genome-wide association was 17q21.  ORMDL3 , located near the top association signal, belongs to the  ORMDL  gene family including  ORMDL1, -2  and  -3 . ORMDL proteins participate in the sphingolipid metabolism and maintain the ceramide homeostasis.ORMDL3 regulates the intracellular Ca 2+  levels, cellular stress responses and lymphocyte activation. Strong sequence homology between  ORMDL s and protein conservation among different species suggest that they may have shared functions.   Objectives:  We hypothesized that single nucleotide polymorphisms (SNPs) in  ORMDL  genesare associated with asthma and that expression of  ORMDL s correlates with asthma.   Methods:  Associations of 44 genotyped SNPs (Illumina HumanHap300Chip, MALDI-TOF MS) were assessed in 1,303 subjects (651 asthmatics) from MAGIC and ISAAC II studies. Expression in: (1) peripheral blood mononuclear cells (PBMC) (n=55, 8 asthmatics) before and after (48h) allergen stimulation; and (2) blood (n=60, 5 asthmatics) was determined. Allele-specific effects on the  ORMDL s expression were evaluated.   Results:  Sixteen SNPs in all three  ORMDL  genes were associated with asthma (most in  ORMDL3 ). Baseline expression in PBMC was significantly higher in asthmatics for  ORMDL1  ( p =1.7*10 -6 ) and  -2  ( p =4.9*10 -5 ) while induction of  ORMDL s upon stimulation was stronger in unaffected subjects. Asthma associated rs8079416 and rs8076131 influenced  ORMDL3  expression in allele-specific manner.   Conclusions:  SNPs in all three  ORMDL s are associated with asthma. Asthmatics exhibit increased  ORMDL  levels, suggesting that  ORMDL s contribute to asthma development.  These authors contributed equally: Antoaneta Toncheva, Daniel Potaczek and Michaela Schedel.
Bioactive Glass Foam Scaffolds are Remodelled by Osteoclasts and Support the Formation of Mineralized Matrix and Vascular Networks In Vitro
Authors: Swati Midha, Wouter van den Bergh, Taek B. Kim, Peter D. Lee, Julian R. Jones, Christopher A. Mitchell
Journal: Advanced Healthcare Materials (2012)

Remodelling of scaffolds and new bone formation is critical for effective bone regeneration. Herein is reported the first demonstration of resorption pits due to osteoclast activity on the surface of sol-gel bioactive glass foam scaffolds. Bioactive glass foam scaffolds are known to have osteogenic potential and suitable pore networks for bone regeneration. Degradation of the scaffolds is known to be initially solution mediated, but for effective bone regeneration, remodelling of the scaffold by osteoclasts and vascularisation of the scaffold is necessary. The culture of C7 macrophages on a bioactive glass scaffold induces the cells to differentiate into (TRAP(+ve) ) osteoclasts. They then form distinctive resorption pits within 3 weeks, while MC3T3-E1 pre-osteoblasts deposit mineralized osteoid on their surfaces in co-culture. The scaffolds are of the 70S30C (70 mol% SiO2 , 30 mol% CaO) composition, with modal pore and interconnect diameters of 373 μm and 172 μm respectively (quantified by X-ray micro-tomography and 3D image analysis). The release of soluble silica and calcium ions from 70S30C scaffolds induces an increase in osteoblast numbers as determined via the MTT assay. Scaffolds also support growth of endothelial cells on their surface and tube formation (characteristic of functional microvasculature) following 4 days in culture. This data supports the hypothesis that 70S30C bioactive glass scaffolds promote the differentiation of the 3 main cell types involved in vascularized bone regeneration.
Use of Radioiodinated Fatty Acid for Photoscans of the Heart
Authors: JOHN R. EVANS, RAMSAY W. GUNTON, ROBERT G. BAKER, DONALD S. BEANLANDS, JOHN C. SPEARS
Journal: Circulation Research (1965)

Radioiodinated fatty acid bound to albumin (RIFA) was given by intravenous injection to dogs and moribund human subjects in order to label heart muscle. Photoscans of the thorax of dogs given RIFA revealed concentration of radioactivity in the ventricular region of the heart due to incorporation of the labeled fatty acid into myocardial triglyceride and phospholipid. Photoscans of the thorax following intravenous injection of radioiodinated serum albumin or NaI 131 showed a different density pattern in the region of the heart due to radioactivity in blood within the cardiac chambers. Areas of myocardial infarction were detected in photoscans of the thorax in 11 of 14 dogs in which one coronary artery was ligated. At necropsy the concentration of radioactivity was much higher in healthy myocardium than in infarcted muscle. The same distribution of radioactivity was observed in hearts from three human subjects with myocardial infarction given RIFA shortly before death. It is proposed that areas of myocardial infarction might be demonstrated during life by photoscans of the thorax following intravenous injection of RIFA.
Retropubic, Laparoscopic, and Robot-Assisted Radical Prostatectomy: A Systematic Review and Cumulative Analysis of Comparative Studies
Authors: Vincenzo Ficarra, Giacomo Novara, Walter Artibani, Andrea Cestari, Antonio Galfano, Markus Graefen, Giorgio Guazzoni, Bertrand Guillonneau, Mani Menon, Francesco Montorsi, Vipul Patel, Jens Rassweiler, Hendrik Van Poppel
Journal: European Urology (2009)
Anti-Inflammatory and Anticoagulant Effects of Pravastatin in Patients With Type 2 Diabetes
Authors: Dirkje W. Sommeijer, Melvin R. MacGillavry, Joost C.M. Meijers, Anton P. Van Zanten, Pieter H. Reitsma, Hugo Ten Cate
Journal: Diabetes Care (2004)

OBJECTIVE—Type 2 diabetes is associated with increased plasma concentrations of coagulation and inflammation markers. Different studies have shown that treatment with hydroxymethylglutaryl-CoA reductase inhibitors (statins) is associated with antithrombotic and anti-inflammatory effects in addition to a cholesterol-lowering effect. Our objective was to evaluate the effect of pravastatin (40 mg/day) on coagulation and inflammation markers in type 2 diabetic patients. RESEARCH DESIGN AND METHODS—This was an open, randomized, crossover study designed with an 8-week intervention period. The study group was comprised of 50 patients with type 2 diabetes (median HbA1c 7.1%) and serum total cholesterol of 5–10 mmol/l. We evaluated plasma levels of fibrinogen, F1 + 2, d-dimer, soluble tissue factor (sTF), von Willebrand Factor antigen (vWFag), and C-reactive protein (CRP) in blood samples drawn after fasting on day 1 and after 8 and 16 weeks. RESULTS—Significant reductions of total cholesterol (−22%; P &amp;lt; 0.001), LDL cholesterol (−32%; P &amp;lt; 0.001), and triglycerides (−10%; P &amp;lt; 0.05) were achieved after 8 weeks of treatment with pravastatin. In addition, significant reductions of plasma levels of F1 + 2 (−4.4%; P &amp;lt; 0.05), vWFag (−5.3%; P &amp;lt; 0.05), and sTF (−3.4%; P &amp;lt; 0.05) were observed after treatment with pravastatin. Furthermore, plasma levels of CRP were also significantly reduced (−13%; P &amp;lt; 0.05). Levels of fibrinogen and d-dimer did not decrease after treatment with pravastatin. CONCLUSIONS—The results indicated that pravastatin reduces levels of coagulation and inflammation markers in type 2 diabetic patients. These antithrombotic and anti-inflammatory effects of treatment with statins could play a role in reducing cardiovascular complications in type 2 diabetic patients.
Two functional variants of the superoxide dismutase genes in Finnish families with asthma
Authors: V L Kinnula
Journal: Thorax (2004)

<b>Background:</b> Functional polymorphisms in the genes encoding superoxide dismutases (SOD)—that is, superoxide scavenging antioxidant enzymes—may play an important role in the development of inflammatory airway diseases such as asthma. <b>Methods:</b> The allele frequencies of two missense polymorphisms of SOD genes (Ala16Val in MnSOD (SOD2) and Arg213Gly in ECSOD (SOD3)) were investigated in Finnish patients with asthma and compared with family based controls. Both variants have been shown to be functionally interesting in the lung. The polymorphism at the exon–intron 3 boundary of a third SOD, CuZnSOD (SOD1), was also included in the analysis. <b>Results:</b> None of the SOD genetic variants studied appeared to be major genetic regulators in the development of asthma. We could exclude all models of inheritance that increased the risk of asthma more than 1.2 fold for MnSOD*Val (frequency of allele 0.74 in the population) and more than 6.6 fold for ECSOD*Gly213 (frequency of allele 0.03 in the population) compared with non-carriers. For the intronic polymorphism in CuZnSOD, a relative risk of more than 3.3 (frequency of allele 0.10 in the population) could be excluded. <b>Conclusions:</b> It is highly unlikely that the functionally important genetic variants Ala16Val and Arg213Gly of SODs play a major role in the genetic susceptibility of asthma.
The Identification and Characterization of Breast Cancer CTCs Competent for Brain Metastasis
Authors: Lixin Zhang, Lon D. Ridgway, Michael D. Wetzel, Jason Ngo, Wei Yin, Disha Kumar, Jerry C. Goodman, Morris D. Groves, Dario Marchetti
Journal: Science Translational Medicine (2013)

EpCAM − CTCs isolated from breast cancer patients express markers needed to promote brain metastasis.
Cigarette Smoking, N-Acetyltransferase 2 Genetic Polymorphisms, and Breast Cancer Risk
Authors: Christine B. Ambrosone
Journal: JAMA (1996)

To determine if N-acetyltransferase 2 (NAT2) polymorphisms result in decreased capacity to detoxify carcinogenic aromatic amines in cigarette smoke, thus making some women who smoke more susceptible to breast cancer.Case-control study with genetic analyses. DNA analyses were performed for 3 polymorphisms accounting for 90% to 95% of the slow acetylation phenotype among whites.White women with incident primary breast cancer (n=304) and community controls (n=327).Neither smoking nor NAT2 status was independently associated with breast cancer risk. There were no clear patterns of increased risk associated with smoking by NAT2 status among premenopausal women. In postmenopausal women, NAT2 strongly modified the association of smoking with risk. For slow acetylators, current smoking and smoking in the distant past increased breast cancer risk in a dose-dependent manner (odds ratios [95% confidence intervals] for the highest quartile of cigarettes smoked 2 and 20 years previously, 4.4 [1.3-14.8] and 3.9 [1.4-10.8], respectively). Among rapid acetylators, smoking was not associated with increased breast cancer risk.Our results suggest that smoking may be an important risk factor for breast cancer among postmenopausal women who are slow acetylators, demonstrate heterogeneity in response to carcinogenic exposures, and may explain previous inconsistent findings for cigarette smoking as a breast cancer risk factor.
Oncolytic Vaccinia Virus Disrupts Tumor-Associated Vasculature in Humans
Authors: Caroline J. Breitbach, Rozanne Arulanandam, Naomi De Silva, Steve H. Thorne, Richard Patt, Manijeh Daneshmand, Anne Moon, Carolina Ilkow, James Burke, Tae-Ho Hwang, Jeong Heo, Mong Cho, Hannah Chen, Fernando A. Angarita, Christina Addison, J. Andrea McCart, John C. Bell, David H. Kirn
Journal: Cancer Research (2013)

Abstract Efforts to selectively target and disrupt established tumor vasculature have largely failed to date. We hypothesized that a vaccinia virus engineered to target cells with activation of the ras/MAPK signaling pathway (JX-594) could specifically infect and express transgenes (hGM-CSF, β-galactosidase) in tumor-associated vascular endothelial cells in humans. Efficient replication and transgene expression in normal human endothelial cells in vitro required either VEGF or FGF-2 stimulation. Intravenous infusion in mice resulted in virus replication in tumor-associated endothelial cells, disruption of tumor blood flow, and hypoxia within 48 hours; massive tumor necrosis ensued within 5 days. Normal vessels were not affected. In patients treated with intravenous JX-594 in a phase I clinical trial, we showed dose-dependent endothelial cell infection and transgene expression in tumor biopsies of diverse histologies. Finally, patients with advanced hepatocellular carcinoma, a hypervascular and VEGF-rich tumor type, were treated with JX-594 on phase II clinical trials. JX-594 treatment caused disruption of tumor perfusion as early as 5 days in both VEGF receptor inhibitor-naïve and -refractory patients. Toxicities to normal blood vessels or to wound healing were not evident clinically or on MRI scans. This platform technology opens up the possibility of multifunctional engineered vaccinia products that selectively target and infect tumor-associated endothelial cells, as well as cancer cells, resulting in transgene expression, vasculature disruption, and tumor destruction in humans systemically. Cancer Res; 73(4); 1265–75. ©2012 AACR.
Temozolomide and cisplatin in relapsed/refractory acute leukemia
Authors: Karen Seiter, Sreedhar Katragadda, Doris Ponce, Muhammad Rasul, Nasir Ahmed
Journal: Journal of Hematology & Oncology (2009)

Cisplatin depletes MGMT and increases the sensitivity of leukemia cells to temozolomide. We performed a phase I study of cisplatin and temozolomide in patients with relapsed and refractory acute leukemia. Fifteen patients had AML, 3 had ALL, and 2 had biphenotypic leukemia. The median number of prior chemotherapy regimens was 3 (1–5). Treatment was well tolerated up to the maximal doses of temozolomide 200 mg/m2/d times 7 days and cisplatin 100 mg/m2 on day 1. There was one complete remission in this heavily pretreated patient population. Five of 20 (25%) patients demonstrated a significant reduction in bone marrow blasts.