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PubMed1999

Optimization of beam orientations and weights for coplanar conformal beams in treating pancreatic cancer.

In treating pancreatic cancer with external-beam radiotherapy, radiation dose given to the tumor volume is largely limited by the tolerance of the normal structures near the disease site, including the kidneys, liver, stomach, small bowel, and spinal cord. The purpose of this work was to investigate whether a coplanar conformal therapy technique with beam optimization could reduce dose to the normal tissues compared to the conventional 4-field technique; and if this was true, whether other beam arrangements were more effective than the 4-field technique in treating pancreatic cancer. In this study, 9 patients who were treated previously for T3N0 or T3N1 pancreatic cancer with external-beam therapy of 30 Gy in 10 fractions were selected. Beam orientations and weights were optimized for 4 to 6 coplanar conformal beams using a simulated annealing algorithm to minimize the kidney volume receiving more than 20 Gy. Optimized plans were compared with standard plans using a 4-field technique with respect to the isodose distributions and dose volume histograms. For the standard 4-field plans giving 30 Gy to the tumor volume, the total kidney volume above 20 Gy ranged from 10% to 35%, with a mean of 22% and a standard deviation of 7%. Optimization of the beam orientations and weights reduced this volume by approximately 2 times without a significant increase of dose to the liver, stomach, and small bowel. This indicated that the radiation toxicity to the kidneys could be reduced substantially by a careful selection of oblique beam angles and weights. Analysis of the optimized plans showed that beam arrangements which involved left and right anterior oblique beams were superior to the conventional 4-field technique for reducing the kidney dose in treating pancreatic cancer.

Adenocarcinoma↗

PubMed1994

Use of an oriented peptide library to determine the optimal substrates of protein kinases.

BACKGROUND: Phosphorylation by protein kinases is an important general mechanism for controlling intracellular processes, and plays an essential part in the signal transduction pathways that regulate cell growth in response to extracellular signals. A great number of protein kinases have been discovered, and the identification of their biological targets is still a very active research area. Protein kinases must have the appropriate substrate specificity to ensure that signals are transmitted correctly. Previous studies have demonstrated the importance of primary sequences within substrate proteins in determining protein kinase specificity, but efficient ways of identifying these sequences are lacking. RESULTS: We have developed a new technique for determining the substrate specificity of protein kinases, using an oriented library of more than 2.5 billion peptide substrates. In this approach, the consensus sequence of optimal substrates is determined by sequencing the mixture of products generated during a brief reaction with the kinase of interest. The optimal substrate predicted for cAMP-dependent protein kinase (PKA) by this technique is consistent with the sequences of known PKA substrates. The optimal sequences predicted for cyclin-dependent kinases (CDKs) cyclin B-Cdc2 and cyclin A-CDK2 also agree well with sites thought to be phosphorylated in vivo by these kinases. In addition, we determined the optimal substrate for SLK1, a homologue of the STE20 protein serine kinase of hitherto unknown substrate specificity. We also discuss a model incorporating the optimal cyclin B-Cdc2 substrate into the known crystal structure of this kinase. CONCLUSIONS: Using the new technique we have developed, the sequence specificity of protein kinases can rapidly be predicted and, from this information, potential targets of the kinases can be identified.

Amino Acid Sequence↗

PubMed1999

Branch-and-terminate: a combinatorial optimization algorithm for protein design.

BACKGROUND: Several deterministic and stochastic combinatorial optimization algorithms have been applied to computational protein design and homology modeling. As structural targets increase in size, however, it has become necessary to find more powerful methods to address the increased combinatorial complexity. RESULTS: We present a new deterministic combinatorial search algorithm called 'Branch-and-Terminate' (B&T), which is derived from the Branch-and-Bound search method. The B&T approach is based on the construction of an efficient but very restrictive bounding expression, which is used for the search of a combinatorial tree representing the protein system. The bounding expression is used both to determine the optimal organization of the tree and to perform a highly effective pruning procedure named 'termination'. For some calculations, the B&T method rivals the current deterministic standard, dead-end elimination (DEE), sometimes finding the solution up to 21 times faster. A more significant feature of the B&T algorithm is that it can provide an efficient way to complete the optimization of problems that have been partially reduced by a DEE algorithm. CONCLUSIONS: The B&T algorithm is an effective optimization algorithm when used alone. Moreover, it can increase the problem size limit of amino acid sidechain placement calculations, such as protein design, by completing DEE optimizations that reach a point at which the DEE criteria become inefficient. Together the two algorithms make it possible to find solutions to problems that are intractable by either algorithm alone.

Algorithms↗

PubMedDate not supplied

Determination of optimal injection parameters for intraarterial gadolinium-enhanced MR angiography.

PURPOSE: Rapid vascular depiction with use of a minimum of gadolinium (Gd) contrast agent will be required to generate road-map vascular images for magnetic resonance (MR) imaging-guided endovascular interventions. The objective of this study was to optimize intraarterial injections of MR contrast agent during magnetic resonance angiography (MRA), obtained during interventions, by determining the optimal Gd vascular concentration ([Gd]) for vessel depiction. MATERIALS AND METHODS: The authors derived theoretical expressions to estimate the [Gd] resulting in maximal signal in blood. A model was developed to account for flow dilution to estimate [Gd] given the injected Gd concentration, injection rate, and the blood flow rate. Experiments in four animals (three dogs, one pig) were conducted to verify this model with use of both time-resolved two-dimensional (2D) thick-slab and single-phase three-dimensional (3D) MRA acquisitions. The authors also determined the optimal [Gd] required for vessel depiction in animal models. RESULTS: The theoretical expressions yielded optimal [Gd] of 10.2 mmol/L in blood. The animal experiments used the flow dilution model and examined signal enhancement in the aorta and the renal and iliac arteries. Maximal enhancement occurred at [Gd] = 16.2 +/- 4.0 mmol/L (mean +/- SE). CONCLUSIONS: The theoretically predicted values for [Gd]optimal and the flow dilution model were successfully validated. The relationship between injected [Gd], injection rate, and blood flow rate permits rapid intraarterial administration of contrast material, using less overall contrast material than with standard intravenous Gd-enhanced MRA.

Animals↗

PubMed1999

Optimized planning using physical objectives and constraints.

Intensity-modulated radiation therapy (IMRT) allows one to achieve a better conformation of the high-dose region to the prescribed tumor target volume than uniform beam therapy, especially in complex treatment situations. Still, perfect conformation is impossible. Hence the goal of optimized IMRT planning or inverse planning is to find the beam profiles that yield the optimum among the physically achievable treatment plans. The principal physical advantage of IMRT is best exploited if the optimization is driven by physical criteria. This article presents an overview of such physical, yet clinically relevant, criteria along with optimization algorithms that take these criteria into account. Practical computer implementations are described, which allow one to perform the optimization in an interactive manner within a few minutes. The application of these methods to some complex clinical example cases is presented, and the results are compared with uniform beam treatment plans and with biologically optimized plans.

Algorithms↗

PubMed1997

[Optimization of dose distribution of radiation in cancers of the cavum: association of an expert-system and a mathematical algorithm].

Optimization of radiation therapy in nasopharyngeal carcinoma is particularly complex due to both the proximity of at risk organs and the high dose that has to be delivered. To obtain an optimal dose distribution, a knowledge-based optimization technique has been designed that associates an expert-system, named CAVCAV, with numeric optimization (gradient projection method). Based on clinical and physical criteria, CAVCAV determines the geometric characteristics of the radiation fields (beam direction, location and shape of the shielding blocks) for the three stages of radiation therapy of nasopharyngeal carcinomas. Stage 2-treatment fields proposed by CAVCAV, though not perfectly adapted to the patient, are mathematically (beam weights, beam directions, isocenter position) and geometrically (adaptation of fields and shape of blocks by virtual simulation) optimized.

Algorithms↗

PubMed1999

Vitamin C: prospective functional markers for defining optimal nutritional status.

Most species of plants and animals synthesize ascorbic acid, but human subjects cannot, making vitamin C an essential component of our diet. Relationships between vitamin C intake and status, and between status and health are not yet clear. There is evidence, however, that higher intake of vitamin C is associated with lower risk of disease, supporting the concept that optimal intake is needed for optimal vitamin C status, and that both factors are required for optimal health. Vitamin C has low toxicity in healthy subjects, but a clear definition of optimal status and the dietary intake required to meet and maintain this status is needed before a change in the current recommended intake can be considered. Available evidence suggests that intake of 200 mg vitamin C/d saturates tissues and maintains fasting plasma levels above the proposed threshold (50 mumol/l) for minimum risk of CHD. However, the issue of whether or not these levels produce 'optimal vitamin C status' awaits the clear and accepted definition of the term. This definition in turn awaits the development of reliable functional markers capable of assessing the effects of varying levels of vitamin C nutriture. In the present paper the relationship between intake and body stores of vitamin C and the role of vitamin C in human health are reviewed briefly. The requirements of a reliable functional marker of human vitamin C status are defined, three classes of functional markers (molecular, biochemical and physiological) are described, and possible candidate markers are examined.

Ascorbic Acid↗

PubMed2006

Optimal depth of insertion of left-sided double-lumen endobronchial tubes cannot be predicted from body height in below average-sized adult patients.

BACKGROUND AND OBJECTIVE: The optimal depth of insertion of left-sided double-lumen endobronchial tubes is strongly correlated with body height in average-sized adults. However, this relationship has not been studied in below average-sized adult patients. We investigated whether or not there is a clinically useful relationship in below average-sized adult patients. METHODS: One hundred and ninety six consecutive adult patients undergoing thoracic surgery under one-lung anaesthesia (body height < or = 155 cm) were included in this study. Left-sided double-lumen tubes were inserted under the guidance of a fibre-optic bronchoscope. Optimal depth was defined as the proximal surface of the bronchial cuff positioned just below the carina. RESULTS: There was a statistically significant positive correlation between body height and the optimal depth of insertion (r = 0.61, P < 0.0001); however, the correlation coefficient was low. The actual optimal depth of insertion of one patient was even 4.5 cm shorter than that obtained from the equation. CONCLUSION: Although there was a statistically significant correlation between body height and the optimal depth of insertion of left sided double lumen tubes in adult patients of short stature (< or = 155 cm), clinical application of the equation is not warranted and these tubes should be inserted under direct vision with a fibre-optic bronchoscope.

Aged↗

PubMed2001

Optimized gating scheme for rapid lifetime determinations of single-exponential luminescence lifetimes.

The rapid lifetime method (RLD) for determining excited-state lifetimes uses the ratio of the areas under two regions of the decay. To get good precision with the standard method, prior knowledge of the lifetime is essential to selecting the integration regions. As will be shown, the usual method of selecting integration regions is far from optimal. An optimal gating scheme that is more precise and much more forgiving in the selection of integration region than any of the prior methods will be shown. Monte Carlo simulations were performed to determine the optimal gating. Experimental data was used to confirm the capabilities of the optimized RLD. The speed of the optimal RLD is similar to the standard RLD but without the necessity of matching the integration interval to the lifetime for precise results.

Journal Article↗

PubMed2004

Model selection and optimal sampling in high-throughput experimentation.

The practical difficulties encountered in analyzing the kinetics of new reactions are considered from the viewpoint of the capabilities of state-of-the-art high-throughput systems. There are three problems. The first problem is that of model selection, i.e., choosing the correct reaction rate law. The second problem is how to obtain good estimates of the reaction parameters using only a small number of samples once a kinetic model is selected. The third problem is how to perform both functions using just one small set of measurements. To solve the first problem, we present an optimal sampling protocol to choose the correct kinetic model for a given reaction, based on T-optimal design. This protocol is then tested for the case of second-order and pseudo-first-order reactions using both experiments and computer simulations. To solve the second problem, we derive the information function for second-order reactions and use this function to find the optimal sampling points for estimating the kinetic constants. The third problem is further complicated by the fact that the optimal measurement times for determining the correct kinetic model differ from those needed to obtain good estimates of the kinetic constants. To solve this problem, we propose a Pareto optimal approach that can be tuned to give the set of best possible solutions for the two criteria. One important advantage of this approach is that it enables the integration of a priori knowledge into the workflow.

Journal Article↗

PubMed1994

Relationship between the optimal temperature for oxidative refolding and the thermal stability of refolded state of hen lysozyme three-disulfide derivatives.

The temperature dependence of the efficiency of oxidative refolding was examined for hen lysozyme three-disulfide derivatives produced in Escherichia coli. Each derivative was designed to lack one of the four disulfide bridges in authentic lysozyme: delta 1 (Cys6-->Ser, Cys127-->Ser), delta 2 (Cys30-->Ser, Cys115-->Ser), delta 3 (Cys64-->Ser, Cys80-->Ser), delta 4 (Cys76-->Ser, Cys94-->Ser), delta 2Ala (Cys30-->Ala, Cys115-->Ala), and delta 4Ala (Cys76-->Ala, Cys94-->Ala). The optimal refolding temperature was lowest for delta 1 (19 degrees C) and highest for delta 4Ala (30 degrees C). The chromatographically purified, completely refolded three-disulfide species were not stable above the optimal refolding temperature in the presence of glutathione. The stability of each of them was determined from the far-UV CD thermal denaturation measurement at pH 3.9 in the absence of glutathione, where the denaturation was reversible. The transition temperature was lowest for delta 1 and highest for delta 4Ala. Precise values of difference in the transition temperature among the three-disulfide derivatives were found to correlate with those in the optimal refolding temperature. Next, the effect of glycerol, which has been shown to increase the refolding efficiency [Sawano et al. (1992) FEBS Lett. 303, 11-14], was examined for delta 1 in detail. The optimal temperature for refolding increased by 3-4 degrees C with the increase in glycerol concentration by 10%. The amount of increase in the optimal refolding temperature was nearly equal to the amount of the increase in thermal stability in the presence of glycerol of refolded and purified delta 1.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

UpGene: Application of a web-based DNA codon optimization algorithm.

Although DNA codon optimization is a standard molecular biology strategy to overcome poor gene expression, to date no public software exists to facilitate this process. Among the uses of codon optimization, human immunodeficiency virus (HIV) vaccine development represents one of the most difficult challenges. A key obstacle to an effective DNA-based vaccine is the low-level expression of HIV genes in mammalian cells, which is due primarily to the instability of HIV mRNAs resulting from AU-rich elements and rare codon usage. In this report we describe the development of a DNA optimization algorithm integrated with a PCR primer design program to redesign specific coding sequences for maximal gene expression. Using this algorithm combination, together with PCR-based gene assembly, we have successfully optimized gene sequences for simian immunodeficiency virus (SIV) strain mac239 structural antigenic proteins gag and env, resulting in high-level gene expression in eukaryotic cells. Our findings demonstrate that our user-friendly algorithm is a valuable tool for DNA-based HIV vaccine development. Moreover, it can be used to optimize any other genes of interest and is freely available online at http://www.vectorcore.pitt.edu/upgene.html.

Algorithms↗

PubMedDate not supplied

A hybrid model framework for the optimization of preparative chromatographic processes.

An optimization framework based on the use of hybrid models is presented for preparative chromatographic processes. The first step in the hybrid model strategy involves the experimental determination of the parameters of the physical model, which consists of the full general rate model coupled with the kinetic form of the steric mass action isotherm. These parameters are then used to carry out a set of simulations with the physical model to obtain data on the functional relationship between various objective functions and decision variables. The resulting data is then used to estimate the parameters for neural-network-based empirical models. These empirical models are developed in order to enable the exploration of a wide variety of different design scenarios without any additional computational requirements. The resulting empirical models are then used with a sequential quadratic programming optimization algorithm to maximize the objective function, production rate times yield (in the presence of solubility and purity constraints), for binary and tertiary model protein systems. The use of hybrid empirical models to represent complex preparative chromatographic systems significantly reduces the computational time required for simulation and optimization. In addition, it allows both multivariable optimization and rapid exploration of different scenarios for optimal design.

Algorithms↗

PubMedDate not supplied

On the optimal ratio of heavy to light chain genes for efficient recombinant antibody production by CHO cells.

Monoclonal antibodies (Mab) are heterotetramers consisting of an equimolar ratio of heavy chain (HC) and light chain (LC) polypeptides. Accordingly, most recombinant Mab expression systems utilize an equimolar ratio of heavy chain (hc) to light chain (lc) genes encoded on either one or two plasmids. However, there is no evidence to suggest that this gene ratio is optimal for stable or transient production of recombinant Mab. In this study we have determined the optimal ratio of hc:lc genes for production of a recombinant IgG4 Mab, cB72.3, by Chinese hamster ovary (CHO) cells using both empirical and mathematical modeling approaches. Polyethyleneimine-mediated transient expression of cB72.3 at varying ratios of hc:lc genes encoded on separate plasmids yielded an optimal Mab titer at a hc:lc gene ratio of 3:2; a conclusion confirmed by separate mathematical modeling of the Mab folding and assembly process using transient expression data. On the basis of this information, we hypothesized that utilization of hc genes at low hc:lc gene ratios is more efficient. To confirm this, cB72.3 Mab was transiently produced by CHO cells at constant hc and varying lc gene dose. Under these conditions, Mab yield was increased with a concomitant increase in lc gene dose. To determine if the above findings also apply to stably transfected CHO cells producing recombinant Mab, we compared the intra- and extracellular ratios of HC and LC polypeptides for three GS-CHO cells lines transfected with a 1:1 ratio of hc:lc genes and selected for stable expression of the same recombinant Mab, cB72.3. Intra- and extracellular HC:LC polypeptide ratios ranged from 1:2 to 1:5, less than that observed on transient expression of the same Mab in parental CHO cells using the same vector. In conclusion, our data suggest that the optimal ratio of hc:lc genes used for transient and stable expression of Mab differ. In the case of the latter, we infer that optimal Mab production by stably transfected cells represents a compromise between HC abundance limiting productivity and the requirement for excess LC to render Mab folding and assembly more efficient.

Animals↗

PubMedDate not supplied

Bioprocess iterative batch-to-batch optimization based on hybrid parametric/nonparametric models.

This paper presents a novel method for iterative batch-to-batch dynamic optimization of bioprocesses. The relationship between process performance and control inputs is established by means of hybrid grey-box models combining parametric and nonparametric structures. The bioreactor dynamics are defined by material balance equations, whereas the cell population subsystem is represented by an adjustable mixture of nonparametric and parametric models. Thus optimizations are possible without detailed mechanistic knowledge concerning the biological system. A clustering technique is used to supervise the reliability of the nonparametric subsystem during the optimization. Whenever the nonparametric outputs are unreliable, the objective function is penalized. The technique was evaluated with three simulation case studies. The overall results suggest that the convergence to the optimal process performance may be achieved after a small number of batches. The model unreliability risk constraint along with sampling scheduling are crucial to minimize the experimental effort required to attain a given process performance. In general terms, it may be concluded that the proposed method broadens the application of the hybrid parametric/nonparametric modeling technique to "newer" processes with higher potential for optimization.

Bioreactors↗

PubMedDate not supplied

Optimization of fed-batch Saccharomyces cerevisiae fermentation using dynamic flux balance models.

We developed a dynamic flux balance model for fed-batch Saccharomyces cerevisiae fermentation that couples a detailed steady-state description of primary carbon metabolism with dynamic mass balances on key extracellular species. Model-based dynamic optimization is performed to determine fed-batch operating policies that maximize ethanol productivity and/or ethanol yield on glucose. The initial volume and glucose concentrations, the feed flow rate and dissolved oxygen concentration profiles, and the final batch time are treated as decision variables in the dynamic optimization problem. Optimal solutions are generated to analyze the tradeoff between maximal productivity and yield objectives. We find that for both cases the prediction of a microaerobic region is significant. The optimization results are sensitive to network model parameters for the growth associated maintenance and P/O ratio. The results of our computational study motivate continued development of dynamic flux balance models and further exploration of their application to productivity optimization in biochemical reactors.

Amino Acids↗

PubMed1999

Development of a novel methodology To validate optimal sterilization conditions for maximizing the texture quality of white beans in glass jars

Optimal thermal processes were designed for white beans in glass jars heated in a still and end-over-end rotary pilot water cascading retort. For this purpose, isothermal kinetics of thermal softening of white beans were studied in detail using a tenderometer and a texturometer. The fractional conversion model was applied in both cases to model the texture degradation. The Arrhenius equation described well the temperature dependence of the reaction rate constant. With regard to the heat transfer, heat penetration parameters (fh and jh) were experimentally determined from 100 containers under static as well as rotational (end-over-end) conditions at 4, 7, 10, and 15 rpm. Theoretical optimal temperatures, maximizing volume average quality retention, were calculated using a computer program valid for conduction heating foods. Experimental verification of the calculated results was conducted. Considering the finite surface heat transfer coefficient, theoretical and experimental optimal temperatures were of the same order of magnitude, around 130 degrees C, while for an infinite surface heat transfer coefficient the calculated optimum temperature was much lower than the experimental value. The type of reaction kinetic model, fractional conversion or first-order models, does not significantly affect optimal sterilization temperatures. Although some differences were found, the developed theoretical approach was successfully applied to convective and mixed heating mode products. The use of the correct surface heat transfer coefficient is crucial to design optimal processing conditions.

Journal Article↗

PubMed2006

Application of heuristic optimization techniques and algorithm tuning to multilayered sorptive barrier design.

Although heuristic optimization techniques are increasingly applied in environmental engineering applications, algorithm selection and configuration are often approached in an ad hoc fashion. In this study, the design of a multilayer sorptive barrier system served as a benchmark problem for evaluating several algorithm-tuning procedures, as applied to three global optimization techniques (genetic algorithms, simulated annealing, and particle swarm optimization). Each design problem was configured as a combinatorial optimization in which sorptive materials were selected for inclusion in a landfill liner to minimize the transport of three common organic contaminants. Relative to multilayer sorptive barrier design, study results indicate (i) the binary-coded genetic algorithm is highly efficient and requires minimal tuning, (ii) constraint violations must be carefully integrated to avoid poor algorithm convergence, and (iii) search algorithm performance is strongly influenced by the physical-chemical properties of the organic contaminants of concern. More generally, the results suggest that formal algorithm tuning, which has not been widely applied to environmental engineering optimization, can significantly improve algorithm performance and provide insight into the physical processes that control environmental systems.

Algorithms↗