Biomedical subjects

B Novak

Publications and source records attributed to B Novak.

At least 19 recordsLinked to original sources

PubMed2004

Computerized evaluation of mammographic lesions: what diagnostic role does the shape of the individual microcalcifications play compared with the geometry of the cluster?

OBJECTIVE: The objective of this study was to compare the diagnostic role of features reflecting the geometry of clusters with features reflecting the shape of the individual microcalcification in a mammographic computer-aided diagnosis system. MATERIALS AND METHODS: Three hundred twenty-four cases of clustered microcalcifications with biopsy-proven results were digitized at 42-microm resolution and analyzed on a computerized system. The shape factor and number of neighbors were computed for each microcalcification, and the eccentricity of the cluster was computed as well. The shape factor is related to the individual microcalcification; the average number of neighbors and the cluster eccentricity reflect the cluster geometry. Stepwise discriminant analysis was used to evaluate the contribution of the extracted features in predicting malignancy. The performance of a classifier based on the features selected by stepwise discriminant analysis was evaluated by receiver operating characteristic (ROC) analysis. RESULTS: To obtain the best discrimination model, we used stepwise discriminant analysis to select the average number of neighbors and the shape of the individual microcalcification, but excluded cluster eccentricity. A classification scheme assigned the average number of neighbors a weighting factor, which was 1.49 times greater than that assigned to the shape factor of the individual microcalcification. A scheme based only on these two features yielded an ROC curve with an area under the curve (A(z)) of 0.87, indicating a positive predictive value of 61% for 98% sensitivity. CONCLUSION: Computerized analysis permitted calculations reflecting the shape of individual microcalcification and the geometry of clusters of microcalcifications. For the computerized classification scheme studied, the cluster geometry was more effective in differentiating benign from malignant clusters than was the shape of individual microcalcification.

Adult↗

PubMed2001

A stochastic, molecular model of the fission yeast cell cycle: role of the nucleocytoplasmic ratio in cycle time regulation.

We propose a stochastic version of a recently published, deterministic model of the molecular mechanism regulating the mitotic cell cycle of fission yeast, Schizosaccharomyces pombe. Stochasticity is introduced in two ways: (i) by considering the known asymmetry of cell division, which produces daughter cells of slightly different sizes; and (ii) by assuming that the nuclear volumes of the two newborn cells may also differ. In this model, the accumulation of cyclins in the nucleus is proportional to the ratio of cytoplasmic to nuclear volumes. We have simulated the cell-cycle statistics of populations of wild-type cells and of wee1(-) mutant cells. Our results are consistent with well known experimental observations.

Algorithms↗

PubMed2001

Regulation of the eukaryotic cell cycle: molecular antagonism, hysteresis, and irreversible transitions.

In recent years, molecular biologists have uncovered a wealth of information about the proteins controlling cell growth and division in eukaryotes. The regulatory system is so complex that it defies understanding by verbal arguments alone. Quantitative tools are necessary to probe reliably into the details of cell cycle control. To this end, we convert hypothetical molecular mechanisms into sets of nonlinear ordinary differential equations and use standard analytical and numerical methods to study their solutions. First, we present a simple model of the antagonistic interactions between cyclin-dependent kinases and the anaphase promoting complex, which shows how progress through the cell cycle can be thought of as irreversible transitions (Start and Finish) between two stable states (G1 and S-G2-M) of the regulatory system. Then we add new pieces to the "puzzle" until we obtain reasonable models of the control systems in yeast cells, frog eggs, and cultured mammalian cells.

Anaphase↗

PubMed2001

Network dynamics and cell physiology.

Complex assemblies of interacting proteins carry out most of the interesting jobs in a cell, such as metabolism, DNA synthesis, movement and information processing. These physiological properties play out as a subtle molecular dance, choreographed by underlying regulatory networks. To understand this dance, a new breed of theoretical molecular biologists reproduces these networks in computers and in the mathematical language of dynamical systems.

CDC2 Protein Kinase↗

PubMed2001

Angiotensin-converting enzyme gene polymorphism in patients with systemic lupus.

The renin-angiotensin-aldosterone system (RAAS) has been considered one of the probable pathophysiologic mechanisms involved in disease progression. Genetic polymorphism of the RAAS has been associated with the clinical course of renal disease. One of the genetic polymorphisms is a deletion or insertion of a 287 base pair fragment in intron 16 of the angiotensin-converting enzyme (ACE) gene. It is known that ACE gene polymorphism is present in humans and that it is associated with an increased risk of cardiovascular diseases, renal disease progression and sarcoidosis. In this study, the potential significance of ACE gene polymorphism in patients with systemic lupus erythematosus (SLE) was investigated. ACE gene polymorphism was determined in 18 patients with SLE and in 21 healthy volunteers as a control group. The mean age of patients was 38.5 years. All patients had a mean follow-up of 30.7 +/- 20.2 months (range 5-95 months). ACE genotypes were determined by the method of polymerase chain reaction. Proteinuria and creatinine were also followed. The frequency of DD, ID and II genotypes was 50%, 28% and 22% in SLE patients and 25%, 50% and 25% in healthy controls, respectively. DD genotype was more common in SLE patients than in the control group. The patients with II genotype had lower proteinuria and creatinine level than those with DD genotype (p < 0.05). The time to disease remission was shorter in patients with II genotype (p < 0.05). Study results indicated an increased frequency of D allele in SLE patients. The increased ACE activity in these patients pointed to the need of further studies of ACE gene polymorphism in SLE.

Adult↗

PubMed2000

Modeling the fission yeast cell cycle: quantized cycle times in wee1- cdc25Delta mutant cells.

A detailed mathematical model for the fission yeast mitotic cycle is developed based on positive and negative feedback loops by which Cdc13/Cdc2 kinase activates and inactivates itself. Positive feedbacks are created by Cdc13/Cdc2-dependent phosphorylation of specific substrates: inactivating its negative regulators (Rum1, Ste9 and Wee1/Mik1) and activating its positive regulator (Cdc25). A slow negative feedback loop is turned on during mitosis by activation of Slp1/anaphase-promoting complex (APC), which indirectly re-activates the negative regulators, leading to a drop in Cdc13/Cdc2 activity and exit from mitosis. The model explains how fission yeast cells can exit mitosis in the absence of Ste9 (Cdc13 degradation) and Rum1 (an inhibitor of Cdc13/Cdc2). We also show that, if the positive feedback loops accelerating the G(2)/M transition (through Wee1 and Cdc25) are weak, then cells can reset back to G(2) from early stages of mitosis by premature activation of the negative feedback loop. This resetting can happen more than once, resulting in a quantized distribution of cycle times, as observed experimentally in wee1(-) cdc25Delta mutant cells. Our quantitative description of these quantized cycles demonstrates the utility of mathematical modeling, because these cycles cannot be understood by intuitive arguments alone.

CDC2 Protein Kinase↗

PubMed2000

Electrochemiluminescence of ruthenium (II) tris(bipyridine) encapsulated in sol-gel glasses

The electrogenerated chemiluminescence (ECL) of Ru(bpy)3 2+ and tripropylamine, tributylamine, triethylamine, trimethylamine, or sodium oxalate encapsulated within sol-gel-derived silica monoliths have been investigated using an immobilized ultramicroelectrode assembly. The major purpose of this study was to investigate the role of the reductant on the magnitude and stability of the ECL in this solid host matrix. For gel-entrapped Ru(bpy)3 2-/tertiary amines, the shape and intensity of the ECL-potential curves were highly dependent on scan rate. At 10 mV/s, the ECL intensity was ca. 6-fold higher relative to that observed at 500 mV/s. When the ECL acquired at low scan rates was normalized by that obtained in solution under similar conditions, a value of 0.03-0.06 was obtained. In direct contrast, the ECL of the Ru(bpy)3 2+-oxalate system showed little dependence on scan rate, and the ECL was ca. 65-75% of that measured in solution. These differences can be attributed to differences in rotational and translational mobility between the reductants (amines vs oxalate) trapped in this porous solid host For both systems, the ECL was found to be stable upon continuous oxidation or upon drying the gels in a high-humidity environment for over 10 days.

Journal Article↗

PubMed2000

Improved mammographic interpretation of masses using computer-aided diagnosis.

The aim of this study was to evaluate the effectiveness of computerized image enhancement, to investigate criteria for discriminating benign from malignant mammographic findings by computer-aided diagnosis (CAD), and to test the role of quantitative analysis in improving the accuracy of interpretation of mass lesions. Forty sequential mammographically detected mass lesions referred for biopsy were digitized at high resolution for computerized evaluation. A prototype CAD system which included image enhancement algorithms was used for a better visualization of the lesions. Quantitative features which characterize the spiculation were automatically extracted by the CAD system for a user-defined region of interest (ROI). Reference ranges for malignant and benign cases were acquired from data generated by 214 known retrospective cases. The extracted parameters together with the reference ranges were presented to the radiologist for the analysis of 40 prospective cases. A pattern recognition scheme based on discriminant analysis was trained on the 214 retrospective cases, and applied to the prospective cases. Accuracy of interpretation with and without the CAD system, as well as the performance of the pattern recognition scheme, were analyzed using receiver operating characteristics (ROC) curves. A significant difference (p < 0.005) was found between features extracted by the CAD system for benign and malignant cases. Specificity of the CAD-assisted diagnosis improved significantly (p < 0.02) from 14 % for the conventional assessment to 50 %, and the positive predictive value increased from 0.47 to 0.62 (p < 0.04). The area under the ROC curve (A(z)) increased significantly (p < 0. 001) from 0.66 for the conventional assessment to 0.81 for the CAD-assisted analysis. The A(z) for the results of the pattern recognition scheme was higher (0.95). The results indicate that there is an improved accuracy of diagnosis with the use of the mammographic CAD system above that of the unassisted radiologist. Our findings suggest that objective quantitative features extracted from digitized mammographic findings may help in differentiating between benign and malignant masses, and can assist the radiologist in the interpretation of mass lesions.

Breast Neoplasms↗

PubMed2000

Optimizing parameters for computer-aided diagnosis of microcalcifications at mammography.

RATIONALE AND OBJECTIVES: The purpose of this study was to optimize selection of the mammographic features most useful in discriminating benign from malignant clustered microcalcifications. MATERIALS AND METHODS: The computer-aided diagnosis (CAD) system automatically extracted from digitized mammograms 13 quantitative features characterizing microcalcification clusters. Archival cases (n = 134; patient age range, 31-77 years; mean age, 56.8 years) with known histopathologic results (79 malignant, 55 benign) were selected. Three radiologists at three facilities independently analyzed the microcalcifications by using the CAD system. Stepwise discriminant analysis selected the features best discriminating benign from malignant microcalcifications. A classification scheme was constructed on the basis of these optimized features, and its performance was evaluated by using receiver operating characteristic (ROC) analysis. RESULTS: Six of the 13 variables extracted by the CAD system were selected by stepwise determinant analysis for generating the classification scheme, which yielded an ROC curve with an area (Az) of 0.98, specificity of 83.64%, positive predictive value of 89.53%, and accuracy of 91.79% for 98% sensitivity. When patient age was an additional variable, the scheme's performance improved, but this was not statistically significant (Az = 0.98). The ROC curve of the classifier (without age as an additional variable) yielded a high Az of 0.96 for patients younger than 50 years and an even higher (P < .02) Az of 0.99 for those 50 years or older. CONCLUSION: Stepwise discriminant analysis optimized performance of a classification scheme for microcalcifications by selecting six optimized features. Scheme performance was significantly (P < .02) higher for women 50 years or older, but the addition of patient age as a variable did not produce a statistically significant increase in performance.

Adult↗

PubMed2000

Kinetic analysis of a molecular model of the budding yeast cell cycle.

The molecular machinery of cell cycle control is known in more detail for budding yeast, Saccharomyces cerevisiae, than for any other eukaryotic organism. In recent years, many elegant experiments on budding yeast have dissected the roles of cyclin molecules (Cln1-3 and Clb1-6) in coordinating the events of DNA synthesis, bud emergence, spindle formation, nuclear division, and cell separation. These experimental clues suggest a mechanism for the principal molecular interactions controlling cyclin synthesis and degradation. Using standard techniques of biochemical kinetics, we convert the mechanism into a set of differential equations, which describe the time courses of three major classes of cyclin-dependent kinase activities. Model in hand, we examine the molecular events controlling "Start" (the commitment step to a new round of chromosome replication, bud formation, and mitosis) and "Finish" (the transition from metaphase to anaphase, when sister chromatids are pulled apart and the bud separates from the mother cell) in wild-type cells and 50 mutants. The model accounts for many details of the physiology, biochemistry, and genetics of cell cycle control in budding yeast.

Cell Cycle↗

PubMed2000

Quantitative characterization of mass lesions on digitized mammograms for computer-assisted diagnosis.

RATIONALE AND OBJECTIVES: To investigate features for discriminating benign from malignant mammographic findings by using computer-aided diagnosis (CAD) and to test the accuracy of CAD interpretations of mass lesions. METHODS: Fifty-five sequential, mammographically detected mass lesions, referred for biopsy, were digitized for computerized reevaluation with a CAD system. Quantitative features that characterize spiculation were automatically extracted by the CAD system. Data generated by 271 known retrospective cases were used to set reference values indicating the range for malignant and benign lesions. After conventional interpretation of the 55 prospective cases, they were evaluated a second time by the radiologist using the extracted features and the reference ranges. In addition, a pattern-recognition scheme based on the extracted features was used to classify the prospective cases. Accuracy of interpretation with and without the CAD system was evaluated using receiver operating characteristic (ROC) curve analysis. RESULTS: Sensitivity of the CAD diagnosis for the prospective cases improved from 92% to 100%. Specificity improved significantly from 26.7% to 66.7%. This was accompanied by a significant increase in the accuracy of diagnosis from 56.4% to 81.8% and in the positive predictive value from 51.1% to 71.4%. The Az for the CAD ROC curve significantly increased from 0.73 to 0.90. The performance of the classification scheme was slightly lower than that of the radiologists' interpretation with the CAD system. CONCLUSIONS: Use of the CAD system significantly improved the accuracy of diagnosis. The findings suggest that the classification scheme may improve the radiologist's ability to differentiate benign from malignant mass lesions in the interpretation of mammograms.

Adult↗

PubMed1999

The use of an interactive software program for quantitative characterization of microcalcifications on digitized film-screen mammograms.

RATIONALE AND OBJECTIVES: Mammography is relatively nonspecific for the early detection of breast cancer. This study evaluates the accuracy of mammographic interpretation using quantitative features characterizing microcalcifications, which are extracted by a computerized system. METHODS: A computer-aided diagnosis (CAD) system enabling digitization of film-screen mammograms and automatic feature extraction was developed. A classification scheme (discriminant analysis) based on these features was constructed and trained on 217 cases with known pathology. The diagnostic performance of the classification scheme was tested against the radiologist's conventional interpretation on 45 additional cases of microcalcifications, each analyzed independently by four radiologists. RESULTS: The sensitivity of the CAD system analysis (95.7%) was significantly better than that of conventional interpretation (84.8%). The positive predictive value of interpretation increased significantly, as did the area under the receiver operating characteristic curve. CONCLUSIONS: This classification scheme for microcalcifications, based on quantitative features characterizing the lesion, significantly improved the accuracy of mammographic interpretation.

Breast Diseases↗

PubMed1999

Mitotic control in the absence of cdc25 mitotic inducer in fission yeast.

Fission yeast cells tolerate the total absence of the cdc25 mitotic inducer in two cases, either in cdc2-3w or in wee1 genetic backgrounds. In the cdc2-3w cdc25Delta double mutant, the rate-limiting step leading to mitosis is reaching a critical size. However, the size control of this mutant operates in late G2, which is different from wild-type (WT) cells. This fact suggests that in WT the rate-limiting molecular process during the G2 timer is the Tyr15 dephosphorylation of cdc2, for which the cdc25 phosphatase (together with its back-up, pyp3) is dependent. In the wee1-50 cdc25Delta mutant, the population splits into different clusters, all lacking mitotic size control. This strain maintains size homeostasis by a novel method, which is random movement of the cells from one cluster to another in the successive generations. These cells should normally have a 'minimal cycle', a 'timer' with short G1 and G2 phases. However, very often the cells abort mitosis, possibly at an early event and return back to early G2, thus lengthening their cycles. The inability of these cells to start anaphase might be caused by the absence of the main mitotic regulators (wee1 and cdc25) and the improper regulation of their back-up copies (mik1 and pyp3, respectively).

Cell Cycle Proteins↗

PubMed1999

Intelligent systems in medical diagnosis.

From an intelligent system for a computer supported medical diagnosis it is expected to achieve high accuracy and ability to draw conclusions from a small data sets. Medical practice could takes many years to generate a large database. A new mathematical method that is able to learn on a small data set is presented.

Algorithms↗

PubMed1998

Model scenarios for evolution of the eukaryotic cell cycle.

Progress through the division cycle of present day eukaryotic cells is controlled by a complex network consisting of (i) cyclin-dependent kinases (CDKs) and their associated cyclins, (ii) kinases and phosphatases that regulate CDK activity, and (iii) stoichiometric inhibitors that sequester cyclin-CDK dimers. Presumably regulation of cell division in the earliest ancestors of eukaryotes was a considerably simpler affair. Nasmyth (1995) recently proposed a mechanism for control of a putative, primordial, eukaryotic cell cycle, based on antagonistic interactions between a cyclin-CDK and the anaphase promoting complex (APC) that labels the cyclin subunit for proteolysis. We recast this idea in mathematical form and show that the model exhibits hysteretic behaviour between alternative steady states: a Gl-like state (APC on, CDK activity low, DNA unreplicated and replication complexes assembled) and an S/M-like state (APC off, CDK activity high, DNA replicated and replication complexes disassembled). In our model, the transition from G1 to S/M ('Start') is driven by cell growth, and the reverse transition ('Finish') is driven by completion of DNA synthesis and proper alignment of chromosomes on the metaphase plate. This simple and effective mechanism for coupling growth and division and for accurately copying and partitioning a genome consisting of numerous chromosomes, each with multiple origins of replication, could represent the core of the eukaryotic cell cycle. Furthermore, we show how other controls could be added to this core and speculate on the reasons why stoichiometric inhibitors and CDK inhibitory phosphorylation might have been appended to the primitive alternation between cyclin accumulation and degradation.

Animals↗

PubMed1998

Modeling M-phase control in Xenopus oocyte extracts: the surveillance mechanism for unreplicated DNA.

Alternating phases of DNA synthesis and mitosis, during the first 12 cell divisions of frog embryos, are driven by autonomous cytoplasmic oscillations of M-phase promoting factor (MPF). Cell-free extracts of frog eggs provide a convenient preparation for studying the molecular machinery that generates MPF oscillations and the surveillance mechanism that normally prevents entry into mitosis until chromosomal DNA is fully replicated. Early experiments suggested that unreplicated DNA blocks MPF activity by inducing phosphorylation of a crucial tyrosine residue, but recent evidence implicates a stoichiometric inhibitor (an MPF binding protein) as the 'braking' agent. Using a realistic mathematical model of the mitotic control system in frog egg extracts, we suggest that both tyrosine phosphorylation and a stoichiometric inhibitors are involved in the block of MPF by unreplicated DNA. Both pathways operate by raising the cyclin threshold for MPF activation. As a bonus, in the process of analyzing these experiments, we obtain more direct and reliable estimates of the rate constants in the model.

Animals↗

PubMed1998

Mathematical model of the fission yeast cell cycle with checkpoint controls at the G1/S, G2/M and metaphase/anaphase transitions.

All events of the fission yeast cell cycle can be orchestrated by fluctuations of a single cyclin-dependent protein kinase, the Cdc13/Cdc2 heterodimer. The G1/S transition is controlled by interactions of Cdc13/Cdc2 and its stoichiometric inhibitor, Rum1. The G2/M transition is regulated by a kinase-phosphatase pair, Wee1 and Cdc25, which determine the phosphorylation state of the Tyr-15 residue of Cdc2. The meta/anaphase transition is controlled by interactions between Cdc13/Cdc2 and the anaphase promoting complex, which labels Cdc13 subunits for proteolysis. We construct a mathematical model of fission yeast growth and division that encompasses all three crucial checkpoint controls. By numerical simulations we show that the model is consistent with a broad selection of cell cycle mutants, and we predict the phenotypes of several multiple-mutant strains that have not yet been constructed.

Anaphase↗

PubMed1998

Analysis of clustered microcalcifications by using a single numeric classifier extracted from mammographic digital images.

RATIONALE AND OBJECTIVES: The authors prospectively tested the performance of a single numeric classifier constructed from a discriminative analysis classification system based on automatic computer-extracted quantitative features of clustered microcalcifications. MATERIALS AND METHODS: Mammographically detected clustered microcalcifications in patients who had been referred for biopsy were digitized at 600 dpi with an 8-bit gray scale. A software program was developed to extract features automatically from digitized images to describe the clustered microcalcifications quantitatively. The significance of these features was evaluated by using the Wilcoxon test, the Welch modified two-sample t test, and the two-sample Kolmogorov-Smirnov test. A discriminant analysis pattern recognition system was constructed to generate a single numeric classifier for each case, based on the extracted features. This system was trained on 137 archival known reference cases and its performance tested on 24 unknown prospective cases. The results were evaluated by using receiver operating characteristic analysis. RESULTS: Thirty-seven extracted parameters demonstrated a statistically significant difference between the values for the benign and for the malignant lesions. Seven independent factors were selected to construct the classifier and to evaluate the unknown prospective cases. The area under the receiver operating characteristic curve for the prospective cases was 0.88. CONCLUSION: A pattern recognition classifier based on quantitative features for clustered microcalcifications at screen-film mammography was found to perform satisfactorily. The software may be of value in the interpretation of mammographically detected microcalcifications.

Adult↗