bluuebunny/crossref_metadata_2025_split huggingface dataset:
Population pharmacokinetics and pharmacodynamics of hydroxyurea in sickle cell anemia patients, a basis for optimizing the dosing regimen
Authors: Paule Ines , Sassi Hind , Habibi Anoosha , Pham Kim PD , Bachir Dora , Galactéros Frédéric , Girard Pascal , Hulin Anne , Tod Michel 
Published: May 2011

Abstract

Background
Hydroxyurea (HU) is the first approved pharmacological treatment of sickle cell anemia (SCA). The objectives of this study were to develop population pharmacokinetic(PK)-pharmacodynamic(PD) models for HU in order to characterize the exposure-efficacy relationships and their variability, compare two dosing regimens by simulations and develop some recommendations for monitoring the treatment.

Methods
The models were built using population modelling software NONMEM VII based on data from two clinical studies of SCA adult patients receiving 500-2000 mg of HU once daily. Fetal hemoglobin percentage (HbF%) and mean corpuscular volume (MCV) were used as biomarkers for response. A sequential modelling approach was applied. Models were evaluated using simulation-based techniques. Comparisons of two dosing regimens were performed by simulating 10000 patients in each arm during 12 months.

Results
The PK profiles were described by a bicompartmental model. The median (and interindividual coefficient of variation (CV)) of clearance was 11.6 L/h (30%), the central volume was 45.3 L (35%). PK steady-state was reached in about 35 days. For a given dosing regimen, HU exposure varied approximately fivefold among patients. The dynamics of HbF% and MCV were described by turnover models with inhibition of elimination of response. In the studied range of drug exposures, the effect of HU on HbF% was at its maximum (median Imax was 0.57, CV was 27%); the effect on MCV was close to its maximum, with median value of 0.14 and CV of 49%. Simulations showed that 95% of the steady-state levels of HbF% and MCV need 26 months and 3 months to be reached, respectively. The CV of the steady-state value of HbF% was about 7 times larger than that of MCV. Simulations with two different dosing regimens showed that continuous dosing led to a stronger HbF% increase in some patients.

Conclusions
The high variability of response to HU was related in part to pharmacokinetics and to pharmacodynamics. The steady-state value of MCV at month 3 is not predictive of the HbF% value at month 26. Hence, HbF% level may be a better biomarker for monitoring HU treatment. Continuous dosing might be more advantageous in terms of HbF% for patients who have a strong response to HU.

Trial Registration
The clinical studies whose data are analysed and reported in this work were not required to be registered in France at their time. Both studies were approved by local ethics committees (of Mondor Hospital and of Kremlin-Bicetre Hospital) and written informed consent was obtained from each patient.
Development of an ELISA for sensitive and specific detection of IgA autoantibodies against BP180 in pemphigoid diseases
Authors: Csorba Kinga , Schmidt Sabine , Florea Florina , Ishii Norito , Hashimoto Takashi , Hertl Michael , Kárpáti Sarolta , Bruckner-Tuderman Leena , Nishie Wataru , Sitaru Cassian 
Published: May 2011

Abstract

Background
Pemphigoids are rare diseases associated with IgG, IgE and IgA autoantibodies against collagen XVII/BP180. An entity of the pemphigoid group is the lamina lucida-type of linear IgA disease (IgA pemphigoid) characterized by IgA autoantibodies against BP180. While for the detection of IgG and IgE autoantibodies specific to collagen XVII several ELISA systems have been established, no quantitative immunoassay has been yet developed for IgA autoantibodies. Therefore, the aim of the present study was to develop an ELISA to detect IgA autoantibodies against collagen XVII in the sera of patients with pemphigoids.

Methods
We expressed a soluble recombinant form of the collagen XVII ectodomain in mammalian cells. Reactivity of IgA autoantibodies from patients with IgA pemphigoid was assessed by immunofluorescence microscopy and immunoblot analysis. ELISA test conditions were determined by chessboard titration experiments. The sensitivity, specificity and the cut-off were determined by receiver-operating characteristics analysis.

Results
The optimized assay was carried out using sera from patients with IgA pemphigoid (n = 30) and healthy donors (n = 105). By receiver operating characteristics (ROC) analysis, an area under the curve of 0.993 was calculated, indicating an excellent discriminatory capacity. Thus, a sensitivity and specificity of 83.3% and 100%, respectively, was determined for a cut-off point of 0.48. As additional control groups, sera from patients with bullous pemphigoid (n = 31) and dermatitis herpetiformis (n = 50), a disease associated with IgA autoantibodies against epidermal transglutaminase, were tested. In 26% of bullous pemphigoid patients, IgA autoantibodies recognized the ectodomain of collagen XVII. One of 50 (2%) of dermatitis herpetiformis patients sera slightly topped the cut-off value.

Conclusions
We developed the first ELISA for the specific and sensitive detection of serum IgA autoantibodies specific to collagen XVII in patients with pemphigoids. This immunoassay should prove a useful tool for clinical and translational research and should essentially improve the diagnosis and disease monitoring of patients with IgA pemphigoid. Moreover, our findings strongly suggest that IgA pemphigoid and IgG bullous pemphigoid represent two ends of the clinical spectrum of an immunological loss of tolerance against components of hemidesmosomes, which is mediated by both IgG and IgA autoantibodies.
Lack of a-disintegrin-and-metalloproteinase ADAM10 leads to intracellular accumulation and loss of shedding of the cellular prion protein in vivo
Authors: Altmeppen Hermann C , Prox Johannes , Puig Berta , Kluth Mark A , Bernreuther Christian , Thurm Dana , Jorissen Ellen , Petrowitz Bettina , Bartsch Udo , De Strooper Bart , Saftig Paul , Glatzel Markus 
Published: May 2011

Abstract

Background
The cellular prion protein (PrPC) fulfils several yet not completely understood physiological functions. Apart from these functions, it has the ability to misfold into a pathogenic scrapie form (PrPSc) leading to fatal transmissible spongiform encephalopathies. Proteolytic processing of PrPC generates N- and C-terminal fragments which play crucial roles both in the pathophysiology of prion diseases and in transducing physiological functions of PrPC. A-disintegrin-and-metalloproteinase 10 (ADAM10) has been proposed by cell culture experiments to be responsible for both shedding of PrPC and its α-cleavage. Here, we analyzed the role of ADAM10 in the proteolytic processing of PrPC
in vivo.

Results
Using neuron-specific Adam10 knockout mice, we show that ADAM10 is the sheddase of PrPC and that its absence in vivo leads to increased amounts and accumulation of PrPC in the early secretory pathway by affecting its posttranslational processing. Elevated PrPC levels do not induce apoptotic signalling via p53. Furthermore, we show that ADAM10 is not responsible for the α-cleavage of PrPC.

Conclusion
Our study elucidates the proteolytic processing of PrPC and proves a role of ADAM10 in shedding of PrPC
in vivo. We suggest that ADAM10 is a mediator of PrPC homeostasis at the plasma membrane and, thus, might be a regulator of the multiple functions discussed for PrPC. Furthermore, identification of ADAM10 as the sheddase of PrPC opens the avenue to devising novel approaches for therapeutic interventions against prion diseases.
Analysis of complex metabolic behavior through pathway decomposition
Authors: Ip Kuhn , Colijn Caroline , Lun Desmond S 
Published: June 2011

Abstract

Background
Understanding complex systems through decomposition into simple interacting components is a pervasive paradigm throughout modern science and engineering. For cellular metabolism, complexity can be reduced by decomposition into pathways with particular biochemical functions, and the concept of elementary flux modes provides a systematic way for organizing metabolic networks into such pathways. While decomposition using elementary flux modes has proven to be a powerful tool for understanding and manipulating cellular metabolism, its utility, however, is severely limited since the number of modes in a network increases exponentially with its size.

Results
Here, we present a new method for decomposition of metabolic flux distributions into elementary flux modes. Our method can easily operate on large, genome-scale networks since it does not require all relevant modes of the metabolic network to be generated. We illustrate the utility of our method for metabolic engineering of Escherichia coli and for understanding the survival of Mycobacterium tuberculosis (MTB) during infection.

Conclusions
Our method can achieve computational time improvements exceeding 2000-fold and requires only several seconds to generate elementary mode decompositions on genome-scale networks. These improvements arise from not having to generate all relevant elementary modes prior to initiating the decomposition. The decompositions from our method are useful for understanding complex flux distributions and debugging genome-scale models.
Retroperitoneal smooth muscle tumor of uncertain malignant potential after hysterectomy: a case report
Authors: Won Hye Sung , Chun Hoo Geun , Lee Kyungji 
Published: May 2011

Abstract

Introduction
Smooth muscle tumors of uncertain malignant potential represent a histologically heterogeneous group of uterine smooth muscle tumors that cannot be diagnosed as either benign or malignant. Smooth muscle tumors of uncertain malignant potential are usually clinically benign, but should be considered tumors of low malignant potential because they can occasionally recur or metastasize to distant sites.

Case presentation
We report the case of a 62-year-old Mongol woman diagnosed with a retroperitoneal smooth muscle tumor of uncertain malignant potential and lung metastasis, with a history of prior hysterectomy. The case was initially misdiagnosed as retroperitoneal sarcoma, and our patient received chemotherapy. However, no interval change in the size of the retroperitoneal mass and metastatic lung nodules was seen over a period of at least five years. She underwent partial resection of the retroperitoneal mass for the purposes of debulking and establishing a histopathological diagnosis. The diagnosis of the retroperitoneal mass was then confirmed as a smooth muscle tumor of uncertain malignant potential.

Conclusion
Smooth muscle tumors of uncertain malignant potential have an unpredictable clinical course, and relapses generally appear to occur after a long disease-free interval of up to several years. Therefore, patients diagnosed with smooth muscle tumors of uncertain malignant potential should receive long-term follow-up.
Comparison of analyses of the QTLMAS XIV common dataset. I: genomic selection
Authors: Pszczola Marcin , Strabel Tomasz , Wolc Anna , Mucha Sebastian , Szydlowski Maciej 
Published: May 2011

Abstract

Background
For the XIV QTLMAS workshop, a dataset for traits with complex genetic architecture has been simulated and released for analyses by participants. One of the tasks was to estimate direct genomic values for individuals without phenotypes. The aim of this paper was to compare results of different approaches used by the participants to calculate direct genomic values for quantitative trait (QT) and binary trait (BT).

Results
Participants applied 26 approaches for QT and 15 approaches for BT. Accuracy for QT was between 0.26 and 0.89 for males and between 0.31 and 0.89 for females, and for BT ranged from 0.27 to 0.85. For QT, percentage of lost response to selection varied from 8% to 83%, whereas for BT the loss was between 15% and 71%.

Conclusions
Bayesian model averaging methods predicted breeding values slightly better than GBLUP in a simulated data set. The methods utilizing genomic information performed better than traditional pedigree based BLUP analyses. Bivariate analyses was slightly advantageous over single trait for the same method. None of the methods estimated the non-additivity of QTL affecting the QT, which may be one of the constrains in accuracy observed in real data.
Pre-selection of markers for genomic selection
Authors: Schulz-Streeck Torben , Ogutu Joseph O , Piepho Hans-Peter 
Published: May 2011

Abstract

Background
Accurate prediction of genomic breeding values (GEBVs) requires numerous markers. However, predictive accuracy can be enhanced by excluding markers with no effects or with inconsistent effects among crosses that can adversely affect the prediction of GEBVs.

Methods
We present three different approaches for pre-selecting markers prior to predicting GEBVs using four different BLUP methods, including ridge regression and three spatial models. Performances of the models were evaluated using 5-fold cross-validation.

Results and conclusions
Ridge regression and the spatial models gave essentially similar fits. Pre-selecting markers was evidently beneficial since excluding markers with inconsistent effects among crosses increased the correlation between GEBVs and true breeding values of the non-phenotyped individuals from 0.607 (using all markers) to 0.625 (using pre-selected markers). Moreover, extension of the ridge regression model to allow for heterogeneous variances between the most significant subset and the complementary subset of pre-selected markers increased predictive accuracy (from 0.625 to 0.648) for the simulated dataset for the QTL-MAS 2010 workshop.
Genomic breeding value prediction and QTL mapping of QTLMAS2010 data using Bayesian Methods
Authors: Sun Xiaochen , Habier David , Fernando Rohan L , Garrick Dorian J , Dekkers Jack CM 
Published: May 2011

Abstract

Background
Bayesian methods allow prediction of genomic breeding values (GEBVs) using high-density single nucleotide polymorphisms (SNPs) covering the whole genome with effective shrinkage of SNP effects using appropriate priors. In this study we applied a modification of the well-known BayesA and BayesB methods to estimate the proportion of SNPs with zero effects (π) and a common variance for non-zero effects. The method, termed BayesCπ, was used to predict the GEBVs of the last generation of the QTLMAS2010 data. The accuracy of GEBVs from various methods was estimated by the correlation with phenotypes in the last generation. The methods were BayesCPi and BayesB with different π values, both with and without polygenic effects, and best linear unbiased prediction using an animal model with a genomic or numerator relationship matrix. Positions of quantitative trait loci (QTLs) were identified based on the variances of GEBVs for windows of 10 consecutive SNPs. We also proposed a novel approach to set significance thresholds for claiming QTL in this specific case by using pedigree-based simulation of genotypes. All analyses were focused on detecting and evaluating QTL with additive effects.

Results
The accuracy of GEBVs was highest for BayesCπ, but the accuracy of BayesB with π equal to 0.99 was similar to that of BayesCπ. The accuracy of BayesB dropped with a decrease in π. Including polygenic effects into the model only had marginal effects on accuracy and bias of predictions. The number of QTL identified was 15 when based on a stringent 10% chromosome-wise threshold and increased to 21 when a 20% chromosome-wise threshold was used.

Conclusions
The BayesCπ method without polygenic effects was identified to be the best method for the QTLMAS2010 dataset, because it had highest accuracy and least bias. The significance criterion based on variance of 10-SNP windows allowed detection of more than half of the QTL, with few false positives.
Small interference RNA targeting tissue factor inhibits human lung adenocarcinoma growth in vitro and in vivo
Authors: Xu Chengcheng , Gui Qi , Chen Wenshu , Wu Leiming , Sun Wei , Zhang Ni , Xu Qinzi , Wang Jianing , Fu Xiangning 
Published: May 2011

Abstract

Background
The human coagulation trigger tissue factor (TF) is overexpressed in several types of cancer and involved in tumor growth, vascularization, and metastasis. To explore the role of TF in biological processes of lung adenocarcinoma, we used RNA interference (RNAi) technology to silence TF in a lung adenocarcinoma cell line A549 with high-level expression of TF and evaluate its antitumor effects in vitro and in vivo.

Methods
The specific small interfering RNA (siRNA) designed for targeting human TF was transfected into A549 cells. The expression of TF was detected by reverse transcription-PCR and Western blot. Cell proliferation was measured by MTT and clonogenic assays. Cell apoptosis was assessed by flow cytometry. The metastatic potential of A549 cells was determined by wound healing, the mobility and Matrigel invasion assays. Expressions of PI3K/Akt, Erk1/2, VEGF and MMP-2/-9 in transfected cells were detected by Western blot. In vivo, the effect of TF-siRNA on the growth of A549 lung adenocarcinoma xenografts in nude mice was investigated.

Results
TF -siRNA significantly reduced the expression of TF in the mRNA and protein levels. The down-regulation of TF in A549 cells resulted in the suppression of cell proliferation, invasion and metastasis and induced cell apoptosis in dose-dependent manner. Erk MAPK, PI3K/Akt pathways as well as VEGF and MMP-2/-9 expressions were inhibited in TF-siRNA transfected cells. Moreover, intratumoral injection of siRNA targeting TF suppressed the tumor growth of A549 cells in vivo model of lung adenocarcinoma.

Conclusions
Down-regulation of TF using siRNA could provide a potential approach for gene therapy against lung adenocarcinoma, and the antitumor effects may be associated with inhibition of Erk MAPK, PI3K/Akt pathways.
Comparisons of 7- to 78-joint ultrasonography scores: all different joint combinations show equal response to adalimumab treatment in patients with rheumatoid arthritis
Authors: Hammer Hilde Berner , Kvien Tore K 
Published: May 2011

Abstract
Introduction
The primary objectives were to explore the associations between a comprehensive ultrasonographic (US) assessment of joints, tendons and bursae and previously described reduced joint counts (7-, 12-, 28- and 44-joint score) as well as to assess the sensitivity to change of these different US joint combinations during biological treatment.

Methods
Twenty patients with rheumatoid arthritis (RA) were examined by US (B-mode (BM) and power Doppler (PD)) with use of a semi-quantitative (0 to 3) score of 78 joints, 36 tendons/tendon groups and two bursae (hereafter described as the 78-joint score) at baseline and 1, 3, 6 and 12 months after initiating treatment with adalimumab. BM and PD scores for the different joint combinations were generated.

Results
The reduced joint scores had high correlation coefficients with the 78-joint score at all examinations (range 0.79 to 0.99 for BM and 0.77 to 0.99 for PD, each P < 0.001) and sum BM and PD scores of all the different joint combinations improved significantly during follow-up (P ≤ 0.05 to 0.001).

Conclusions
The reduced joint combinations were highly associated to the 78-joint score. Furthermore, all the joint combinations presently explored responded well to biological treatment. This indicates that an approach focusing on few joints and tendons gives equivalent information about the inflammatory activity in RA patients as a comprehensive US examination. The optimal combination of joints and tendons for a valid, reliable and feasible US measurement should be further explored to define a US score for follow-up of RA patients on biological treatment.
Videoradiographic analysis of the range of motion in unilateral experimental knee joint arthritis in rats
Authors: Boettger Michael K , Leuchtweis Johannes , Schaible Hans-Georg , Schmidt Manuela 
Published: May 2011

Abstract
Introduction
The translational and predictive value of animal models highly depends on the validity of respective readout parameters. In arthritis research, there has been a shift from sole threshold testing for pain-related behavior, as well as from swelling and histology assessment for inflammation, toward an analysis of joint function as indicated, for instance, by an increasing number of studies on gait abnormalities. Clinically, the range of motion (ROM) of the affected joint plays a major role in diagnosis and the assessment of treatment benefits. This parameter, however, is only insufficiently detected by currently used analytic systems in animals.

Methods
Here we used high-resolution videoradiographic analysis to assess ROM in experimental knee joint arthritis in rats. This parameter is described during the 21-day course of antigen-induced arthritis in rats. Furthermore, the therapeutic effects of antinociceptive (morphine) and anti-inflammatory (dexamethasone) treatment on ROM are documented. To obtain additional information on the implications of ROM in animal models, correlations were performed to measure pain-related behavior and inflammation.

Results
The study animals showed a significant reduction in ROM of the inflamed knee joint in the acute phase of arthritis. This was accompanied by an increase in knee joint movement on the contralateral side, indicating a compensational mechanism. Both morphine and dexamethasone treatment increased and thus normalized ROM. Changes in ROM were further stage-dependently correlated with weight bearing and joint swelling, that is, with both pain-related behavior and signs of inflammation.

Conclusions
The dynamic ROM observed in freely moving rats in our model of knee joint arthritis might serve as a parameter for global disease activity and might thus represent a promising readout parameter for preclinical assessment regarding the overall efficacy not only of antiarthritic but also of antinociceptive compounds.