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PubMed2004

Enhanced expression of a recombinant malaria candidate vaccine in Escherichia coli by codon optimization.

This study was conducted to compare the expression of three constructs of a multistage candidate vaccine (FALVAC-1) against Plasmodium falciparum in an Escherichia coli system: a synthetic gene with P. falciparum codons, a synthetic gene with optimized E. coli codons, and a synthetic gene with P. falciparum codons co-transformed with a RIG plasmid, which encodes three tRNAs (AG(A/G), ATA, GGA) that recognize rare E. coli codons. The expression of the protein increased at least threefold with codon optimization. The presence of the RIG plasmid in the co-transforming cells did not significantly increase the expression level of the gene with P. falciparum codons. The growth of cells transformed by the construct with P. falciparum codons was significantly slower than that of cells transformed by the construct with optimized E. coli codons after induction of protein expression with IPTG. The cells containing the non-codon optimized gene co-expressed with RIG plasmid had the slowest growth at all time points in culture. Thus, codon optimization significantly increases the yield of P. falciparum candidate vaccines in the E. coli expression system.

Amino Acid Sequence↗

PubMed2003

Computer optimization of class solutions designed on a beam segmentation basis.

BACKGROUND AND PURPOSE: A method for analytically solving the optimization of beam weighting in radiotherapy treatments using beam segmentation is presented. PATIENTS AND METHODS: A technique has been elaborated permitting the optimization of a flexible objective function which is defined by considering 'importance factors' for each anatomical region and 'allowed deviations' from the prescribed dose. As any change in these importance factors may lead to very different solutions, a statistical tool has been developed which varies the objective function automatically and iteratively to get the best possible results compatible with the chosen class solution. In addition, the spatial symmetry found in many anatomical sites is taken advantage of. Furthermore, freeware code has been written to run this optimization approach. The guidelines to design the beam segmentation used in our institution using organ avoidance criteria, and hence the suitable class solution for different anatomical sites, are given. A treatment-planning study for three anatomical sites is presented and, for two of them, the results obtained with both the suggested and the classical inverse approach are presented. RESULTS: The work presented might be used for beam weighting optimization in any radiotherapy treatment and furthermore, the suggested procedure may successfully confront the intensity-modulated radiation therapy (IMRT) problem and the obtained dose distributions fit the clinical constraints for all anatomical sites studied. When comparing with the classical inverse approach, both results are comparable in terms of dose distribution, but the suggested technique reduces the integral dose as the total number of monitor units is lower. CONCLUSIONS: The developed code performs the optimization with a very low time cost and in addition, this process can be carried out with a conventional treatment-planning system with no need of dedicated IMRT software.

Breast Neoplasms↗

PubMed2005

Optimization of a breast implant in Brachytherapy PDR: validation with Monte Carlo simulation and measurements with TLDs and GafChromic films.

BACKGROUND AND PURPOSE: The calculation of the dose distribution of Brachytherapy breast implant has been carried out in accordance with the Paris System (PS) in the majority of the radiotherapy departments in Europe. PDR (Pulsed Dose Rate) has lead to an improvement of the treatment procedure, optimization tools, however, allow an improvement of the treatment technique. The goal of this study was to perform a dosimetric verification of an optimized seven needles implant and to try to decrease the active length while preserving the same treatment volume. This corresponds to a ratio "treated length/active length" (L(t)/L(a)) that tends towards 1. MATERIAL AND METHODS: A dosimetry phantom was made of polystyrene, capable of receiving the implant, TLDs (LiF100 1mm(3) micro cubes) and films (GafChromic MD 55-2). Dose distributions for one source position and for the implant in conformity with the PS were calculated, utilizing version 14.2 of the Plato TPS (Nucletron); the remote afterloading system was a microSelectron-PDR (Nucletron). MCNP (Monte Carlo N-Particles transport) modeling was used for various configurations to evaluate the influence of the composition of the medium, of the presence of the needles and the lack of scatter. RESULTS: The benefit of the optimization was shown by the determination of a L(t)/L(a) factor of 1.05 instead of 0.7 for the standard PS. The dose distributions calculated by Plato are in agreement with TLD and film measurements for the optimization and the PS (<5%). The TPS results were confirmed by MC calculation as well as by measurements. MC calculations also showed that only the lack of scatter had a significant influence on the dose received by the skin (20%) CONCLUSIONS: The optimization brings a significant benefit in protecting the skin and in homogeneity of the dose distribution in the treated volume. Through MC simulation, this work made it possible to update a parameter significantly influencing dose distribution calculations: the lack of scattering.

Brachytherapy↗

PubMed2004

Parameter optimization of pulse compression in ultrasound imaging systems with coded excitation.

A linear array imaging system with coded excitation is considered, where the proposed excitation/compression scheme maximizes the signal-to-noise ratio (SNR) and minimizes sidelobes at the output of the compression filter. A pulse with linear frequency modulation (LFM) is used for coded excitation. The excitation/compression scheme is based on the fast digital mismatched filtering. The parameter optimization of the excitation/compression scheme includes (i) choice of an optimal filtering function for the mismatched filtering; (ii) choice of an optimal window function for tapering of the chirp amplitude; (iii) optimization of a chirp-to-transducer bandwidth ratio; (iv) choice of an appropriate n-bit quantizer. The simulation results show that the excitation/compression scheme can be implemented as a Dolph-Chebyshev filter including amplitude tapering of the chirp with a Lanczos window. An example of such an optimized system is given where the chirp bandwidth is chosen to be 2.5 times the transducer bandwidth and equals 6 MHz: The sidelobes are suppressed to -80 dB, for a central frequency of 4 MHz, and to -94 dB, for a central frequency of 8 MHz. The corresponding improvement of the SNR is 18 and 21 dB, respectively, when compared to a conventional short pulse imaging system. Simulation of B-mode images demonstrates the advantage of coded excitation systems of detecting regions with low contrast.

Journal Article↗

PubMed2004

Plasmid encoding papillomavirus Type 16 (HPV16) DNA constructed with codon optimization improved the immunogenicity against HPV infection.

Human papillomavirus Type 16 (HPV16) infections can cause neoplasia, which is thought to be closely associated with the development of cervical cancers. In the study, we attempted to construct a DNA plasmid encoding a HPV16 capsid protein (L1) and a HPV16 oncoprotein (E7), which was capable of preventing HPV16 infection and eliminating HPV16-infected cells. A plasmid, L1E7hpSCA1, encoding the L1 and E7 genes with the codon usage optimized for mammalian cell expression, was constructed. Mutations were introduced into the E7 gene sequence for reducing its oncogenicity. C57BL/6 mice were intramuscularly immunized at tibialis anterior (TA) muscles with the newly constructed L1E7hpSCA1 plasmid. The immune responses induced by the L1E7hpSCA1 plasmid (with codon optimization) and a control L1E7pSCA1 plasmid (without codon optimization) were compared. It is shown that the L1E7hpSCA1 was able to induce much stronger immune responses than the L1E7pSCA1. Sera obtained from immunized animals were found to contain anti-HPV16 antibodies as detected by ELISA and hemagglutination inhibition (HAI) assays. Cytotoxicity and interferon-gamma assays showed that spleenocytes from immunized animals were able to recognize and lyze E7 expressing tumor TC-1 cells. Moreover, the growth of E7 expressing tumor mass was inhibited in vaccinated mice. In vivo tumor protection test indicated that tumor formation was prevented in the experimental animals (67%) after vaccination with L1E7hpSCA1, while for the control group injected with L1E7pSCA1 only and the animal group injected with pSCA1 only, tumor formation was observed in all experimental animals. Our results suggest that the L1E7h gene (with codon optimization) is more effective against HPV16 than the L1E7 gene (without codon optimization). The L1E7hpSCA1 plasmid was able to provide protection against E7 expressing tumor, and it might have the potential to be a vaccine candidate for HPV prevention.

Animals↗

PubMed2004

The role of optimal debulking in advanced stage serous carcinoma of the uterus.

OBJECTIVE: To evaluate the role of optimal surgical cytoreduction and postoperative therapy in women with advanced uterine serous carcinoma (USC). METHODS: A multi-institutional, retrospective review identified 52 women with stage IV USC. Patient factors, surgical findings, and follow-up data were collected. Differences in demographics, surgical treatments, and adjuvant therapies administered were assessed with Fisher's exact test. Analysis of survival was performed using Kaplan-Meier and comparisons of survival were made using the log-rank test. RESULTS: Twenty-six women were optimally debulked ( 0.05). Median survival was longer in the optimal group (15 vs. 8 m), however, this did not reach statistical significance (P > 0.05). Women who received adjuvant platinum-based chemotherapy had a longer median survival than those who did not receive platinum chemotherapy (21 vs. 2 m) (P < 0.0001). Optimal cytoreduction combined with adjuvant therapy demonstrated a trend toward prolonged survival when compared to suboptimal cytoreduction combined with adjuvant therapy. However, the results did not achieve statistical significance (P > 0.05). CONCLUSION: Although no clear survival advantage is shown in the women who underwent optimal versus suboptimal debulking, there was a trend towards longer median survival in those who were maximally cytoreduced. Adjuvant platinum-based chemotherapy is associated with significantly longer survival in all women, regardless of amount of residual disease.

Aged↗

PubMed2005

Role of laparoscopy to assess the chance of optimal cytoreductive surgery in advanced ovarian cancer: a pilot study.

OBJECTIVE: To investigate whether laparoscopy can be considered as adequate and reliable as standard laparotomy in predicting optimal cytoreduction (RT < or = 1 cm) in patients with advanced ovarian cancer. METHODS: From March to November 2003, 95 patients with suspected advanced ovarian or peritoneal cancer have been evaluated. Thirty-one cases were excluded due to an anesthesiological class of risk ASA III-IV (51.6%) and for the presence of a large size mass reaching the xiphoid (48.4%). Sixty-four patients completed the study. All patients were submitted to preoperative clinico-radiological evaluation and then to both laparoscopy and standard longitudinal laparotomy, sequentially. Some specific preoperatively defined parameters were analyzed during each procedure in order to obtain the most accurate evaluation on the possibility to get an optimal cytoreduction. RESULTS: The overall accuracy rate of laparoscopy in assessing optimal cytoreduction was 90%. The negative predictive value (NPV) of the clinical-radiologic evaluation corresponded to 73%, whereas in no case was the judgment of unresectable disease obtained by laparoscopy changed by the laparotomic approach (NPV 100%). On the contrary, an optimal debulking was achievable in 34 of 39 cases (87%) selected as completely resectable by explorative laparoscopy. CONCLUSIONS: Laparoscopy can be considered super imposable to standard longitudinal laparotomy in identifying not optimally resectable advanced ovarian cancer patients.

Female↗

PubMed2006

The addition of extensive upper abdominal surgery to achieve optimal cytoreduction improves survival in patients with stages IIIC-IV epithelial ovarian cancer.

OBJECTIVES: To determine the survival impact of adding extensive upper abdominal surgical cytoreduction to standard surgical techniques for advanced ovarian cancer. METHODS: The records of all patients with stages IIIC-IV epithelial ovarian cancer who underwent primary surgery at our institution from 1998 to 2003 were reviewed. The cohort was divided into 3 groups. Group 1 patients required extensive upper abdominal surgery, such as diaphragm peritonectomy/resection, resection of parenchymal liver or porta hepatis disease and/or splenectomy with or without distal pancreatectomy, to achieve optimal cytoreduction (residual disease<or=1 cm). Group 2 patients were optimally cytoreduced by standard surgical techniques, including hysterectomy, oophorectomy, omentectomy, and bowel resection. Group 3 patients were suboptimally cytoreduced. Primary outcome measures were response to primary chemotherapy, progression-free survival, and overall survival. RESULTS: The cohort of 262 patients was divided as follows: Group 1, 57 patients; Group 2, 122 patients; and Group 3, 83 patients. The median follow-up was 36 months (range, 1-94 months). Frequency of clinical complete response in Groups 1, 2, and 3 was 82%, 78%, and 57%, respectively. The median progression-free survival for Groups 1, 2, and 3 was 24, 23, and 11 months, respectively. Progression-free survival for Groups 1 and 2 were equivalent (P=0.53) and were significantly longer than for Group 3 (P<0.001). The median overall survival was 84 and 38 months for Groups 2 and 3, respectively, and had not been reached for Group 1 by 68 months. Patients in Group 1 had equivalent overall survival to patients in Group 2 (P=0.74) and improved survival over patients in Group 3 (P<0.001). Prognostic factors significant on multivariate analysis included stage, optimal status, and ascites. CONCLUSIONS: Patients requiring extensive upper abdominal procedures to achieve optimal cytoreduction demonstrated a similar initial response, progression-free survival, and overall survival to patients optimally cytoreduced by standard surgical techniques. The presence of bulky upper abdominal disease alone did not appear to indicate poor tumor biology. This initial maximal surgical effort was associated with improved survival in patients who would have otherwise been suboptimally cytoreduced.

Adult↗

PubMed2004

Psychometric properties of optimism and pessimism: results from the Girls' Health Enrichment Multisite Studies.

UNLABELLED: Background. This study investigated the relationships among optimism, pessimism, physical activity, and dietary behaviors among 8- to 10-year-old African-American girls in the Girls' Health Enrichment Multisite Studies (GEMS). Methods. Ninety-two girls were randomly assigned to a 12-week physical activity and diet intervention or comparison group and completed psychosocial assessments including the Youth Life Orientation Test (YLOT) of optimism and pessimism, physical performance self-concept, physical activity self-efficacy, physical activity outcome expectancies, and physical activity and sedentary preferences. Also, preferences for bottled water and sweetened beverages were assessed. Physical activity and dietary intake were assessed by self-report and parent-report at baseline and follow-up. Also, physical activity was objectively assessed by wearing an accelerometer for 3 days. The psychometric properties of the optimism-pessimism subscales were analyzed. Results. The measures of optimism and pessimism in children were reliable (r = 0.75-0.82). In the multiple regression analyses without the intervention interaction terms, pessimism was positively and significantly related to increases in MET-adjusted usual activity (P = 0.008) and sedentary behaviors (P = 0.0004). Additionally, a negative (P = 0.026) pessimism by intervention interaction term for MET-adjusted usual activity was found such that the intervention group had a lower change in physical activity per unit increase in pessimism compared to the control group. CONCLUSIONS: Among 8- to 10-year-old African-American girls, pessimism was related to increased sedentary behaviors and usual activity. Previous studies have reported relationships between optimism and health-compromising behaviors. This study found that pessimism may positively or negatively influence efforts to increase health-promoting behaviors. Future research should confirm and clarify the meaning of these findings.

Black or African American↗

PubMed2001

Time is on my side: optimism in intertemporal choice.

The present research examines the role of optimism on time preferences for both losses and gains. It is argued that optimism has asymmetric effects on time preferences for gains versus losses: one reason why decision makers prefer immediate gains is because they are optimistic that these gains will be followed by additional gains in future. In contrast, decision makers prefer to delay losses because they are optimistic that losses are avoidable in the future. Optimism about outcomes affects time preferences for both gains and losses, such that low optimism reduces the discount rates while increased optimism is associated with higher discount rates. This prediction was supported in two different domains: monetary outcomes (Study 1), and health (Study 2). Implications of these results for both research practice and time preferences in the real world are discussed.

Analysis of Variance↗

PubMed1995

Frequency of "optimal anticoagulation" for acute myocardial infarction after thrombolysis with front-loaded recombinant tissue-type plasminogen activator and conjunctive therapy with recombinant hirudin (HBW 023). ALKK Study Group.

This retrospective analysis reviewed 183 patients with acute myocardial infarction who were given front-loaded recombinant tissue-type plasminogen activator (rt-PA) and r-hirudin (HBW 023) in 1 of 4 dose groups (bolus dose of 0.07, 0.1, 0.2, or 0.4 mg/kg, followed by an infusion of 0.05, 0.06, 0.1, or 0.15 mg/kg/hour over 48 hours). Activated partial thromboplastin time (aPTT) levels were determined at baseline and at 4, 8, 12, 16, 20, 24, 32, 40, and 48 hours. Of the 178 patients with r-hirudin treatment for > or = 12 hours, anticoagulation was optimal in 55.1% (all aPTTs > 2 x baseline), suboptimal in 33.7% (lowest aPTT > 1.5 but < 2 x baseline), and inadequate in 11.2% (> or = 1 aPTT but < 1.5 x baseline). Optimal anticoagulation was observed more frequently in the higher dose groups (dose 1, 15%; dose 2, 44.4%; dose 3, 63.4%; dose 4, 73.4%; p for trend < 0.0001). Patency (according to Thrombolysis in Myocardial Infarction trial grade 2 or 3) of the infarct artery after 36 to 48 hours was higher in the group with optimal anticoagulation compared with those with suboptimal or inadequate anticoagulation: 97.9%, 88.4%, and 85%, respectively (p = 0.03 optimal vs suboptimal or inadequate anticoagulation). In conclusion, r-hirudin in a dose of 0.1 or 0.15 mg/kg/hour achieves an optimal anticoagulation in about 63% or 74% of patients, which is associated with an enhanced patency 24 to 48 hours after rt-PA. A subsequent study revealed that this effective anticoagulation may be accompanied by an increased risk of severe bleeding complications after thrombolysis.

Adult↗

PubMed2003

Optimal operation of batch processes via the tracking of active constraints.

This paper presents a new measurement-based optimization framework for batch processes whereby optimal operation can be achieved via the tracking of active constraints. It is shown that, under mild assumptions and to a first-order approximation, tracking the necessary conditions of optimality is equivalent to tracking active constraints (both during the batch and at the end of the batch). Thus the optimal input trajectories can be adjusted using measurements without the use of a model of the process. When only batch-end measurements are available, the proposed method leads itself to an efficient batch-to-batch optimization scheme. The approach is illustrated via the simulation of a semibatch reactor under uncertainty.

Chemical Industry↗

PubMed2001

Static and dynamic optimization solutions for gait are practically equivalent.

The proposition that dynamic optimization provides better estimates of muscle forces during gait than static optimization is examined by comparing a dynamic solution with two static solutions. A 23-degree-of-freedom musculoskeletal model actuated by 54 Hill-type musculotendon units was used to simulate one cycle of normal gait. The dynamic problem was to find the muscle excitations which minimized metabolic energy per unit distance traveled, and which produced a repeatable gait cycle. In the dynamic problem, activation dynamics was described by a first-order differential equation. The joint moments predicted by the dynamic solution were used as input to the static problems. In each static problem, the problem was to find the muscle activations which minimized the sum of muscle activations squared, and which generated the joint moments input from the dynamic solution. In the first static problem, muscles were treated as ideal force generators; in the second, they were constrained by their force-length-velocity properties; and in both, activation dynamics was neglected. In terms of predicted muscle forces and joint contact forces, the dynamic and static solutions were remarkably similar. Also, activation dynamics and the force-length-velocity properties of muscle had little influence on the static solutions. Thus, for normal gait, if one can accurately solve the inverse dynamics problem and if one seeks only to estimate muscle forces, the use of dynamic optimization rather than static optimization is currently not justified. Scenarios in which the use of dynamic optimization is justified are suggested.

Computer Simulation↗

PubMed2001

Sensitivity of predicted muscle forces to parameters of the optimization-based human leg model revealed by analytical and numerical analyses.

There are different opinions in the literature on whether the cost functions: the sum of muscle stresses squared and the sum of muscle stresses cubed, can reasonably predict muscle forces in humans. One potential reason for the discrepancy in the results could be that different authors use different sets of model parameters which could substantially affect forces predicted by optimization-based models. In this study, the sensitivity of the optimal solution obtained by minimizing the above cost functions for a planar three degrees-of-freedom (DOF) model of the leg with nine muscles was investigated analytically for the quadratic function and numerically for the cubic function. Analytical results revealed that, generally, the non-zero optimal force of each muscle depends in a very complex non-linear way on moments at all three joints and moment arms and physiological cross-sectional areas (PCSAs) of all muscles. Deviations of the model parameters (moment arms and PCSAs) from their nominal values within a physiologically feasible range affected not only the magnitude of the forces predicted by both criteria, but also the number of non-zero forces in the optimal solution and the combination of muscles with non-zero predicted forces. Muscle force magnitudes calculated by both criteria were similar. They could change several times as model parameters changed, whereas patterns of muscle forces were typically not as sensitive. It is concluded that different opinions in the literature about the behavior of optimization-based models can be potentially explained by differences in employed model parameters.

Humans↗

PubMed1988

Selection of high-performance liquid chromatographic methods in pharmaceutical analysis. I. Optimization for selectivity in reversed-phase chromatography.

The application of solvent optimization to the development of isocratic reversed-phase liquid chromatography has been reported in several publications. Two different approaches to solvent optimization for controlling band spacing for the maximum resolution of samples are "solvent strength" and "solvent type" optimization. To improve the separation selectivity further the combination of these two approaches was examined, as a (global) optimum mobile phase composition requires the optimization of the solvent strength by varying the percentage of organic component and of the solvent selectivity of methanol, acetonitrile, tetrahydrofuran and water. It was found that the combination of "solvent strength" and "solvent type" optimization provides a markedly better separation than either procedure alone.

Chromatography, High Pressure Liquid↗

PubMed2003

Computer-assisted method development and optimization in high-performance liquid chromatography.

This paper reports the use of DryLab, a computer simulation software package, to assist in the development and optimization of a reversed-phase high-performance liquid chromatographic (HPLC) method for the separation of a model drug candidate and its degradation products. Prior to the optimization process, columns with various bonded phases are evaluated for their chromatographic performance using the sample of interest. Simultaneous optimization of two separation variables and the use of resolution maps to predict the optimal conditions are illustrated. Options to optimize column conditions (column length and flow-rate) to further reduce run time are briefly discussed. The accuracy of DryLab-predicted retention times and resolution is compared with experimental values. The DryLab software used in this study provided satisfactory predictions for the selected model, with average errors of less than 3.5 and 11.8% for retention time and resolution, respectively.

Chromatography, High Pressure Liquid↗

PubMed1977

Determination of optimal continuous positive airway pressure for the treatment of IRDS by measurement of esophageal pressure.

We describe a simple and reliable method to determine optimal airway pressure in infants with idiopathic respiratory distress syndrome who require continuous positive airway pressure treatment. Esophageal pressure was monitored in ten infants with IRDS during initial application of CPAP. As the level of CPAP was increased in 2 cm H2O increments, changes in Pes were compared with changes in PaO2. Below optimal airway pressure, Pes as well as PaO2 increased insignificantly. When optimal airway pressure (8.1 +/- 0.8 cm H2O) was applied, there was a marked increase in Pes (3.6 +/- 0.8 cm H2O. p less than 0.001) and PaO2 (39.0 +/- 10.0 mm Hg, p less than 0.01). Further increase in CPAP did not result in any subsequent appreciable increase in Pes while PaO2 decreased slightly and PaCO2 increased. Less than optimal CPAP increases F102 requirements and may increase the associated risk of bronchopulmonary dysplasia, while excessive levels of CPAP may increase the risk of pneumothorax. We suggest that esophageal pressure be monitored routinely to determine the optimal level of CPAP for each infant during the initial application of therapy.

Carbon Dioxide↗

PubMed2002

Optimizing the hybrid capture II human papillomavirus test to detect cervical intraepithelial neoplasia.

OBJECTIVE: To estimate the optimal relative light unit ratio, and correspondingly viral load, of the hybrid capture II oncogenic human papillomavirus deoxyribonucleic acid test for detecting cervical intraepithelial neoplasia (CIN). METHODS: Women with abnormal cytology were referred for colposcopy, and a cervical swab or brush specimen was obtained for human papillomavirus testing. Sensitivities, specificities, and likelihood ratios of different relative light unit ratio cutoffs were calculated using a reference standard of colposcopy or biopsy of either CIN II+ (CIN II, III, or carcinoma), or CIN I+ (CIN I, CIN II+). The receiver operating characteristic curve was used to estimate optimal test-positive cutoff points for the hybrid capture II test. RESULTS: CIN II+ was found in 18.7% (98 of 524) and CIN I in 10.5% (55 of 524) of the women. The optimal relative light unit ratio was 15.56, giving a sensitivity and specificity of 82.7% and 73.2% for CIN II+, and 74.2% and 77.8% for CIN I+. In a stratified analysis, a higher relative light unit cutoff (15.19) optimized sensitivity and specificity for CIN II+ (sensitivity 81.8%, specificity 51.5%) for women with low-grade squamous intraepithelial lesions cytology, whereas the optimal cutoff was 2.36 (sensitivity 100%, specificity 73.0%) for women with atypical squamous cells of undetermined significance, yielding referral rates of 53.3% and 28.7%, respectively. Use of a swab or brush was not associated with the level of human papillomavirus detected (P >.05). CONCLUSION: Use of a higher cutoff for the relative light unit ratio (higher viral load) of the hybrid capture II test may improve the management of women, especially those with low-grade squamous intraepithelial lesions cytology.

Adolescent↗