A phase I trial of antibody directed enzyme prodrug therapy (ADEPT) in patients with advanced colorectal carcinoma or other CEA producing tumours

Antibody-directed enzyme prodrug therapy is a targeted therapy in which a prodrug is activated selectively at the tumour site by an enzyme, which has been targeted to the tumour by an antibody (antibody-enzyme conjugate). Previous clinical trials have shown evidence of tumour response, however, the activated drug had a long half-life, which resulted in dose-limiting myelosuppression. Also, the targeting system, although giving high tumour to blood ratios of antibody-enzyme conjugate (10 000 : 1) required administration of a clearing antibody in addition to the antibody-enzyme conjugate. The purpose of this current study therefore was to attempt tumour targeting of the antibody-enzyme conjugate without the clearing antibody, and to investigate a new prodrug (bis-iodo phenol mustard, ZD2767P) whose activated form is highly potent and has a short half-life. Twenty-seven patients were treated with antibody-directed enzyme prodrug therapy using A5CP antibody-enzyme conjugate and ZD2767P prodrug, in a dose-escalating phase I trial. The maximum tolerated dose of ZD2767P was reached at 15.5 mg m−2×three administrations with a serum carboxypeptidase G2 level of 0.05 U ml−1. Myelosuppression limited dose escalation. Other toxicities were mild. Patients' quality of life was not adversely affected during the trial as assessed by the measures used. There were no clinical or radiological responses seen in the study, but three patients had stable disease at day 56. Human anti-mouse antibody and human anti-carboxypeptidase G2 antibody were produced in response to the antibody enzyme conjugate (A5CP). The antibody-enzyme conjugate localisation data (carboxypeptidase G2 enzyme levels by HPLC on tumour and normal tissue samples, and gamma camera analysis of I-131 radiolabelled conjugate) are consistent with inadequate tumour localisation (median tumour: normal tissue ratios of antibody-enzyme conjugate of less than 1). A clearance system is therefore desirable with this antibody-enzyme conjugate or a more efficient targeting system is required. ZD2767P was shown to clear rapidly from the circulation and activated drug was not measurable in the blood. ZD2767P has potential for use in future antibody-directed enzyme prodrug therapy systems

Structure/activity relationships of antitumour diazridinylquinones

SIGLEAvailable from British Library Document Supply Centre-DSC:DXN006008 / BLDSC - British Library Document Supply CentreGBUnited Kingdo

Development of a Kalman filter estimator for simulation and control of particulate matter distribution of a diesel catalyzed particulate filter

The knowledge of the temperature and particulate matter mass distribution is essential for monitoring the performance and durability of a catalyzed particulate filter. A catalyzed particulate filter model was developed, and it showed capability to accurately predict temperature and particulate matter mass distribution and pressure drop across the catalyzed particulate filter. However, the high-fidelity model is computationally demanding. Therefore, a reduced order multi-zone particulate filter model was developed to reduce computational complexity with an acceptable level of accuracy. In order to develop a reduced order model, a parametric study was carried out to determine the number of zones necessary for aftertreatment control applications. The catalyzed particulate filter model was further reduced by carrying out a sensitivity study of the selected model assumptions. The reduced order multi-zone particulate filter model with 5 × 5 zones was selected to develop a catalyzed particulate filter state estimator considering its computational time and accuracy. Next, a Kalman filter–based catalyzed particulate filter estimator was developed to estimate unknown states of the catalyzed particulate filter such as temperature and particulate matter mass distribution and pressure drop (ΔP) using the sensor inputs to the engine electronic control unit and the reduced order multi-zone particulate filter model. A diesel oxidation catalyst estimator was also integrated with the catalyzed particulate filter estimator in order to provide estimates of diesel oxidation catalyst outlet concentrations of NO2 and hydrocarbons and inlet temperature for the catalyzed particulate filter estimator. The combined diesel oxidation catalyst–catalyzed particulate filter estimator was validated for an active regeneration experiment. The validation results for catalyzed particulate filter temperature distribution showed that the root mean square temperature error by using the diesel oxidation catalyst–catalyzed particulate filter estimator is within 3.2 °C compared to the experimental data. Similarly, the ΔP estimator closely simulated the measured total ΔP and the estimated cake pressure drop error is within 0.2 kPa compared to the high-fidelity catalyzed particulate filter model

Designing a Family Concept Model in Divorce Applicant Couples Based on Grounded Theory

The present study tries to identify the concept of family in the lived experiences of divorced applicants, using a qualitative method of Foundation data. The aim of this study was to gain an understanding of the life experience of divorce applicants and to discover and extract models from these experiences and to map the relevant paradigms, including the interrelationships between conditions (structure), action (process), and consequences. Data obtained through in-depth and semi-structured interviews with divorce applicants of the Karaj Family Court. The study reached theoretical saturation through the purposive sampling method with a sample size of 9 spouses (n = 18). The data were analyzed through the Strauss & Corbin method in three stages of open, axial and selective coding. The findings show that the causal conditions are the family ideological and structural tyans formation, the family evolution, the cultural problems, and economic problems. The basis conditions include family disorder, the lack of the state interactions, having the tool interaction and neglect to the religion outcome dimension. Intervention conditions are composed of the lack of life skill, the incorrect culture of the modern technology use and the lack of the separation of the family public and private scope. The consequences are of three main categories: the inevitability of divorce, the consequences of divorce, and the loss of family support. The results of the research showed that the phenomenon or category of the family concept in the living experience of divorce applicants is the unbalanced development of the family. As a result, unbalanced family development is largely eliminated by life skills training and social support

Development of a Catalyzed Diesel Particulate Filter Multi-zone Model for Simulation of Axial and Radial Substrate Temperature and Particulate Matter Distribution

© 2015, Springer SIP, AG. The catalyzed particulate filter (CPF) is an important exhaust aftertreatment subsystem that is managed by the electronic control unit (ECU) of an engine. CPFs need periodic regeneration to avoid temperature exotherms and excess engine back pressure. To this end, a multi-zone particulate filter (MPF) model was developed in this research to serve as a simulation tool to provide on-board diagnostics (OBD) data for managing CPF active regeneration (AR). The MPF model runs in real time within the ECU to provide feedback on temperature and particulate matter (PM) loading distribution within each axial and radial zone of the filter substrate. The MPF model accounts for the internal and external heat transfer mechanisms, inlet temperature distribution using the fully developed boundary layer concept, and PM oxidation by thermal (O2)- and NO2-assisted oxidation mechanisms. A calibration procedure was developed to calibrate the PM kinetics and heat transfer coefficients of the MPF model. The model shows the good capability to predict temperature and PM loading distribution within the filter

Experimental and Simulation Analysis of Temperature and Particulate Matter Distribution for a Catalyzed Diesel Particulate Filter

© 2015, Springer SIP, AG. A multi-zone particulate filter (MPF) model from reference [1] was extended to analyze temperature and particulate matter (PM) distribution within each axial and radial zone of the filter substrate. A parametric study was used to determine the optimum required number of zones in the MPF model in the range of 5 × 5 to 20 × 20 zones for aftertreatment control applications. The MPF model with 10 × 10 zones was optimum and ran 12.2 times faster than real time. The 10 × 10 zone MPF model was calibrated using eighteen runs of data from a 2007 Cummins ISL engine that consisted of passive and active regeneration data sets for ultra-low-sulfur diesel (ULSD), diesel blend (ULSD) with 10 % biodiesel (B10), and diesel blend (ULSD) with 20 % biodiesel (B20) fuels. The MPF model was accurate, with maximum root mean square (RMS) error of 2.1 g for predicting PM loading and RMS error of within 10 °C for predicting temperature distribution within the filter. The PM distribution trends simulated by the MPF model were in good agreement with the experimental data measured using a terahertz wave scanner. The study of PM distribution during loading and at the end of PM oxidation (passive oxidation and active regeneration) showed that the PM oxidation by active regeneration leads to greater non-uniform PM loading of the filter compared to the passive oxidation as quantified using the uniformity index (UI) which was developed in the research to quantify the PM and temperature distribution

Predicting Pressure Drop, Temperature, and Particulate Matter Distribution of a Catalyzed Diesel Particulate Filter Using a Multi-Zone Model Including Cake Permeability

© 2017, Springer International Publishing Switzerland. A multi-zone particulate filter (MPF) model was developed to predict pressure drop and PM oxidation of a catalyzed diesel particulate filter (CPF). The MPF model builds upon our previous work (Mahadevan et al., J Emiss Control Sci Technol 1:183–202, 2015; Mahadevan et al., J Emiss Control Sci Technol 1:255–283, 2015) by adding a new multi-zone version of a classical 1-D filtration model (Konstandopoulos and Johnson, 1989) to account for PM filtration within the substrate wall and PM cake of a CPF. In addition, pressure drop (∆P) simulation capability was also developed for the MPF model in order to simulate the pressure drop across the substrate wall and PM cake of the CPF. A cake permeability model was developed based on fundamental research findings in the literature. The PM cake and wall pressure drop simulation accounts for the wall and cake permeability variation during loading, PM oxidation, and an additional post-loading after oxidation. This extended MPF model was calibrated using 18 runs of experimental data from a Cummins ISL engine that consisted of passive and active regeneration data sets for ULSD, B10, and B20 fuels. The validation results show that the new MPF model can predict PM loading with a maximum root mean square (RMS) error of 7.4% and predict (∆P) across the filter with an RMS error of within 7.2%. It is found that the permeability of the PM cake layer increases rapidly during PM oxidation. The increase in permeability was attributed to the damage in the PM cake and was simulated using the newly developed cake permeability model. The increased permeability of the damaged PM cake layer and oxidation of cake PM leads to near zero cake PM pressure drop during PM oxidation for the passive and active regeneration experiments

An experimental investigation on combustion and performance characteristics of supercharged HCCI operation in low compression ratio engine setting

This study investigates the effects of boost pressure on combustion and performance of an early direct injection homogenous charge compression ignition (HCCI) engine at a low compression ratio (CR). A 2.0 L, four-cylinder, four-stroke, gasoline direct injection engine was converted to operate in early direct injection HCCI mode. In addition, a supercharger unit was developed for engine boosting. The experiments were performed at different intake manifold absolute pressures (MAP) from 1.0 to 1.6 bar at different engine loads using n-heptane fuel. The effects of boost pressure were investigated on HCCI combustion and engine performance characteristics using volumetric efficiency, in-cylinder pressure, heat release rate (HRR), maximum in-cylinder pressure and gas temperature, CA50 (crank angle by which 50% of the fuel is burnt), combustion duration, apparent combustion efficiency, indicated mean effective pressure (IMEP), brake mean effective pressure (BMEP), friction mean effective pressure (FMEP), indicated thermal efficiency (ITE), brake thermal efficiency (BTE), heat loss, exergy of heat loss, coefficient of variation of IMEP (COVIMEP), maximum pressure rise rate (MPRR) and ringing intensity (RI). The experimental results showed that high-efficiency HCCI operation is feasible at an engine compression ratio as low as 9.2 once the engine variables are properly optimized and an appropriate level of supercharging is utilized. An increase in indicated thermal efficiency was seen as boost pressure increased. In addition, combustion phasing advanced by increasing boost pressure or increasing air–fuel equivalence ratio values. Combustion events with CA50 2–3 °CA aTDC show the highest thermal efficiency especially at low boost pressure conditions. In addition, the pressure rise rate and ringing intensity increased by increasing air–fuel equivalence ratio and MAP. The test results also showed that HCCI operating range can be extended with the increase of intake manifold pressure especially at high load limits

IJER-18-0031-R2-Supplementary_Appendices – Supplemental material for Development of a Kalman filter estimator for simulation and control of particulate matter distribution of a diesel catalyzed particulate filter

<p>Supplemental material, IJER-18-0031-R2-Supplementary_Appendices for Development of a Kalman filter estimator for simulation and control of particulate matter distribution of a diesel catalyzed particulate filter by Boopathi Singalandapuram Mahadevan, John H Johnson and Mahdi Shahbakhti in International Journal of Engine Research</p