tbuckley/cabot-search huggingface dataset:
von Willebrand Factor as a Biological Sensor of Blood Flow to Monitor Percutaneous Aortic Valve Interventions
Authors: Eric Van Belle, Antoine Rauch, André Vincentelli, Emmanuelle Jeanpierre, Paulette Legendre, Francis Juthier, Christopher Hurt, Carlo Banfi, Natacha Rousse, Anne Godier, Claudine Caron, Ahmed Elkalioubie, Delphine Corseaux, Annabelle Dupont, Christophe Zawadzki, Cédric Delhaye, Frédéric Mouquet, Guillaume Schurtz, Dominique Deplanque, Giulia Chinetti, Bart Staels, Jenny Goudemand, Brigitte Jude, Peter J. Lenting, Sophie Susen
Journal: Circulation Research (2015)

Rationale: Percutaneous aortic valve procedures are a major breakthrough in the management of patients with aortic stenosis. Residual gradient and residual aortic regurgitation are major predictors of midterm and long-term outcome after percutaneous aortic valve procedures. We hypothesized that (1) induction/recovery of high molecular weight (HMW) multimers of von Willebrand factor defect could be instantaneous after acute changes in blood flow, (2) a bedside point-of-care assay (platelet function analyzer-closure time adenine DI-phosphate [PFA-CADP]), reflecting HMW multimers changes, could be used to monitor in real-time percutaneous aortic valve procedures. Objective: To investigate the time course of HMW multimers changes in models and patients with instantaneous induction/reversal of pathological high shear and its related bedside assessment. Methods and Results: We investigated the time course of the induction/recovery of HMW multimers defects under instantaneous changes in shear stress in an aortic stenosis rabbit model and in patients undergoing implantation of a continuous flow left ventricular assist device. We further investigated the recovery of HMW multimers and monitored these changes with PFA-CADP in aortic stenosis patients undergoing transcatheter aortic valve implantation or balloon valvuloplasty. Experiments in the aortic stenosis rabbit model and in left ventricular assist device patients demonstrated that induction/recovery of HMW multimers occurs within 5 minutes. Transcatheter aortic valve implantation patients experienced an acute decrease in shear stress and a recovery of HMW multimers within minutes of implantation which was sustained overtime. In patients with residual high shear or with residual aortic regurgitation, no recovery of HMW multimers was observed. PFA-CADP profiles mimicked HMW multimers recovery both in transcatheter aortic valve implantation patients without aortic regurgitation (correction) and transcatheter aortic valve implantation patients with aortic regurgitation or balloon valvuloplasty patients (no correction). Conclusions: These results demonstrate that variations in von Willebrand factor multimeric pattern are highly dynamic, occurring within minutes after changes in blood flow. It also demonstrates that PFA-CADP can evaluate in real time the results of transcatheter aortic valve procedures.
Coevolution with Bacteriophages Drives Genome-Wide Host Evolution and Constrains the Acquisition of Abiotic-Beneficial Mutations
Authors: Pauline D. Scanlan, Alex R. Hall, Gordon Blackshields, Ville-P. Friman, Michael R. Davis, Joanna B. Goldberg, Angus Buckling
Journal: Molecular Biology and Evolution (2015)

Studies of antagonistic coevolution between hosts and parasites typically focus on resistance and infectivity traits. However, coevolution could also have genome-wide effects on the hosts due to pleiotropy, epistasis, or selection for evolvability. Here, we investigate these effects in the bacterium Pseudomonas fluorescens SBW25 during approximately 400 generations of evolution in the presence or absence of bacteriophage (coevolution or evolution treatments, respectively). Coevolution resulted in variable phage resistance, lower competitive fitness in the absence of phages, and greater genome-wide divergence both from the ancestor and between replicates, in part due to the evolution of increased mutation rates. Hosts from coevolution and evolution treatments had different suites of mutations. A high proportion of mutations observed in coevolved hosts were associated with a known phage target binding site, the lipopolysaccharide (LPS), and correlated with altered LPS length and phage resistance. Mutations in evolved bacteria were correlated with higher fitness in the absence of phages. However, the benefits of these growth-promoting mutations were completely lost when these bacteria were subsequently coevolved with phages, indicating that they were not beneficial in the presence of resistance mutations (consistent with negative epistasis). Our results show that in addition to affecting genome-wide evolution in loci not obviously linked to parasite resistance, coevolution can also constrain the acquisition of mutations beneficial for growth in the abiotic environment.
Cortical and medullary hemodynamics in deoxycorticosterone acetate-salt hypertensive mice.
Authors: V Gross, A Lippoldt, J Bohlender, M Bader, A Hansson, F C Luft
Journal: Journal of the American Society of Nephrology (1998)

The effect of acutely increasing renal perfusion pressure or extracellular fluid volume on renal medullary and cortical blood flow was examined in the low-renin deoxycorticosterone acetate (DOCA)-salt hypertension model in mice. A 50-mg DOCA tablet was implanted, and 1% saline was given as drinking water for 3 wk. Medullary and cortical blood flow were determined with laser-Doppler flowmetry, and whole-kidney blood flow was measured with a transit-time ultrasound flowprobe around the renal artery. In control mice, total renal blood flow ranged from 6.3 and 7.6 ml/min per g kidney weight and in DOCA-salt mice from 4.3 and 4.7 ml/min per g kidney weight, respectively, and was minimally affected as renal perfusion pressure was increased. Renal vascular resistance increased correspondingly. During stepwise increases in renal artery pressure from 90 to 140 mmHg, medullary blood flow progressively increased in control mice to 125% of baseline values, whereas cortical blood flow did not change. In DOCA-salt mice, increasing BP from 100 to 154 mmHg had no effect on either cortical or medullary blood flow. Urine flow and sodium excretion were lower in DOCA-salt mice than in controls and increased nearly to the same extent in both groups after volume expansion with isotonic saline. Total renal blood flow increased after saline loading, more in controls than in DOCA-salt mice. Increases in medullary blood flow after saline loading were up to 122% of baseline values in controls and demonstrated a significantly steeper slope than the 110% of baseline increases in DOCA-salt mice. Cortical blood flow, however, was not different between the groups. Thus, medullary blood flow is not as tightly autoregulated as cortical blood flow in normal mice. Natriuresis with acute volume loading is facilitated by increased medullary blood flow. In DOCA-salt mice, the medullary blood flow reaction to renal perfusion pressure increases is abolished, whereas flow increases with extracellular volume expansion are diminished. These results suggest that diminished pressure-natriuresis responses in DOCA-salt mice are related to perturbed medullary blood flow.
RNA-seq in Pulmonary Medicine: How Much Is Enough?
Authors: Mondira Ray, William Horne, Jeremy P. McAleer, David M. Ricks, James L. Kreindler, Michael S. Fitzsimons, Patricia P. Chan, Giraldina Trevejo-Nunez, Kong Chen, Merritt Fajt, Wei Chen, Anuradha Ray, Sally Wenzel, Jay K. Kolls
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

How Much Is Enough?To the Editor: RNA-seq is eclipsing microarray techniques to measure gene expression in tissues (1) because of several factors including reduced costs, increased sensitivity (1, 2), and the ability to detect splice variants (1) and nonhuman sequences in the sample (3).We investigated the use of RNA-seq to assess the transcriptome of three types of tissues relevant to pulmonary research: bronchial brushes obtained from healthy volunteers, normal human bronchial epithelial (NHBE) cells cultured at the air-liquid interface, and healthy whole-lung samples obtained from the Lung Tissue Research Consortium (LTRC).Our analysis suggests that 40-60 million reads are sufficient to assess the majority of the host transcriptome in these samples, whereas higher depths are needed for very low expressed genes or rare splice variants.We also analyzed read depths of human bronchial epithelial (HBE) cells treated with IL-13 or IL-17 to determine whether inflammation affects the parameters.Treatment with IL-13 or IL-17 showed no significant effect on the results, suggesting that 40 million reads is adequate to assess the transcriptome of HBE cells in either resting or cytokine-stimulated conditions.
Comprehensive variation discovery in single human genomes
Authors: Neil I Weisenfeld, Shuangye Yin, Ted Sharpe, Bayo Lau, Ryan Hegarty, Laurie Holmes, Brian Sogoloff, Diana Tabbaa, Louise Williams, Carsten Russ, Chad Nusbaum, Eric S Lander, Iain MacCallum, David B Jaffe
Journal: Nature Genetics (2014)
Statistics Notes: Validating scales and indexes
Authors: J M. Bland
Journal: BMJ (2002)

An index of quality is a measurement like any other, whether it is assessing a website, as in today's BMJ ,1 a clinical trial used in a meta-analysis,2 or the quality of a life experienced by a patient.3 As with all measurements, we have to decide whether it measures what we want it to measure, and how well.

The simplest measurements, such as length and distance, can be validated by an objective criterion. The earliest criteria must have been biological: the length of a pace, a foot, a thumb. The obvious problem, that the criterion varies from person to person, was eventually solved by establishing a fundamental unit and defining all others in terms of it. Other measurements can then be defined in terms of a fundamental unit. To define a unit of weight we find a handy substance which appears the same everywhere, such as water. The unit of weight is then the weight of a volume of water specified in the basic unit of length, such as 100 …
The volume effect in paediatric oncology: a systematic review
Authors: R.R.G. Knops, E.C. van Dalen, R.L. Mulder, E. Leclercq, S.L. Knijnenburg, G.J.L. Kaspers, R. Pieters, H.N. Caron, L.C.M. Kremer
Journal: Annals of Oncology (2013)
Assessing the potential carcinogenic activity of magnetic fields using animal models.
Authors: J McCann, R Kavet, C N Rafferty
Journal: Environmental Health Perspectives (2000)

We update our 1997 publication by reviewing 29 new reports of tests of magnetic fields (MFs) in six different in vivo animal models of carcinogenesis: 2-year, lifetime, or multigeneration exposure studies in rats or mice; and promotion/progression models (rat mammary carcinoma, rat liver focus, mouse skin, several models of human leukemia/lymphoma in rats and mice, and brain cancer in rats). Individual experiments are evaluated using a set of data quality criteria, and summary judgments are made across multiple experiments by applying a criterion of rough reproducibility. The potential for carcinogenicity of MFs is discussed in light of the significant body of carcinogenesis data from animal bioassays that now exists. Excluding abstracts, approximately 80% of the 41 completed studies identified in this and our previous review roughly satisfy data quality criteria. Among these studies, the criterion for independent reproducibility is not satisfied for any positive results but is satisfied for negative results in chronic bioassays in rats and mice and for negative results in both promotion and co-promotion assays using the SENCAR mouse skin model. Results of independent replication studies using the rat mammary carcinoma model were conflicting. We conclude that long-term exposure to continuous 50- or 60-Hz MFs in the range of 0.002-5 mT is unlikely to result in carcinogenesis in rats or mice. Though results of most promotion/progression assays are negative, a weak promoting effect of MFs under certain exposure conditions cannot be ruled out based on available data.
ERK Pathway Inhibitors: How Low Should We Go?
Authors: Moriah H. Nissan, Neal Rosen, David B. Solit
Journal: Cancer Discovery (2013)

Resistance to RAF inhibitors is generally accompanied by reactivation of extracellular signal-regulated kinase (ERK) signaling. SCH772984, a selective, ATP-competitive inhibitor of ERK1 and ERK2, is effective in BRAF-mutant models in which resistance is the result of ERK reactivation. SCH772984 may also have a role in the treatment of tumors in which ERK is dysregulated by mutant RAS, NF1, or activated receptor tyrosine kinases, settings in which current RAF inhibitors are ineffective.
Nine-year Follow-up for a Study of Diffusion-weighted Magnetic Resonance Imaging in a Prospective Prostate Cancer Active Surveillance Cohort
Authors: Daniel R. Henderson, Nandita M. de Souza, Karen Thomas, Sophie F. Riches, Veronica A. Morgan, Syed A. Sohaib, David P. Dearnaley, Christopher C. Parker, Nicholas J. van As
Journal: European Urology (2015)
In palliative care, discontinuation of statins did not differ from continuation for mortality
Authors: Martin Stockler
Journal: Annals of Internal Medicine (2015)

Source Citation Kutner JS, Blatchford PJ, Taylor DH, et al. Safety and benefit of discontinuing statin therapy in the setting of advanced, life-limiting illness: a randomized clinical trial. JAMA Intern Med. 2015;175:691-700. 25798575
Differences in the mechanism of metabolic regulation of ATP-sensitive K+ channels containing Kir6.1 and Kir6.2 subunits
Authors: Tabasum Farzaneh, Andrew Tinker
Journal: Cardiovascular Research (2008)

ATP sensitive K+ channels (KATP) sense adenine nucleotide concentrations and thus couple the metabolic state of the cell to membrane potential. The hetero-octameric complex of a sulphonylurea receptor (SUR2B) and an inwardly rectifying K+ channel (Kir6.1) and the corresponding native channel in smooth muscle are relatively insensitive to variations in intracellular ATP. Activation of these channels in blood vessels during hypoxia/ischaemia is thought to be mediated via hormonal regulation such as cellular adenosine release or the release of mediators from the endothelium. In contrast, intracellular ATP prominently inhibits Kir6.2 containing complexes, such as those present in cardiac myocytes. Thus, we investigated differences in the mechanism of metabolic regulation of Kir6.1 and Kir6.2 containing KATP channels. We have heterologously expressed KATP channel subunits in HEK293 and CHO cells and studied their function using 86Rb efflux and patch clamping. We show that rodent Kir6.1/SUR2B has direct intrinsic metabolic sensitivity independent of any regulation by protein kinase A. In contrast to Kir6.2 containing complexes, this was not endowed by the ATP sensitivity of the pore forming subunit but was instead a property of the SUR2B subunit. Mutagenesis of key residues within the nucleotide-binding domains (NBD) implicated both domains in governing the metabolic sensitivity. Kir6.1\SUR2B has intrinsic sensitivity to metabolism endowed by the likely processing of adenine nucleotides at the NBD of SUR2B.
Phase II Multicenter Study of the Epidermal Growth Factor Receptor Antibody Cetuximab and Cisplatin for Recurrent and Refractory Squamous Cell Carcinoma of the Head and Neck
Authors: Roy S. Herbst, Matthew Arquette, Dong M. Shin, Karel Dicke, Everett E. Vokes, Nozar Azarnia, Waun Ki Hong, Merrill S. Kies
Journal: Journal of Clinical Oncology (2005)

This multicenter phase II study was undertaken to define the efficacy and safety of cetuximab, an antiepidermal growth factor receptor chimeric human and murine monoclonal antibody, administered with cisplatin to patients with refractory metastatic or recurrent squamous cell carcinoma of the head and neck (SCCHN).One hundred thirty-two patients were to receive two 3-week cycles with cisplatin/paclitaxel or cisplatin/fluorouracil. Patients (n = 30) with a complete or partial response continued standard therapy. Seventy-six patients with stable disease (SD; n = 51) or progressive disease (PD/1; n = 25) received combination therapy with cetuximab (400 mg/m2 intravenously on day 1, then 250 mg/m2/wk) and cisplatin (75 or 100 mg/m2 intravenously on day 1 every 3 weeks). The protocol was subsequently amended to enroll patients who had developed PD within 90 days after platinum-based therapy (PD/2; n = 54).Five patients (20%) in PD/1, three patients (6%) in PD/2, and nine patients (18%) with SD achieved an objective response. Median duration of response was 4.2, 4.1, and 7.4 months for the PD/1, PD/2, and SD groups, respectively, with median overall survival times of 6.1, 4.3, and 11.7 months. The most common toxicities were anemia, acne-like skin rash, leukopenia, fatigue and malaise, and nausea and vomiting. Seven patients (5%) developed a grade 3 or 4 hypersensitivity reaction to cetuximab.Cetuximab and cisplatin is an active regimen in refractory SCCHN. The relative contribution of cetuximab is better defined in a single-agent trial. Cetuximab did not exacerbate cisplatin toxicity but was associated with skin rash in a majority of patients and occasional serious allergic reactions. Further study of this compound is warranted.
Metabolism of Alpha-And Beta-Adrenergic Receptors In Vitro and In Vivo
Authors: Lawrence C. Mahan, Ruth M. McKernan, Paul A. Insel
Journal: The Annual Review of Pharmacology and Toxicology (1987)

Due to the massive data sets available for drug candidates, modern drug discovery has advanced to the big data era. Central to this shift is the development of artificial intelligence approaches to implementing innovative modeling based on the dynamic, ...Read More
Pregnant women should have two scans, Scottish agency says
Authors: Bryan Christie
Journal: BMJ (2004)

All pregnant women in Scotland should be routinely offered two ultrasound scans to check the health of the fetus, a Scottish NHS agency has recommended. Currently the service is offered by justover half of Scotland's maternity units.

NHS Quality Improvement Scotland (NHS QIS) has carried out a full assessment of the clinical and cost effectiveness of routine ultrasonography in the first 24 weeks of pregnancy. It has concluded that a system that offers scans in both the first and second trimester is the …
Proximity ligation assay evaluates IDH1R132H presentation in gliomas
Authors: Lukas Bunse, Theresa Schumacher, Felix Sahm, Stefan Pusch, Iris Oezen, Katharina Rauschenbach, Marina Gonzalez, Gergely Solecki, Matthias Osswald, David Capper, Benedikt Wiestler, Frank Winkler, Christel Herold-Mende, Andreas von Deimling, Wolfgang Wick, Michael Platten
Journal: Journal of Clinical Investigation (2015)

For a targeted cancer vaccine to be effective, the antigen of interest needs to be naturally processed and presented on MHC by the target cell or an antigen-presenting cell (APC) in the tumor stroma. The presence of these characteristics is often assumed based on animal models, evaluation of antigen-overexpressing APCs in vitro, or assays of material-consuming immune precipitation from fresh solid tissue. Here, we evaluated the use of an alternative approach that uses the proximity ligation assay (PLA) to identify the presentation of an MHC class II–restricted antigen in paraffin-embedded tissue sections from patients with brain tumors. This approach required a specific antibody directed against the epitope that was presented. We used an antibody that specifically binds an epitope of mutated isocitrate dehydrogenase type 1 (IDH1R132H), which is frequently expressed in gliomas and other types of tumors. In situ PLA showed that the IDH1R132H epitope colocalizes with MHC class II in IDH1R132H-mutated glioma tissue. Moreover, PLA demonstrated colocalization between the class II epitope-containing melanoma antigen New York esophageal 1 and MHC class II. Collectively, our data suggest that PLA may be a useful tool to acquire information on whether an antigen is presented in situ, and this technique has potential to guide clinical studies that use antigen-specific cancer immunotherapy.
S.H.M.O. Wage-freeze?
Authors: G. W. Robinson
Journal: BMJ (1964)

Virus isolation tests on 72 sudden unexplained infant deaths and 34 cases of explained death showed that 42 and 29% respectively had virus infections. A wide range of viruses was encountered, mainly enteroviruses and adenoviruses, mostly from bowel specimens. The findings did not suggest that overwhelming virus infection was a common feature of sudden death in infancy.
The Leukotriene Receptor Antagonist Zafirlukast Inhibits Sulfur Dioxide–induced Bronchoconstriction in Patients with Asthma
Authors: STEPHEN C. LAZARUS, HOFER H. WONG, MICHAEL J. WATTS, HOMER A. BOUSHEY, BERNARD J. LAVINS, MARGARET C. MINKWITZ
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

Inhalation of sulfur dioxide (SO2) causes bronchoconstriction in most people with asthma. To examine the role of leukotrienes in this response, the antagonism of SO2-induced bronchoconstriction by a single oral dose of the leukotriene receptor antagonist zafirlukast was assessed in a double-blind, placebo-controlled, two-period crossover trial in 12 subjects with mild-to-moderate asthma. Subjects had bronchial hyperresponsiveness, an FEV1 ⩾ 70% of predicted, and a positive response to inhaled SO2 (an 8-unit increase in specific airway resistance on inhaling an SO2 concentration of ⩽ 4 ppm (PC8SRaw). Subjects were treated with zafirlukast (20 mg) or placebo on two treatment days 5 to 14 d apart. Two and 10 hours after treatment, subjects inhaled SO2 (0.25, 0.5, 1.0, 2.0, 4.0, and 8.0 ppm) during eucapnic hyperventilation at 20 L/min. PC8SRaw was determined after each challenge. Blood samples were collected to assess zafirlukast plasma concentrations versus effect. PC8SRaw was significantly higher 2 h after zafirlukast compared with placebo (3.1 versus 1.5 ppm; p = 0.02) and remained higher 10 h after treatment with zafirlukast (2.7 versus 1.9 ppm; p = 0.09). An association was found between zafirlukast plasma concentrations and increases in PC8SRaw 10 h after treatment (p = 0.001). The safety profile of zafirlukast was not clinically different from placebo. A single 20-mg dose of zafirlukast attenuated SO2-induced bronchoconstriction. We conclude that SO2-induced bronchoconstriction involves release of leukotrienes and that treatment with zafirlukast attenuates the bronchoconstrictor response.
Paclitaxel and gemcitabine versus paclitaxel and vinorelbine in patients with advanced non-small-cell lung cancer. A phase III study of the Hellenic Cooperative Oncology Group (HeCOG)
Authors: P.A. Kosmidis, G. Fountzilas, A.G. Eleftheraki, H.P. Kalofonos, G. Pentheroudakis, D. Skarlos, M.A. Dimopoulos, D. Bafaloukos, D. Pectasides, E. Samantas, J. Boukovinas, S. Lambaki, N. Katirtzoglou, C. Bakogiannis, K.N. Syrigos
Journal: Annals of Oncology (2010)

Paclitaxel (Taxol) and vinorelbine have shown synergism of cytotoxic effects in vitro and clinical activity in phase I and II studies. This combination was compared prospectively with the paclitaxel/gemcitabine regimen in non-operable non-small-cell lung cancer.Chemotherapy-naive patients, stage IIIbwet and IV with performance status (0-1), were randomized to receive paclitaxel 200 mg/m(2) on day 1 plus gemcitabine 1 gm/m(2) (group A) on days 1 and 8 every 3 weeks or paclitaxel 80 mg/m(2) plus vinorelbine 22.5 mg/m(2) (group B) on days 1, 8 and 15 every 4 weeks.A total of 398 out of 415 patients were eligible for analysis on intent-to-treat basis (group A: 196, group B: 202). Progression-free survival (PFS) was 5.0 months [95% confidence interval (CI) 4.3-5.6] and 4.4 months (95% CI 3.7-5.2) for groups A and B respectively (P=0.365). Median survival was 11.1 months (95% CI 9.2-13.0) and 8.6 months (95% CI 7.0-10.2) for groups A and B respectively (P = 0.147). Grade 3/4 neutropenia and leukopenia were worse in group B (P<0.001, in both cases). Febrile neutropenia and severe infections were more prominent (P<0.001, P=0.029 respectively) in group B.Although response rate, PFS and survival were non-different in both groups, toxicity was significantly worse in group B and therefore further investigation of P-Vin is of no value.