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PubMed2006

MR-determined metabolic phenotype of breast cancer in prediction of lymphatic spread, grade, and hormone status.

The purpose of the study was to evaluate the use of metabolic phenotype, described by high-resolution magic angle spinning magnetic resonance spectroscopy (HR MAS MRS), as a tool for prediction of histological grade, hormone status, and axillary lymphatic spread in breast cancer patients. Biopsies from breast cancer (n = 91) and adjacent non-involved tissue (n = 48) were excised from patients (n = 77) during surgery. HR MAS MR spectra of intact samples were acquired. Multivariate models relating spectral data to histological grade, lymphatic spread, and hormone status were designed. The multivariate methods applied were variable reduction by principal component analysis (PCA) or partial least-squares regression-uninformative variable elimination (PLS-UVE), and modelling by PLS, probabilistic neural network (PNN), or cascade correlation neural network. In the end, model verification by prediction of blind samples (n = 12) was performed. Validation of PNN training resulted in sensitivity and specificity ranging from 83 to 100% for all predictions. Verification of models by blind sample testing showed that hormone status was well predicted by both PNN and PLS (11 of 12 correct), lymphatic spread was best predicted by PLS (8 of 12), whereas PLS-UVE PNN was the best approach for predicting grade (9 of 12 correct). MR-determined metabolic phenotype may have a future role as a supplement for clinical decision-making-concerning adjuvant treatment and the adaptation to more individualised treatment protocols.

Adult↗
PubMed1994

Modelling of human acute toxicity from physicochemical properties and non-vertebrate acute toxicity of the 38 organic chemicals of the MEIC priority list by PLS regression and neural network.

Linear and non-linear modelling of human acute toxicity (as human lethal concentrations; HLCs) of the 38 organic chemicals from the 50 priority compounds of the Multicentre Evaluation of In Vitro Cytotoxicity (MEIC) programme was investigated. The models obtained were derived either from a set of 23 physicochemical properties of the compounds or from their acute toxicities to five aquatic non-vertebrates together with the physicochemical properties. For the linear type, modelling was performed using a partial least square projection to latent structures (PLS) regression method; for the non-linear models, both PLS regression and neural network were utilized. A neural network using a combination of backpropagation and cascade-correlation algorithms was applied in this study. The results generally reveal a slightly better predictive performance of the models obtained from PLS regression than those obtained from neural networks. However, the model composed of physicochemical properties (PC-model) from the trained neural network using a back propagation algorithm with pruning technique proved superior to that trained with a combination of backpropagation and cascade-correlation algorithms after leave-one-out cross-validation. The predictive power of the PC-models, whether linear or non-linear, was comparable with that of the corresponding models consisting of both structural descriptors and the ecotoxicological tests (ECOPC-models), except for the battery (ECOPC-model) from the neural network. The composition of the 'best' PLS and neural network models points to the importance of the combination of physicochemical properties reflecting lipophilicity, size, volume, intermolecular binding forces and electronic properties of the molecule. All the aquatic non-vertebrate tests are shown to be essential in explaining human acute toxicity. However, the degree of contribution differed, with the crustacean (Artemia salina) and the bacterial (Microtox) bioassays being more important to the linear and non-linear PLS models, whereas the crustacean (Artemia salina and Streptocephalus proboscideus) tests, and the rotifer (Brachionus calyciflorus) assay were important to the neural network models. The organochlorine (lindane) and bipyridinium (paraquat) pesticides were common outliers in all the models. Moreover, the latter two compounds and the organophosphate (malathion) pesticide were also common outliers in all ECOPC-models. Other types of pesticides, however, fit the models. The predicted HLCs of a number of non-pesticides, including some chlorinated compounds, also deviated from the observed HLCs by more than one order of magnitude.

Algorithms↗
PubMed2006

Signaling proteins in raft-like microdomains are essential for Ca2+ wave propagation in glial cells.

The hypothesis that calcium signaling proteins segregate into lipid raft-like microdomains was tested in isolated membranes of rat oligodendrocyte progenitor (OP) cells and astrocytes using Triton X-100 solubilization and density gradient centrifugation. Western blot analysis of gradient fractions showed co-localization of caveolin-1 with proteins involved in the Ca2+ signaling cascade. These included agonist receptors, P2Y1, and M1, TRPC1, IP3R2, ryanodine receptor, as well as the G protein Galphaq and Homer. Membranes isolated from agonist-stimulated astrocytes showed an enhanced recruitment of phospholipase C (PLCbeta1), IP3R2 and protein kinase C (PKC-alpha) into lipid raft fractions. IP3R2, TRPC1 and Homer co-immunoprecipitated, suggesting protein-protein interactions. Disruption of rafts by cholesterol depletion using methyl-beta-cyclodextrin (beta-MCD) altered the distribution of caveolin-1 and GM1 to non-raft fractions with higher densities. beta-MCD-induced disruption of rafts inhibited agonist-evoked Ca2+ wave propagation in astrocytes and attenuated wave speeds. These results indicate that in glial cells, Ca2+ signaling proteins might exist in organized membrane microdomains, and these complexes may include proteins from different cellular membrane systems. Such an organization is essential for Ca2+ wave propagation.

Animals↗
PubMed2005

Modeling of submerged membrane bioreactor treating cheese whey wastewater by artificial neural network.

A submerged membrane bioreactor receiving cheese whey was modeled by artificial neural network and its performance over a period of 100 days at different solids retention times was evaluated with this robust tool. A cascade-forward network was used to model the membrane bioreactor and normalization was used as a preprocessing method. The network was fed with two subsets of operational data, with two-thirds being used for training and one-third for testing the performance of the artificial neural network. The training procedure for effluent chemical oxygen demand (COD), ammonia, nitrate and total phosphate concentrations was very successful and a perfect match was obtained between the measured and the calculated concentrations. The results of the confirmation (or testing) procedure for effluent ammonia and nitrate concentrations were very successful; however, the results of the confirmation procedure for effluent COD and total phosphate concentrations were only satisfactory.

Algorithms↗
PubMed2002

Responding under time pressure: testing two animal learning models and a model of visual categorization.

Two experiments are reported, which employed a Pavlovian eyelid conditioning procedure with human participants. The experiments tested the predictions of three models of the time-course of processing under time pressure. These were the extended generalized context model (Lamberts, 1998), and two variants of the Rescorla-Wagner model (Rescorla & Wagner, 1972), which were activated in cascade mode. Reinforcement schedules in the experiments were equivalent either to an AND rule or to an XOR rule. The time available for processing the conditioned stimulus and initiating a conditioned response was manipulated by varying the interval from the onset of the conditioned stimulus to the onset of the unconditioned stimulus. The results were in accord with the predictions of one of the two variants of the Rescorla-Wagner model.

Adult↗
PubMed2005

A frequency-modulated quantum-cascade laser for spectroscopy of CH4 and N2O isotopomers.

We report the development of a novel laser spectrometer for high-sensitivity detection of methane and nitrous oxide. The system relies on a quantum-cascade laser source emitting wavelength of around 8.06 microm, where strong fundamental absorption bands occur for the considered species and their isotopomers. The detection technique is based on audio-frequency and radio-frequency modulation of laser radiation. First experimental tests have been performed to estimate the achievable detection limits and the signal reproducibility levels in view of possible measurements of (13)C/(12)C, (18)O/(16)O, (17)O/(16)O and (15)N/(14)N isotope ratios.

Carbon Isotopes↗
PubMed2002

Size analysis of a pressurized metered dose inhaler-delivered solution formulation by an Aerosizer-LD time-of-flight aerosol particle size spectrometer.

In a previous study, an Aerosizer-LD time-of-flight (TOF) aerosol spectrometer was shown to underestimate significantly the aerodynamic size of airborne particles produced following actuation of a suspension-based formulation delivered from a pressurized metered-dose inhaler (pMDI) via a nonelectrostatic valved holding chamber (VHC). It was postulated that the nonspecific nature of the particle detection system in terms of chemical composition was responsible for the inclusion of smaller non-drug-containing excipient particles in the measured size distribution data from this analyzer. This limitation may not apply to certain solution formulations in which the only particles remaining after the evaporation of propellant and volatile excipient (solubilizer) are composed of pure drug substance. Such a formulation (QVAR, HFA-formulated beclomethasone di-propionate [BDP]) has recently become available, and the present investigation was therefore designed to test this hypothesis. Aerosizer-LD measured mass-weighted size distribution data for QVAR had a mass median aerodynamic diameter (MMAD) close to 1.1 microm, very similar to published data for this parameter, based on measurement of the aerosol by cascade impactor followed by drug-specific assay. However, the Aerosizer-LD underestimated the spread of the size distribution significantly. The causes are believed to be a combination of two separate effects: (1) lack of sensitivity of the particle detection system to particles finer than about 0.7 microm aerodynamic diameter and (2) preferential removal of particles larger than the MMAD, either by evaporation of residual solvent (ethanol) or by inertial/gravitational deposition in the sampling arrangement upstream of the measurement zone.

Aerosols↗
PubMed2002

Summary of stationary and personal air sampling measurements made during a plutonium glovebox decommissioning project.

Workplace air sampling was performed during the decommissioning of a previously active plutonium glovebox facility located at Argonne National Laboratory. Personal air samplers (PAS) were used to measure breathing zone activity concentrations of workers engaged in size-reducing contaminated gloveboxes. Stationary air samplers (SAS) were used to measure the work area activity concentrations and test their application in providing representative sampling of breathing zone activity concentrations. The relative response of these samplers (PAS:SAS) was tracked during the course of the decommissioning work, with results yielding favorable agreement to within a factor of +/-5. A cascade impactor was used to determine the particle size distribution of workplace aerosols. The average activity median aerodynamic diameter (AMAD) was estimated to be 3.0 microm, with a corresponding geometric standard deviation of 2.4. A gas-flow proportional counter was utilized to measure the gross alpha activity collected on both the SAS glass fiber and the PAS cellulose fiber filters. A subset of this filter group was subsequently analyzed using an alpha spectrometer post radiochemical processing and isotopic separation. The quantity of alpha activity measured on the SAS filters was generally within +/-30% of the alpha spectrometry measurements. However, measurements made of the activity present on the PAS cellulose fiber filters were consistently underestimated using a gas-flow proportional counter, suggesting a small correction factor of 15-20% to account for the absorption of alpha particle emissions.

Air Pollutants, Occupational↗
PubMed2000

What do scaffold proteins really do?

Scaffold proteins play an important role in coordinating signal transduction cascades. However, their exact mechanism of action and the ultimate effect they have on the signal output remain unclear. Ferrell discusses how computer simulations have provided insight into the multiple possible functions that scaffold proteins may have. What remains is to test the predictions in real cells to determine what difference the presence of a scaffold really makes in the output of a signaling pathway.

Animals↗
PubMed2005

A novel splice variant of interleukin-1 receptor (IL-1R)-associated kinase 1 plays a negative regulatory role in Toll/IL-1R-induced inflammatory signaling.

The interleukin-1 (IL-1) receptor-associated kinase 1 (IRAK1) is a member of the IRAK kinase family that plays a pivotal role in the Toll/IL-1 receptor (TIR) family signaling cascade. We have identified a novel splice variant, IRAK1c, which lacks a region encoded by exon 11 of the IRAK1 gene. IRAK1c expression was confirmed by both RNA and protein detection. Although both IRAK1 and IRAK1c are expressed in most tissues tested, IRAK1c is the predominant form of IRAK1 expressed in the brain. Unlike IRAK1, IRAK1c lacks kinase activity and cannot be phosphorylated by IRAK4. However, IRAK1c retains the ability to strongly interact with IRAK2, MyD88, Tollip, and TRAF6. Overexpression of IRAK1c suppressed NF-kappaB activation and blocked IL-1beta-induced IL-6 as well as lipopolysaccharide- and CpG-induced tumor necrosis factor alpha production in multiple cellular systems. Mechanistically, we provide evidence that IRAK1c functions as a dominant negative by failing to be phosphorylated by IRAK4, thus remaining associated with Tollip and blocking NF-kappaB activation. The presence of a regulated, alternative splice variant of IRAK1 that functions as a kinase-dead, dominant-negative protein adds further complexity to the variety of mechanisms that regulate TIR signaling and the subsequent inflammatory response.

Adaptor Proteins, Signal Transducing↗
PubMed1992

Structure and function of cholera toxin and the related Escherichia coli heat-labile enterotoxin.

Cholera and the related Escherichia coli-associated diarrheal disease are important problems confronting Third World nations and any area where water supplies can become contaminated. The disease is extremely debilitating and may be fatal in the absence of treatment. Symptoms are caused by the action of cholera toxin, secreted by the bacterium Vibrio cholerae, or by a closely related heat-labile enterotoxin, produced by Escherichia coli, that causes a milder, more common traveler's diarrhea. Both toxins bind receptors in intestinal epithelial cells and insert an enzymatic subunit that modifies a G protein associated with the adenylate cyclase complex. The consequent stimulated production of cyclic AMP, or other factors such as increased synthesis of prostaglandins by intoxicated cells, initiates a metabolic cascade that results in the excessive secretion of fluid and electrolytes characteristic of the disease. The toxins have a very high degree of structural and functional homology and may be evolutionarily related. Several effective new vaccine formulations have been developed and tested, and a growing family of endogenous cofactors is being discovered in eukaryotic cells. The recent elucidation of the three-dimensional structure of the heat-labile enterotoxin has provided an opportunity to examine and compare the correlations between structure and function of the two toxins. This information may improve our understanding of the disease process itself, as well as illuminate the role of the toxin in studies of signal transduction and G-protein function.

Amino Acid Sequence↗
PubMed2006

Nox2-containing NADPH oxidase and Akt activation play a key role in angiotensin II-induced cardiomyocyte hypertrophy.

Angiotensin II (ANG II) has profound effects on the development and progression of pathological cardiac hypertrophy; however, the intracellular signaling mechanisms are not fully understood. In this study, we used genetic tools to test the hypothesis that increased formation of superoxide (O2-*) radicals from a Rac1-regulated Nox2-containing NADPH oxidase is a key upstream mediator of ANG II-induced activation of serine-threonine kinase Akt, and that this signaling cascade plays a crucial role in ANG II-dependent cardiomyocyte hypertrophy. ANG II caused a significant time-dependent increase in Rac1 activation and O2-* production in primary neonatal rat cardiomyocytes, and these responses were abolished by adenoviral (Ad)-mediated expression of a dominant-negative Rac1 (AdN17Rac1) or cytoplasmic Cu/ZnSOD (AdCu/ZnSOD). Moreover, both AdN17Rac1 and AdCu/ZnSOD significantly attenuated ANG II-stimulated increases in cardiomyocyte size. Quantitative real-time PCR analysis demonstrated that Nox2 is the homolog expressed at highest levels in primary neonatal cardiomyocytes, and small interference RNA (siRNA) directed against it selectively decreased Nox2 expression by >95% and abolished both ANG II-induced O2-* generation and cardiomyocyte hypertrophy. Finally, ANG II caused a time-dependent increase in Akt activity via activation of AT(1) receptors, and this response was abolished by Ad-mediated expression of cytosolic human O2-* dismutase (AdCu/ZnSOD). Furthermore, pretreatment of cardiomyocytes with dominant-negative Akt (AdDNAkt) abolished ANG II-induced cellular hypertrophy. These findings suggest that O2-* generated by a Nox2-containing NADPH oxidase is a central mediator of ANG II-induced Akt activation and cardiomyocyte hypertrophy, and that dysregulation of this signaling cascade may play an important role in cardiac hypertrophy.

Adenoviridae↗
PubMed2006

IL-4 induced MUC4 enhancement in respiratory epithelial cells in vitro is mediated through JAK-3 selective signaling.

BACKGROUND: Recent studies have identified MUC4 mucin as a ligand for activation of ErbB2, a receptor tyrosine kinase that modulates epithelial cell proliferation following epithelial damage in airways of asthmatics. In this study, we investigated the potential role of IL-4, one of the Th2 inflammatory cytokines persistent in asthmatic airways, in regulating MUC4 expression using a cell line NCI-H650. METHODS: Real time PCR analysis was performed to determine concentration and time dependent effects of IL-4 upon MUC4 expression. Nuclear run on experiments were carried out to explore potential transcriptional modulation. Western blotting experiments using a monoclonal antibody specific to ASGP-2 domain of MUC4 were performed to analyze MUC4 glycoprotein levels in plasma membrane fractions. To analyze potential signal transduction cascades, IL-4 treated confluent cultures were co-incubated, separately with a pan-JAK inhibitor, a JAK-3 selective inhibitor or a MEK-1, 2 (MAPK) inhibitor at various concentrations before MUC4 transcript analysis. Corresponding transcription factor activation was tested by western blotting using a monoclonal p-STAT-6 antibody. RESULTS: MUC4 levels increased in a concentration and time specific fashion reaching peak expression at 2.5 ng/ml and 8 h. Nuclear run on experiments revealed transcriptional enhancement. Corresponding increases in MUC4 glycoprotein levels were observed in plasma membrane fractions. Pan-JAK inhibitor revealed marked reduction in IL-4 stimulated MUC4 levels and JAK3 selective inhibitor down-regulated MUC4 mRNA expression in a concentration-dependent fashion. In accordance with the above observations, STAT-6 activation was detected within 5 minutes of IL-4 stimulus. No effect in MUC4 levels was observed on using a MAPK inhibitor. CONCLUSION: These observations signify a potential role for IL-4 in MUC4 up-regulation in airway epithelia.

Cell Line, Tumor↗
PubMed2002

Dose-finding and pharmacokinetic study of cisplatin, gemcitabine, and SU5416 in patients with solid tumors.

PURPOSE: To investigate the feasibility and pharmacokinetics of the combination cisplatin, gemcitabine, and SU5416. PATIENTS AND METHODS: Patients received cisplatin 80 mg/m(2) on day 1, gemcitabine 1,250 mg/m(2) on days 1 and 8, repeated every 3 weeks, and SU5416 (85 and 145 mg/m(2)) intravenously twice weekly. Pharmacokinetics of all three agents, side effects, and antitumor response were investigated in patients with solid tumors amenable to therapy with cisplatin/gemcitabine. RESULTS: In the first cohort of three patients entered at the 85 mg/m(2) dose, no dose-limiting toxicities were observed. In the next cohort (145 mg/m(2)), three patients developed a thromboembolic event. After entry was restricted to patients with low thromboembolic risk, three additional patients enrolled at 145 mg/m(2) developed a thromboembolic event. The dose was then reduced to 85 mg/m(2) in all patients still on the study, and three additional patients were entered on this dose level. In 19 treated patients, eight patients developed nine thromboembolic events (three transient ischemic attacks, two cerebrovascular accidents, and four deep venous thromboses). The most common toxicities observed were those previously reported for SU5416 alone (headache and phlebitis) and for this chemotherapy regimen (nausea, thrombocytopenia, and leucopenia). No significant pharmacologic interaction among the three drugs was observed. Response rates were similar to those expected in the patient population selected for this study. Analysis of variables of the coagulation cascade and of vessel wall activation was performed in three patients and showed significant increases in thrombin generation and endothelial cell perturbation in a treatment cycle-dependent manner. CONCLUSION: The incidence of thromboembolic events, possibly related to the particular regimen tested in this study, discourages further investigation of this regimen.

Adult↗
PubMed1989

Axonal transport and central visual projections of ganglion cells in congenitally blind chickens.

The rd (retinal degenerate) strain of chicken is an example of a recessively inherited mutation characterized by blindness at the time of hatching, as defined by behavioral and electrophysiological tests. Paradoxically, blind mutants have normal retinal morphology, even at the ultrastructural level. Eventually, however, the entire retina degenerates in this strain, perhaps as a result of disuse atrophy. Results of preliminary studies imply that a defect in the visual transduction cascade in photoreceptor cells is responsible for the lack of vision. As well as being an important animal model for studies on photochemistry and transduction, the rd chicken may afford a paradigm for studies on inner retinal physiology and pathology, as electrical input to this inner neuronal system appears to be absent. In the current study we examined axonal transport (both retrograde and anterograde) in rd retinal ganglion cells and connectivity of ganglion cells to visual centers in the brain and compared these to normally sighted chicks. All visuorecipient nuclei were present in rd animals and appeared normal at the light microscopic level. When 3H-proline was injected into one eye of a blind chicken on the day of hatching, labeled polypeptides or proteins were transported via a fast transport mechanism to the same visual centers in roughly the same quantities as in normally sighted chicks. When horseradish peroxidase (HRP) was injected in the optic tectum of blind and normal 1 day old chicks, this label was transported retrogradely to the soma of retinal ganglion cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2005

A direct interaction between TGFbeta activated kinase 1 and the TGFbeta type II receptor: implications for TGFbeta signalling and cardiac hypertrophy.

OBJECTIVE: Transforming growth factor beta (TGFbeta)-activated kinase 1 (TAK1) is a MAP kinase kinase kinase involved in numerous signalling pathways and is strongly implicated in cardiac hypertrophy and heart failure. TGFbeta is also associated with hypertension and heart disease, and evidence suggests that TGFbeta1 and TAK1 act together in a cardiac stress signalling pathway. Canonical TGFbeta signalling is mediated through Smad transcription factors, but TGFbeta can also rapidly activate TAK1. The activation of the Smad cascade is well characterised, but little is known about how TAK1 is activated in response to TGFbeta, and no direct link between any MAPK kinase pathway and the TGFbeta receptors has yet been established. Since TAK1 is activated by TGFbeta within 1 min in cardiomyocytes, we hypothesised there might be a direct interaction between TAK1 and one of the TGFbeta receptors. METHODS: We used a combination of in vitro binding assays and co-immunoprecipitation (IP) experiments to investigate whether TAK1 interacted with the type I (ALK1 or ALK5) or type II (TBRII) TGFbeta receptors. Interactions between endogenous proteins were tested using mouse myoblast and rat cardiomyocyte cells. RESULTS: Immunoprecipitation and in vitro binding assays show that TAK1 binds directly to TBRII. Precipitation of endogenous TAK1 protein in rat cardiomyocytes shows that, in addition to a direct association with TBRII, it also interacts indirectly with ALK5. CONCLUSIONS: We describe a novel and specific interaction between TAK1 and TBRII which, for the first time, directly links TAK1 to the TGFbeta signalling cascade and potentially explains how TGFbeta signalling in cardiomyocytes mediates a hypertrophic response.

Activin Receptors, Type I↗
PubMed1999

The MAPKKK Ste11 regulates vegetative growth through a kinase cascade of shared signaling components.

In haploid Saccharomyces cerevisiae, the mating and invasive growth (IG) pathways use the same mitogen-activated protein kinase kinase kinase kinase (MAPKKKK, Ste20), MAPKKK (Ste11), MAPKK (Ste7), and transcription factor (Ste12) to promote either G(1) arrest and fusion or foraging in response to distinct stimuli. This exquisite specificity is the result of pathway-specific receptors, G proteins, scaffold protein, and MAPKs. It is currently not thought that the shared signaling components function under the basal conditions of vegetative growth. We tested this hypothesis by searching for mutations that cause lethality when the STE11 gene is deleted. Strikingly, we found that Ste11, together with Ste20, Ste7, Ste12, and the IG MAPK Kss1, functions in a third pathway that promotes vegetative growth and is essential in an och1 mutant that does not synthesize mannoproteins. We term this pathway the STE vegetative growth (SVG) pathway. The SVG pathway functions, in part, to promote cell wall integrity in parallel with the protein kinase C pathway. During vegetative growth, the SVG pathway is inhibited by the mating MAPK Fus3. By contrast, the SVG pathway is constitutively activated in an och1 mutant, suggesting that it senses intracellular changes arising from the loss of mannoproteins. We predict that general proliferative functions may also exist for other MAPK cascades thought only to perform specialized functions.

Calcium-Calmodulin-Dependent Protein Kinases↗
PubMed1984

Automated prothrombin-time test with use of a chromogenic peptide substrate and a centrifugal analyzer.

We modified a test for prothrombin time, to automate its performance by centrifugal analysis. The sample is activated with calcium-thromboplastin in the presence of a thrombin-specific chromogenic peptide substrate, Tos-Gly-Pro-Arg-p-nitroaniline (Chromozym TH). The endpoint of the reaction is set as the time after onset until a defined amount of substrate has been cleaved, as reflected in a fixed change in absorbance. The assay is as sensitive as clotting-type methods are to the clotting factors of the extrinsic pathway--except for fibrinogen, which can be estimated from the maximum absorbance difference. Substrate concentration has little effect on the result, and varying it does not significantly change the sensitivity to factor X, which indicates little interference with the enzymes of the coagulation cascade. The method was applied to the Cobas Bio centrifugal analyzer. An external calculator must be used to convert absorbance readings into reaction times, which can be expressed as percent-of-normal values or as "ratios" by use of reagent-specific factors. CVs were less than 2% within run, less than 6% day to day. Overall correlation with the clotting test (r = 0.95) was good. Using the Cobas Bio, we achieved a throughput rate of 200 samples per hour.

Autoanalysis↗