Phase I study of mitoxantrone plus etoposide with multidrug blockade by SDZ PSC-833 in relapsed or refractory acute myelogenous leukemia

PURPOSE: Expression of the multidrug resistance gene (MDR1) p170 protein is frequent in leukemic blasts from patients with relapsed acute myelogenous leukemia (AML). A phase I study using the nonimmunosuppressive MDR1 blocker SDZ PSC-833 (PSC) in combination with mitoxantrone (MITO) and etoposide (VP) was performed. PATIENTS AND METHODS: Starting doses (LVL0) of MITO (3.25 mg/m2/d on days 1 and 3 to 6) and VP (210 mg/m2/d on days 1 and 3 to 5) were 40% of the maximal-tolerated dose (MTD) from a prior study. A 1.5-mg/kg loading dose of PSC was followed by a 120-hour continuous infusion of 10 mg/kg/d on days 2 to 6. Blood samples for PSC, MITO, and VP pharmacokinetics (PK) were taken on days 1 and 3, and samples for MDR1 expression were taken on day 0. RESULTS: Severe mucositis developed in all patients at LVL0; therefore, MITO and VP doses were reduced to 2.5 and 170 mg/m2 (LVL-1) for the next seven patients, and this dose proved to be MTD. All LVL0 and three LVL-1 patients had transient elevations in the serum bilirubin level to > or = 4 mg/dL. Serum creatinine level increased to greater than 2 mg/dL in one case. There were no other grade 3 or 4 nonhematologic toxicities observed. The peripheral blood was cleared of leukemia in three LVL0 and four LVL-1 patients. The marrow was cleared of leukemic cells in one LVL0 and five LVL-1 patients, and a significant reduction in marrow leukemic infiltrate was observed in eight of 10. No patient achieved complete remission (CR), and all died of progressive disease (n = 8) or infection (n = 2). MDR1 expression was detected by fluorescent-activated cell sorter (FACS) analysis in five of seven cases. An elevated MDR1 mRNA level was detected by quantitative polymerase chain reaction (Q-PCR) in six of eight cases studied. Clearing of leukemia cells from the marrow occurred in four of six MDR1-positive and one of three MDR1-negative patients. Despite the fact that LVL0 doses had to be reduced due to toxicity, coadministration of PSC did not produce a consistent effect on MITO PK; however, it did repeatedly lead to increased levels of VP in the serum. CONCLUSION: We conclude that PSC-MITO-VP is a tolerable regimen with antileukemic activity. Addition of PSC necessitated a 66% reduction in MITO and VP doses from a prior study without PSC.     

A model for teaching psychotherapy theory through an integrative structure.

This article discusses a model for teaching psychotherapy theory through an integrative structure from the start of graduate students' training. This model articulates an ordering structure for the reputed 400+ so-called "theories" of psychotherapy. The rationale for such a structure highlights one dimension among several--that is, the recognition that a vast majority of mental health practitioners describe their orientation as eclectic or integrative. Professionals in training are encouraged to use this structure as an organizing principle to create the underpinnings for future professional development. The structure informs all aspects of a graduate-level course, including its syllabus, the textbooks selected, the reader, learning objectives, and tools for learning outcome assessment. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Fibre-reinforced cemented soils compressive and tensile strength assessment as a function of filament length

This study aims to develop a dosage methodology based on tensile and compressive strength for artificially cemented fibre reinforced soils considering filament length. The controlling parameters evaluated were the fibre length (l), the cement content (C), the porosity (η) and the porosity/cement ratio (η/C_iv). A number of unconfined compression and split tensile tests were carried out in the present work. The results show that fibre insertion in the cemented soil, for the whole range of cement content studied, and the increase of reinforcement length improve unconfined compressive and split tensile strengths. It was shown that the porosity/cement ratio, in which volumetric cementitious material content is adjusted by an exponent (0.28 for all the fibre-reinforced and non-reinforced cemented soil mixtures) to end in unique correlations for each mixture, is a good parameter in the evaluation of the unconfined compressive and split tensile strength of the fibre-reinforced and non-reinforced cemented soil studied. Analysis of variance (ANOVA) performed on the results of a factorial experiment considering the effect of adjusted cement content, fibre length and porosity showed that all of these factors are significant in affecting the measured changes in split tensile and unconfined compressive strength values. Finally, unique dosage relationships could be achieved linking the unconfined compressive strength (q_u) and the split tensile strength (q_t) of the sandy soil studied with porosity/cement ratio (η/C_iv) and fibre length (l).     

Fundamental Parameters for the Stiffness and Strength Control of Artificially Cemented Sand

The treatment of soils with cement is an attractive technique when the project requires improvement of the local soil for the construction of subgrades for rail tracks, as a support layer for shallow foundations and to prevent sand liquefaction. As reported by Consoli et al. in 2007, a unique dosage methodology has been established based on rational criteria where the voids/cement ratio plays a fundamental role in the assessment of the target unconfined compressive strength. The present study broadened the research carried out by Consoli et al. in 2007 through quantifying quantifies the influence of voids/cement ratio on the initial shear modulus (G0) and Mohr-Coulomb effective strength parameters (c′,?′) of an artificially cemented sand. A number of unconfined compression and triaxial compression tests with bender elements measurements were carried out. It was shown that the void/cement ratio defined as the ratio between the volume of voids of the compacted mixture and the volume of cement is an appropriate parameter to assess both initial stiffness and effective strength of the sand-cement mixture studied.     

Key Parameters for Strength Control of Artificially Cemented Soils

Often, the use of traditional techniques in geotechnical engineering faces obstacles of economical and environmental nature. The addition of cement becomes an attractive technique when the project requires improvement of the local soil. The treatment of soils with cement finds application, for instance, in the construction of pavement base layers, in slope protection of earth dams, and as a support layer for shallow foundations. However, there are no dosage methodologies based on rational criteria as exist in the case of the concrete technology, where the water/cement ratio plays a fundamental role in the assessment of the target strength. This study therefore aims to quantify the influence of the amount of cement, the porosity and the moisture content on the strength of a sandy soil artificially cemented, as well as to evaluate the use of a water/cement ratio and a voids/cement ratio to assess its unconfined compression strength. A number of unconfined compression tests, triaxial compression tests, and measurements of matric suction were carried out. The results show that the unconfined compression strength increased linearly with the increase in the cement content and exponentially with the reduction in porosity of the compacted mixture. The change in moisture content also has a marked effect on the unconfined compression strength of mixtures compacted at the same dry density. It was shown that, for the soil-cement mixture in an unsaturated state (which is usual for compacted fills), the water/cement ratio is not a good parameter for the assessment of unconfined compression strength. In contrast, the voids/cement ratio, defined as the ratio between the porosity of the compacted mixture and the volumetric cement content, is demonstrated to be the most appropriate parameter to assess the unconfined compression strength of the soil-cement mixture studied.     

Induction Motor Identification by a Microcomputer-Based Structure

The paper deals with the parameter estimation of an induction motor performed through a microcomputer-based data acquisition system and recursive identification algorithms (RLS and RGLS) implemented by means of a general purpose computer. The microcomputer-based data acquisition system is essentially made by connecting the Z80 CPU with its peripherals and auxiliary memories through a bus standard. The motor is represented by a classical fifth-order model linearized around a usual working point; an approximate third-order model, obtained via balanced realization, is in good correlation with the original one according to the identification aims and to the measurement set efficiency. An original CAD procedure is utilized to determine the electrical parameters.