A phase I, pharmacokinetic and pharmacodynamic study of GSK2256098, a focal adhesion kinase inhibitor, in patients with advanced solid tumors.

BACKGROUND: Focal adhesion kinase (FAK) is important in cancer growth, survival, invasion, and migration. The purpose of this study was to determine the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of the FAK inhibitor, GSK2256098, in cancer patients. PATIENTS AND METHODS: The dose of GSK2256098 was escalated, in cohorts of patients with advanced cancer, from 80 to 1500 mg, oral twice daily (BID), until the MTD was determined. Serial blood samples were obtained from all patients, and the PK was determined. Paired tumor biopsies were obtained in select patients, and the level of phospho-FAK (pFAK) was determined. RESULTS: Sixty-two patients (39 males, 23 females; median age 61 y.o., range 21-84) received GSK2256098. Dose-limiting toxicities of grade 2 proteinuria (1000 mg BID), grade 2 fatigue, nausea, vomiting (1250 mg BID), and grade 3 asthenia and grade 2 fatigue (1500 mg BID) were reported with the MTD identified as 1000 mg BID. The most frequent adverse events (AEs) were nausea (76%), diarrhea (65%), vomiting (58%), and decreased appetite (47%) with the majority of AEs being grades 1-2. The PK was generally dose proportional with a geometric mean elimination half-life range of 4-9 h. At the 750, 1000, and 1500 mg BID dose levels evaluated, the pFAK, Y397 autophosphorylation site, was reduced by ∼80% from baseline. Minor responses were observed in a patient with melanoma (-26%) and three patients with mesothelioma (-13%, -15%, and -17%). In the 29 patients with recurrent mesothelioma, the median progression-free survival was 12 weeks with 95% CI 9.1, 23.4 weeks (23.4 weeks merlin negative, n = 14; 11.4 weeks merlin positive, n = 9; 10.9 weeks merlin status unknown, n = 6). CONCLUSIONS: GSK2256098 has an acceptable safety profile, has evidence of target engagement at doses at or below the MTD, and has clinical activity in patients with mesothelioma, particularly those with merlin loss.

Burden of respiratory tract infections among paediatric in and out-patient units during 2010-11.

INTRODUCTION: Respiratory tract infections due to viral etiology were studied with an objective to identify and compare the pathogens between Hospital Indoor and Outdoor Units. MATERIALS AND METHODS: A hospital-based cross-sectional study was conducted among children below 12 years over a period of one year. The throat and nasal swabs were collected from both the Units and screened for viral infections by real time RT-PCR technique. RESULTS: Out of 880 samples collected, 87% and 13% were from outdoor and indoor Department with total viral positivity rate of 30% and 25% respectively. Influenza B virus (IBV) (n=126, 16%) was more prevalent in Outdoor Unit, whereas respiratory syncytial virus (RSV) (n=18, 16%) among indoor admitted cases. The multinomial logistic regression analysis revealed that both RSV and Influenza viruses were predominant in children of pre-school age groups < 5 years. In the year 2010-11, the prevalence of human metapneumovirus (HMPV) was low. The pandemic influenza A virus (pH1N1/2009) accounted for 4% (n=29) and 0.8% (n=1) cases among Outdoor and Indoor Units respectively. CONCLUSIONS: The Outdoor Department outnumbered the Indoor Unit in terms of patient attendees and the rate of viral infections. An effective vaccination and continuous surveillance program is the need of the hour.

Dynamic matrix composition in engineered cartilage with stochastic supplementation of growth factors.

Dynamic extracellular matrix (ECM) synthesis is explored in a hypothesized engineered cartilage construct. Growth (alpha) and decay (beta) rate parameters are developed from a previous engineered cartilage model. The presented mathematical model was constructed from the parameterized experimental data using a deterministic and stochastic examination of ECM synthesis based on a negative feedback control mechanism. A growth factor supplementation is incorporated in a probabilistic mathematical approach. The growth factor component modified an initial deterministic model through a Gaussian white noise fluctuation. As the primary constituents of ECM, the mathematical tool is intended to characterize the probable steady state distribution of glycosaminoglycan (GAG) and collagen molecules as well as mean mass accumulation at homeostasis. Computer simulation of the models is applied to reported data from four similar chondrocyte-polymer construct culture systems. The range in rate ratios reflect the differing nature of GAG and collagen synthesis (alphaGAG/betaGAG = 4.2 to 148.6; alphacollagen/betacollagen = 8.1 to 2590.4). This technique reduced the influencing synthesis factors to a few key descriptive parameters. Additional anabolic and catabolic factors may further be built into the models.

Dynamics of the cell and its extracellular matrix--a simple mathematical approach.

The extracellular matrix (ECM) is produced by the cells and secreted into the surrounding medium, and consists of a complex mixture of structural and functional proteins. It has been recently observed that the ECM can influence the behavior of cell growth in vitro quite remarkably. A simple mathematical model has been constructed based on negative feedback control mechanisms to represent the dynamics of ECM deposition and cellular differentiation. The model analysis shows a strong relationship between the numerical solution and the experimental observations in cell-polymer constructs for the design of engineered cartilage. The current paper may be a useful guide for those who want to explore the studies on cell-matrix interactions.

Effect of environmental fluctuations on the dynamic composition of engineered cartilage: a deterministic model in stochastic environment.

Dynamics of extracellular matrix (ECM) deposition and scaffold degradation in cell-polymer constructs have been studied in a random fluctuating environment created due to the applications of growth factors into the in vitro generation of cartilaginous constructs. Existing models of cell-polymer constructs for the design of engineered cartilage have been discussed and then a new deterministic scheme in random environment proposed taking into account the effects of growth factors as the environmental variability in the form of Gaussian white noise. Steady-state probability distribution of each individual component of the ECM in its homeostasis is found explicitly. The computer-simulated results of the model have been discussed and then compared with the data from a variety of scaffold systems and culture conditions.

A mathematical study of semilunar valve vibration.

A simple mathematical model to describe the valvular vibrations and their role in the production of the second heart sound is presented. The closed semilunar valve is considered as a vibrating stretched membrane secured around a circular edge. An exponential function is used to represent the actual pressure gradient across the closed valve, which is the force that drives the membrane to vibrate. The displacement and the rate of displacement of the centreline are calculated and are found to be similar to the experimental and numerical results given earlier in the literature by Stein and his co-workers.

Developmental and corrective biomechanics for scoliosis.

The developmental mechanism for scoliosis and its surgical correction are studied by modeling the spinal column as a curved nonlinear (large-deformation-sustaining) beam column to which are applied (a) muscle forces to simulate scoliosis development due to asymmetrical bilateral muscle contractions and (b) corrective forces to simulate the action of surgically implanted corrective systems. The two-dimensional model permits curvature in the frontal plane and can simulate and demonstrate the progression of a scoliotic curve from an initially straight configuration for various model parameter values. The calculation of the bonding moments is treated, and a simple algorithm for solving the model equations is presented. Results for an actual clinical case are given.

Effects of multiple stenoses and post-stenotic dilatation on non-Newtonian blood flow in small arteries.

Fully-developed one-dimensional Casson flow through a single vessel of varying radius is proposed as a model of low Reynolds number blood flow in small stenosed coronary arteries. A formula for the resistance-to-flow ratio is derived, and results for yield stresses of tau 0 = 0, 0.005 and 0.01 Nm-2, viscosities of mu = 3.45 x 10(-3), 4.00 x 10(-3) and 4.55 x 10(-3) Pa.s and fluxes of 2.73 x 10(-6), x 10(-5) and x 10(-4) m3 s-1 are determined for segment of 0.45 mm radius and 45 mm length, with 15 mm abnormalities at each end where the radius varies by up to +/- 0.225 mm. When tau 0 = 0.005 N m-2, mu = 4 x 10(-3) Pa.s and Q = 1, the numerical values of the resistance-to-flow ratio vary from lambda = 0.525, when the maximum radii of the two abnormal segments are both 0.675 mm, to lambda = 3.06, when the minimum radii are both 0.225 mm. The resistance-to-flow ratio moves closer to unity as yield stress increases or as blood viscosity or flux decreases, and the magnitude of these alterations is greatest for yield stress and least for flux.

Asymmetrical loads and lateral bending of the human spine.

The human spine is modelled as a cantilever-type beam column. Under the influence of static asymmetrical loads, muscle and low-back forces are predicted from a hypothetical but revealing model. Such forces produced by asymmetrical loads are much larger than for a corresponding symmetrical load. Asymmetrical loads can encourage, especially in young schoolchildren, lateral bending of the spine by alleviating muscle and low-back forces. This could possibly be a factor contributing to the surprisingly high percentage of schoolchildren with measurable scoliotic curves. The wearing of knapsack-type bags is advocated.

Unsteady stenosis flow prediction: a comparative study of non-Newtonian models with operator splitting scheme.

This paper presents a comparative study of non-Newtonian and Newtonian models of blood. A non-Newtonian incompressible 2-D Navier-Stokes (N-S) solver has been developed using Fasttalk language within the Fastflo environment. It is based on the method of operator splitting with artificial compressibility technique. The Power law and Casson models have been used as the constitutive equations for blood with a hematocrit of approximately 45%. These two non-Newtonian models and the Newtonian model are used to simulate unsteady flow through a hypothetical stenotic geometry over an aperiodic time interval of 1 s. Through comparison of the results of the three models, it was found that the wall shear stress (WSS) distribution over the time interval was comparable for both non-Newtonian models. The peak WSS for the Newtonian model had the lowest value. The peak wall shear stress gradient (WSSG) for the Power law was the highest, followed by the Casson and Newtonian models. Flow characteristics such as higher pressure drop across the stenosis, location and movement of vortex were similar in all three models. Non-Newtonian effects were most significant in the vicinity of the stenosis.

A non-invasive study of the third heart sound in children by phono and echo-cardiography.

There has been in the past and still is controversy over the genesis of the third heart sound (S3). Recent studies, however, strongly suggest that S3 is a manifestation of a sudden intrinsic limitation in the expansion of the L.V. The present study has aimed to explore that hypothesis further, using a spectral analysis technique. A FFT technique was used to determine the spectral distribution of S3 in 14 child subjects between the ages of 2 and 19 years. Spectral energies in 15 Hz frequency bandwidths were correlated with various 2D-echocardiographically derived parameters. This study has shown that the spectral energy of S3 is distributed in the lower frequency bands. Fifty percent (47 +/- 16%) is distributed in the 0-15 Hz band. Also it was found that: (i) as mitral orifice size increases, energy in the 0-15 Hz band of S3 decreases. (r = -0.53, p less than 0.05), (ii) S3 occurs earlier in the cardiac cycle with increase in age of the subject. (r = -0.76, p less than 0.005), (iii) the energy distribution of S3 tends towards the higher frequencies with increase in age. (r = 0.52, p less than 0.05). Further, the above results support the hypothesis that S3 is the result of an intrinsic limitation to the expansion of the L.V. due to an early diastolic pressure rise caused by an increased viscoelasticity of the myocardium. This, and the relation of the results in certain pathologies are also discussed.

Three dimensional reconstruction of the left ventricle from four anatomically defined apical two-dimensional echocardiographic views.

A method is described for three dimensional reconstruction of the left ventricle which uses four anatomically defined apical views. It is shown that the algorithms developed for reconstruction and volume estimation provide accurate results when applied to planar views with accurately defined boundaries. The linear regression equation was y = -6.32 + 1.04x, with SEE = +/- 3.4 ml, r = 0.999. For both "in vitro" and "in vivo" studies this method is found to be better than various geometrical models used to estimate volumes from two dimensional tomographic or projection views. The linear regression equation of in vitro fluid volume on volume estimate is y = 8.44 + 0.68x, with SEE = +/- 4.9 ml, r = 0.988. For pooled end diastolic and end systolic volumes (EDV and ESV) determined by three dimensional reconstruction (3-DR) and angiography the linear regression equation is y = 54.50 + 0.50x, with SEE = +/- 33.5 ml, r = 0.670. For stroke volume (SV), the regression equation is y = 21.10 + 0.40x, with SEE = +/- 12.8 ml, r = 0.750, and for ejection fraction (EF) it is y = 1.10 + 0.70x, with SEE = +/- 7.8%, r = 0.840. In patients with ischemic heart disease, the method presented is shown to be better than existing methods of volume estimation. Three dimensional perspective images can be plotted in any orientation as a visual aid to the cardiologist. In vivo studies demonstrate the feasibility of 3-DR, from anatomically defined apical views, in the clinical setting.

A study of orifice shape effects in the determination of mitral valve area by two-dimensional echocardiography.

Real-time two-dimensional echocardiographic studies of the mitral valve in short-axis view were obtained from 10 normal subjects. Stop-action frames of the video-taped echocardiograms were then photographed to obtain diastolic cross-sectional images of the valve at maximal opening. Tracings from the interior of the leaflet echoes were then digitized to provide the perimeter and area of the mitral orifice. From the perimetric data, boundary integration was used to numerically calculate the orifice area corresponding to an elliptical boundary, for aspect ratios ranging from 0.5 to 1.0 (circle). It was found that the mean orifice areas determined echocardiographically and numerically are equal for an aspect ratio of 0.42. For aspect ratios greater than this value, the elliptical areas are larger, while for smaller aspect ratios, the elliptical areas are smaller.

A genetic algorithm based nearest neighbor classification to breast cancer diagnosis.

This paper presents an application of a hybrid approach (the genetic algorithms and the k-nearest neighbour) proposed by Ishbuchi to Wisconsin breast cancer data. For the diagnosis of breast cancer, the determination of the presence of benign/malignant breast tumors represents a very complex problem (even for an experienced cytologist). Therefore the automatic classification of benign and malignant symptoms is highly desirable as a valuable aid to assist oncologists in the decision making of the diagnosis of breast cancer. In this paper, the genetic algorithm based k-nearest neighbour method for classification of benign and malignant breast tumors is presented. The genetic-algorithm (GA) is used for finding a compact reference set by selecting a small number of reference patterns from a large number of training patterns in nearest neighbor classification. The GA simultaneously performs feature selection and pattern selection and prunes unnecessary features. The goal is to maximize the classification performance of the reference set and minimize the number of selected patterns and features. Results are also compared with a fuzzy-genetic approach where each reference patten represents a fuzzy if-then rule with a circular-cone-type membership function.

Mathematical modelling of peristaltic transport of a non-Newtonian fluid.

The paper considers the phenomena of peristaltic transport of a non-Newtonian fluid represented as a power law fluid. The governing equations are the modified Navier-Stokes equations and the continuity equation in axisymmetric form. A solution is sought in terms of a perturbation series and it is shown the close proximity between analytical and numerical solutions when considering stream functions for various values of the flow behaviour index.

Biomathematical modelling of physiological fluids using a Casson fluid with emphasis to peristalsis.

In this paper, the peristaltic flow of rheologically complex physiological fluids when modelled by a non-Newtonian Casson fluid in a two-dimensional channel is considered. Of interest is the difference between peristaltic transport of Newtonian and non-Newtonian fluids. A perturbation series method of solution of the stream function in amplitude ratio is sought. It is found that Newtonian fluid is an important sub-class of non-Newtonian fluids that may adequately represent some physiological phenomena. It is shown that for a Casson fluid, when certain simplifications and approximations are made in the most generalised form of constitutive equation, the fluid may be adequately represented as an improvement of a Newtonian fluid.

A mathematical study of turbulent blood flow through an arterial bifurcation.

A turbulent model of flow through an arterial bifurcation is proposed in order to investigate flow separation, secondary flow and the variation of pressure and stress along the wall when blood passes through a bifurcation. Blood is assumed to behave like a Newtonian fluid, with viscosity depending on the angle of bifurcation. The geometry of the models used here for aortic bifurcations is set by employing the principle of conservation of mass. The results show that: the peak axial velocity in the entrance region of the daughter vessel occurs on the inner wall of the bifurcation; a strong secondary flow may develop in the branch, which has much less effect on axial flow when the Reynolds number is low; there is a tendency toward separation in the branch with low mean flow, and the flow is increasingly disturbed as the bluntness of the apex increases.

Application of fuzzy-classifier system to coronary artery disease and breast cancer.

This paper presents an application of a genetic-algorithm-based representation of fuzzy rules for the classification of coronary artery disease data and breast cancer data. The performance of this fuzzy classifier for classification of coronary artery disease and breast cancer data is evaluated. In this study the concept of fuzzy if-then has been applied of rules proposed by Ishibuchi et al. for a multi dimensional data classification problem which leads to higher classification power. The fitness value of each fuzzy if-then rule was determined by the numbers of correctly and wrongly classified training patterns for that rule. The classification power on real world data for coronary artery disease and breast cancer was thus demonstrated by computer simulations.

Spectral analysis of an acoustic respiratory signal with a view to developing an apnoea monitor.

The movement of air through the air passages during normal respiration generates an acoustic signal which can be detected from the surface of the body at suitable sites with the aid of a microphone applied to the skin. The spectral characteristics of these sounds were analysed to see if they could be differentiated from other sources of sound. During normal respiration the other major source of sound was that transmitted from the heart, and this could be filtered out with a band pass filter. A prototype apnoea monitor was built which utilised these sound signals as an indicator of respiration and underwent preliminary testing. Although such acoustic signals have the potential to indicate respiration, and cardiac sounds can be effectively filtered, further work would be required to recognise and reject other extraneous sources of sound interfering with the respiratory signal.

A mathematical study of blood flow through viscoelastic walled stenosed arteries.

A mathematical model of blood flow through a stenosed artery is presented. The arterial wall and stenosis are assumed to be viscoelastic and axisymmetric. The constitutive equations are solved using pertubation methods and these solutions are compared with the predictions of models that assume Poisseuille and turbulent flow through a rigid stenosed tube. This solution is used to investigate the stress caused by viscoelastic deformation of the wall and the stenosis.