PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “Experimental validation”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 433 records · Page 24Linked to original sources
PubMed2005

A 3D finite element model of an implanted scapula: importance of a multiparametric validation using experimental data.

In order to help to understand the loosening phenomenon around glenoïd prostheses, a 3D finite element model of a previously tested implanted scapula has been developed. The construction of the model was done using CT scans of the tested scapula. Different bone material properties were tested and shell elements or 8 nodes hexaedric elements were used to model the cortical bone. Surface contact elements were introduced on one hand between the bone and the lower part of the plate of the implant, and on the other, between the loading metallic ball and the upper surface of the implant. The results of the model were compared with those issued from in vitro experiments carried out on the same scapula. The evaluation of the model was done for nine cases of loading of 500 N distributed on the implant, in terms of strains (principal strains of six spots around peripheral cortex of the glenoïd) and displacement of four points positioned on the implant. The best configuration of the model presented here, fits with experiments for most of the strains (difference lower than 150microdef) but it seems to be still too stiff (mainly in the lower part). Nevertheless, we want, in this paper, to underline the importance of doing a multiparametric validation for such a model. Indeed, some models can give correct results for one case of loading but bad results for another kind of loading, some others can give good results for one kind of compared parameters (like strains for instance) but bad results for the other one (like displacements).

Aged↗
PubMed2003

Prediction of drug metabolism: the case of cytochrome P450 2D6.

Cytochromes P450 (Cyt P450s) constitute the most important biotransformation enzymes involved in the biotransformation of drugs and other xenobiotics. Because drug metabolism by Cyt P450s plays such an important role in the disposition and in the pharmacological and toxicological effects of drugs, early consideration of ADME-properties is increasingly seen as essential for the discovery and the development of new drugs and drug candidates. The primary aim of this paper is to present various computational approaches used to rationalize and predict the activity and substrate selectivity of Cyt P450s, as well as the possibilities and limitations of these approaches, now and in the future. Attention is also paid to the experimental validation of these approaches by using high-throughput screening (HTS) of affinities to drug-drug interactions at the level of Cyt P450-isoenzymes. Since human Cyt P450 2D6 is one of the most important drug metabolizing enzymes and since in this regard much pioneering work has been done with this Cyt P450, Cyt P450 2D6 is chosen as a model for this discussion. Apart from early mechanism-based ab initio calculations on substrates of Cyt P450 2D6, pharmacophore modeling of ligands (i.e. both substrates and inhibitors) of Cyt P450 2D6 and protein homology modeling have been used successfully for the rationalisation and prediction of metabolite formation by this Cyt P450 isoenzyme. Significant protein structure-related species differences have been reported recently. It is concluded that not one computational approach is capable of rationalizing and reliably predicting metabolite formation by Cyt P450 2D6, but that it is rather the combination of the various complimentary approaches. It is moreover concluded, that experimental validation of the computational models and predictions is often still lacking. With the advent of novel, easily and well applicable in vitro based high throughput assays for ligand binding and turnover this limitation could be overcome soon, however. When effective links with other new and recent developments, such as bioinformatics, neural network computing, genomics and proteomics can be created, in silico rationalisation and prediction of drug metabolism by Cyt P450s is likely to become one of the key technologies in early drug discovery and development processes.

Animals↗
PubMed2006

A panic experimental model: validation of a complex operant behavioral method in undernourished rats, with desipramine to provide a template effect profile.

INTRODUCTION: Clinical studies have shown that some antidepressants may be more efficient than benzodiazepines to alleviate anxiety associated with panic disorders; however, operant conflict procedures in rats developed so far seem not particularly able to model human anxiety sensitive to antidepressant treatments. Previous panic models with learned responses did not statistically subtract the effect of confounding factors from the variable of interest. METHODS: Undernourished rats were selected due to their behavioral and neurobiological resemblance to human patients suffering from panic disorder. The Geller-Seifter paradigm represented the stressful environmental condition in adult life. Desipramine (10 mg/kg/day) or saline were administered IP during 7 days under a cross over design (N=10). Five daily 15 min-operant sessions were carried out on each experiment. Unpunished, unrewarded and punished operant behavioral periods were identical both in their duration and in their reward system (the FR1 schedule) in order to measure response suppression, which has not been considered in previous studies with the Geller-Seifter paradigm. The dependent variable was the difference between comparable unpunished and punished periods. RESULTS: A significant Diet x Drug interaction was observed in the dependent variable, which represented the level of "suppression/suppression release" induced by treatments. DISCUSSION: Compared to control rats, deprived rats showed a significant and selective anticonflict effect of desipramine on the stressful and complex operant performance. The animal model of perinatally protein-deprived rats along with the Geller-Seifter's operant behavioral paradigm may represent a more sensitive approach to model human anxiety sensitive to antidepressant treatments by considering the combined impact of both early biological trauma and adult learned experiences under the same design.

Animal Nutritional Physiological Phenomena↗
PubMed2005

Quantitative assessment of the glyoxalase pathway in Leishmania infantum as a therapeutic target by modelling and computer simulation.

The glyoxalase pathway of Leishmania infantum was kinetically characterized as a trypanothione-dependent system. Using time course analysis based on parameter fitting with a genetic algorithm, kinetic parameters were estimated for both enzymes, with trypanothione derived substrates. A K(m) of 0.253 mm and a V of 0.21 micromol.min(-1).mg(-1)for glyoxalase I, and a K(m) of 0.098 mm and a V of 0.18 micromol.min(-1).mg(-1) for glyoxalase II, were obtained. Modelling and computer simulation were used for evaluating the relevance of the glyoxalase pathway as a potential therapeutic target by revealing the importance of critical parameters of this pathway in Leishmania infantum. A sensitivity analysis of the pathway was performed using experimentally validated kinetic models and experimentally determined metabolite concentrations and kinetic parameters. The measurement of metabolites in L. infantum involved the identification and quantification of methylglyoxal and intracellular thiols. Methylglyoxal formation in L. infantum is nonenzymatic. The sensitivity analysis revealed that the most critical parameters for controlling the intracellular concentration of methylglyoxal are its formation rate and the concentration of trypanothione. Glyoxalase I and II activities play only a minor role in maintaining a low intracellular methylglyoxal concentration. The importance of the glyoxalase pathway as a therapeutic target is very small, compared to the much greater effects caused by decreasing trypanothione concentration or increasing methylglyoxal concentration.

Animals↗
PubMed2006

Structure of the 5' nontranslated region of the coxsackievirus b3 genome: Chemical modification and comparative sequence analysis.

Coxsackievirus B3 (CVB3) is a picornavirus which causes myocarditis and pancreatitis and may play a role in type I diabetes. The viral genome is a single 7,400-nucleotide polyadenylated RNA encoding 11 proteins in a single open reading frame. The 5' end of the viral genome contains a highly structured nontranslated region (5'NTR) which folds to form an internal ribosome entry site (IRES) as well as structures responsible for genome replication, both of which are critical for virulence. A structural model of the CVB3 5'NTR, generated primarily by comparative sequence analysis and energy minimization, shows seven domains (I to VII). While this model provides a preliminary basis for structural analysis, the model lacks comprehensive experimental validation. Here we provide experimental evidence from chemical modification analysis to determine the structure of the CVB3 5'NTR. Chemical probing results show that the theoretical model for the CVB3 5'NTR is largely, but not completely, supported experimentally. In combination with our chemical probing data, we have used the RNASTRUCTURE algorithm and sequence comparison of 105 enterovirus sequences to provide evidence for novel secondary and tertiary interactions. A comprehensive examination of secondary structure is discussed, along with new evidence for tertiary interactions. These include a loop E motif in domain III and a long-range pairing interaction that links domain II to domain V. The results of our work provide mechanistic insight into key functional elements in the cloverleaf and IRES, thereby establishing a base of structural information from which to interpret experiments with CVB3 and other picornaviruses.

5' Untranslated Regions↗
PubMed1996

Stress distributions inside intervertebral discs: the validity of experimental "stress profilometry'.

This paper evaluates a technique for measuring the distribution of compressive stress within cadaveric intervertebral discs. A strain-gauged pressure transducer, side-mounted near the tip of a 1.3 mm diameter needle, was inserted into cubes of disc tissue and into intact discs. Regardless of the position and orientation of the transducer within the tissue or disc, its output was found to be proportional to the compressive force applied to the specimen. The distribution of compressive stress was measured by pulling the instrumented needle through the specimen and the resulting stress profiles were reproducible to within 20 per cent. Profiles obtained at different applied loads showed a similar distribution of stress within the disc, suggesting that the compressive stress at any location and direction increased in proportion to the applied load. Since transducer output was also proportional to applied load, it was reasoned that it must be proportional to compressive stress within the disc. The average vertical compressive stresses acting on various regions within a disc were calculated from the stress profiles and multiplied by the cross-sectional area of each region: the resulting force was then compared with the known applied force in order to assess the calibration coefficient of the transducer. Agreement between the two forces was good, indicating that the calibration coefficient established in a saline bath was applicable to disc tissues also. However, artifactual stress peaks could be generated if the transducer was pulled across a bony asperity. It is concluded that the transducer measures the mean compressive stress acting upon it within disc tissues. Errors associated with the technique are small compared to differences in stress distributions which occur naturally, for example when intervertebral discs are loaded to simulate different postures in a living person.

Adult↗
PubMed2026

A model of cellular proliferation and mitochondrial biogenesis predicts prognosis and immunotherapy response in lung adenocarcinoma.

BACKGROUND: Lung adenocarcinoma (LUAD), which is the leading subtype of non-small cell lung cancer (NSCLC), poses considerable difficulties in accurate prognostic assessment and targeted therapeutic options. Cell proliferation-related genes (CPGs) and mitochondrial biogenesis-related genes (MBGs) play critical roles in tumor metabolic reprogramming; however, their prognostic value and molecular mechanisms in LUAD are poorly understood. This study aims to construct a CPG/MBG-based prognostic risk model for LUAD, evaluate its clinical utility in predicting prognosis and immunotherapy response, and experimentally validate the functional role of key model genes in LUAD progression. METHODS: By utilizing The Cancer Genome Atlas (TCGA)-LUAD and GSE72094 datasets, this investigation formulated a risk scoring model through differential expression screening combined with least absolute shrinkage and selection operator (LASSO)-Cox regression analysis. The molecular characteristics and clinical implications of the risk model were investigated via immune microenvironment evaluation, genomic alteration analysis, and drug sensitivity prediction. The functional contributions of key genes were further substantiated using quantitative reverse transcription polymerase chain reaction (qRT-PCR), commercial assay kits, the JC-1 fluorescent probe, the Cell Counting Kit-8 (CCK-8), Transwell invasion assays, and wound healing assays. RESULTS: A risk model based on seven CPGs and MBGs (PLK1, HMMR, CYP27A1, LDHA, NPAS2, KRT17, CIDEC) showed reliable predictive performance in both GSE72094 and the TCGA-LUAD cohorts. Enhanced tumor heterogeneity and an immunosuppressive microenvironment were observed in the high-risk group. Drug sensitivity analysis indicated that the risk model could guide personalized treatment strategies; for instance, high-risk patients showed increased susceptibility to agents such as docetaxel and 5-fluorouracil. In vitro experiments demonstrated that the key gene CIDEC exhibited upregulated expression in LUAD tissues and cells. Knockdown of CIDEC led to enhanced cellular energy metabolism and increased mitochondrial membrane potential, while also effectively suppressing cell invasion, proliferation, and migration. CONCLUSIONS: The established MBGs/CPGs prognostic model provides a novel tool for stratified treatment planning in LUAD, underscoring the crucial roles of cellular proliferation and mitochondrial biogenesis in tumor progression. Functional validation of CIDEC offers experimental support for the development of potential therapeutic strategies.

Lung adenocarcinoma (LUAD)↗
PubMedDate not supplied

A comprehensive simulator of the human respiratory system: validation with experimental and simulated data.

A comprehensive model of oxygen (O2) and carbon dioxide (CO2) exchange, transport, and storage in the adult human is presented, and its ability to provide realistic responses under different physiological conditions is evaluated. The model comprises three compartments (i.e., lung, body tissue, and brain tissue) and incorporates a controller that adjusts alveolar ventilation and cardiac output dynamically integrating stimuli coming from peripheral and central chemoreceptors. A new realistic CO2 dissociation curve based on a two-buffer model of acid-base chemical regulation is included. In addition, the model explicitly considers relevant physiological factors such as buffer base, the nonlinear interaction between the O2 and CO2 chemoreceptor responses, pulmonary shunt, dead space, variable time delays, and Bohr and Haldane effects. Model simulations provide results consistent with both dynamic and steady-state responses measured in subjects undergoing inhalation of high CO2 (hypercapnia) or low O2 (hypoxia) and subsequent recovery. An analysis of the results indicates that the proposed model fits the experimental data of ventilation and gas partial pressures as some meaningful simulators now available and in a very large range of gas intake fractions. Moreover, it also provides values of blood concentrations of CO2, HCO3-, and hydrogen ions in good agreement with more complex simulators characterized by an implicit formulation of the CO2 dissociation curve. In the experimental conditions analyzed, the model seems to represent a single theoretical framework able to appropriately describe the different phenomena involved in the control of respiration.

Acid-Base Equilibrium↗
PubMed2005

A computational and experimental approach to validating annotations and gene predictions in the Drosophila melanogaster genome.

Five years after the completion of the sequence of the Drosophila melanogaster genome, the number of protein-coding genes it contains remains a matter of debate; the number of computational gene predictions greatly exceeds the number of validated gene annotations. We have assembled a collection of >10,000 gene predictions that do not overlap existing gene annotations and have developed a process for their validation that allows us to efficiently prioritize and experimentally validate predictions from various sources by sequencing RT-PCR products to confirm gene structures. Our data provide experimental evidence for 122 protein-coding genes. Our analyses suggest that the entire collection of predictions contains only approximately 700 additional protein-coding genes. Although we cannot rule out the discovery of genes with unusual features that make them refractory to existing methods, our results suggest that the D. melanogaster genome contains approximately 14,000 protein-coding genes.

Animals↗
PubMed1997

Simulation of the induction of oxidation of low-density lipoprotein by high copper concentrations: evidence for a nonconstant rate of initiation.

Kinetic simulation can help obtain deeper insight into the molecular mechanisms of complex processes, such as lipid peroxidation (LPO) in low-density lipoprotein (LDL). We have previously set up a single-compartment model of this process, initiating with radicals generated externally at a constant rate to show the interplay of radical scavenging and chain propagation. Here we focus on the initiating events, substituting constant rate of initiation (Ri) by redox cycling of Cu2+ and Cu+. Our simulation reveals that early events in copper-mediated LDL oxidation include (1) the reduction of Cu2+ by tocopherol (TocOH) which generates tocopheroxyl radical (TocO.), (2) the fate of TocO. which either is recycled or recombines with lipid peroxyl radical (LOO.), and (3) the reoxidation of Cu+ by lipid hydroperoxide which results in alkoxyl radical (LO.) formation. So TocO., LOO., and LO. can be regarded as primordial radicals, and the sum of their formation rates is the total rate of initiation, Ri. As experimental information of these initiating events cannot be obtained experimentally, the whole model was validated experimentally by comparison of LDL oxidation in the presence and absence of bathocuproine as predicted by simulation. Simulation predicts that Ri decreases by 2 orders of magnitude during lag time. This has important consequences for the estimation of oxidation resistance in copper-mediated LDL oxidation: after consumption of tocopherol, even small amounts of antioxidants may prolong the lag phase for a considerable time.

Computer Simulation↗