Multiphase experiments with at least one later laboratory phase. I. orthogonal designs

The paper provides a systematic approach to designing the laboratory phase of a multiphase experiment, taking into account previous phases. General principles are outlined for experiments in which orthogonal designs can be employed. Multiphase experiments occur widely, although their multiphase nature is often not recognized. The need to randomize the material produced from the first phase in the laboratory phase is emphasized. Factor-allocation diagrams are used to depict the randomizations in a design and the use of skeleton analysis-of-variance (ANOVA) tables to evaluate their properties discussed. The methods are illustrated using a scenario and a case study. A basis for categorizing designs is suggested. This article has supplementary material online.

Manufacturing and use of human placenta-derived mesenchymal stromal cells for phase I clinical trials: Establishment and evaluation of a protocol

Background/Aim. Mesenchymal stromal cells (MSCs) have been utilised in many clinical trials as an experimental treatment in numerous clinical settings. Bone marrow remains the traditional source tissue for MSCs but is relatively hard to access in large volumes. Alternatively, MSCs may be derived from other tissues including the placenta and adipose tissue. In an initial study no obvious differences in parameters such as cell surface phenotype, chemokine receptor display, mesodermal differentiation capacity or immunosuppressive ability, were detected when we compared human marrow derived- MSCs to human placenta-derived MSCs. The aim of this study was to establish and evaluate a protocol and related processes for preparation placenta-derived MSCs for early phase clinical trials. Methods. A full-term placenta was taken after delivery of the baby as a source of MSCs. Isolation, seeding, incubation, cryopreservation of human placentaderived MSCs and used production release criteria were in accordance with the complex regulatory requirements applicable to Code of Good Manufacturing Practice manufacturing of ex vivo expanded cells. Results. We established and evaluated instructions for MSCs preparation protocol and gave an overview of the three clinical areas application. In the first trial, MSCs were co-transplanted iv to patient receiving an allogeneic cord blood transplant as therapy for treatmentrefractory acute myeloid leukemia. In the second trial, MSCs were administered iv in the treatment of idiopathic pulmonary fibrosis and without serious adverse effects. In the third trial, MSCs were injected directly into the site of tendon damage using ultrasound guidance in the treatment of chronic refractory tendinopathy. Conclusion. Clinical trials using both allogeneic and autologous cells demonstrated MSCs to be safe. A described protocol for human placenta-derived MSCs is appropriate for use in a clinical setting, relatively inexpensive and can be relatively easily adjusted to a different set of regulatory requirements, as applicable to early phase clinical trials.

Designs for phase I clinical trials with multiple courses of subjects at different doses

The goal of this article is to provide a new design framework and its corresponding estimation for phase I trials. Existing phase I designs assign each subject to one dose level based on responses from previous subjects. Yet it is possible that subjects with neither toxicity nor efficacy responses can be treated at higher dose levels, and their subsequent responses to higher doses will provide more information. In addition, for some trials, it might be possible to obtain multiple responses (repeated measures) from a subject at different dose levels. In this article, a nonparametric estimation method is developed for such studies. We also explore how the designs of multiple doses per subject can be implemented to improve design efficiency. The gain of efficiency from "single dose per subject" to "multiple doses per subject" is evaluated for several scenarios. Our numerical study shows that using "multiple doses per subject" and the proposed estimation method together increases the efficiency substantially.

Isotonic designs for phase I trials

The purpose of a phase I trial in cancer is to determine the level (dose) of the treatment under study that has an acceptable level of adverse effects. Although substantial progress has recently been made in this area using parametric approaches, the method that is widely used is based on treating small cohorts of patients at escalating doses until the frequency of toxicities seen at a dose exceeds a predefined tolerable toxicity rate. This method is popular because of its simplicity and freedom from parametric assumptions. In this payer, we consider cases in which it is undesirable to assume a parametric dose-toxicity relationship. We propose a simple model-free approach by modifying the method that is in common use. The approach assumes toxicity is nondecreasing with dose and fits an isotonic regression to accumulated data. At any point in a trial, the dose given is that with estimated toxicity deemed closest to the maximum tolerable toxicity. Simulations indicate that this approach performs substantially better than the commonly used method and it compares favorably with other phase I designs.

Chemical Treatment Methods Pilot (CTMP) System for Treatment of Urban Runoff – Phase I. Feasibility and Design

(pdf contains 418 pages)

A Biogeographic Assessment off North/Central California: To Support the Joint Management Plan Review for Cordell Bank, Gulf of the Farallones, and Monterey Bay National Marine Sanctuaries: Phase I - Marine Fishes, Birds and Mammals.

In the spring of 2001, NOAA’s National Marine Sanctuary Program (NMSP) and National Centers for Coastal Ocean Science (NCCOS), in consultation with the National Marine Fisheries Service (NMFS), launched a 24-month effort to define and assess biogeographic patterns of selected marine species found within and adjacent to the boundaries of three west coast National Marine Sanctuaries. These sanctuaries, Monterey Bay, Gulf of the Farallones, and Cordell Bank are conducting a joint review process to update sanctuary management plans. The management plans for these sanctuaries have not been updated for over ten years and the status of the natural resources and their management issues in and around the sanctuaries may have changed. In addition, significant accomplishments in research and resource assessments have been made within the region. Thus, it is important to incorporate new and expanding knowledge into the revised management plans for these Sanctuaries.

River Dart Salmon Project. Summary of Phase I report.

This is the River Dart Salmon Project Summary of Phase I Report (2002) by the Westcountry Rivers Trust. The report contains sections on the introduction to Dart Salmon, factors affecting salmon numbers, salmon rod catch and salmon electro-fishing data, and a summary and discussion of the next phase. It also contains two tables with time series analysis on fry/parr numbers in representative section of the River Dart and figures with trends in fry/parrs numbers at juveniles electro-fishing sites. The section on salmon rod catch data includes trend analysis, cross-correlation of catches in different rivers and a general conclusion.

Liver genomic responses to ciguatoxin: evidence for activation of Phase I and Phase II detoxification pathways following an acute hypothermic response in mice

Ciguatoxins (CTX) are polyether neurotoxins that target voltage-gated sodium channels and are responsible for ciguatera, the most common fish-borne food poisoning in humans. This study characterizes the global transcriptional response of mouse liver to a symptomatic dose (0.26 ng/g) of the highly potent Pacific ciguatoxin-1 (P-CTX-1). At 1 h post-exposure 2.4% of features on a 44K whole genome array were differentially expressed (p ≤ 0.0001), increasing to 5.2% at 4 h and decreasing to 1.4% by 24 h post-CTX exposure. Data were filtered (|fold change| ≥ 1.5 and p ≤ 0.0001 in at least one time point) and a trend set of 1550 genes were used for further analysis. Early gene expression was likely influenced prominently by an acute 4°C decline in core body temperature by 1 h, which resolved by 8 h following exposure. An initial downregulation of 32 different solute carriers, many involved in sodium transport, was observed. Differential gene expression in pathways involving eicosanoid biosynthesis and cholesterol homeostasis was also noted. Cytochrome P450s (Cyps) were of particular interest due to their role in xenobiotic metabolism. Twenty-seven genes, mostly members of Cyp2 and Cyp4 families, showed significant changes in expression. Many Cyps underwent an initial downregulation at 1 h but were quickly and strongly upregulated at 4 and 24 h post-exposure. In addition to Cyps, increases in several glutathione S-transferases were observed, an indication that both phase I and phase II metabolic reactions are involved in the hepatic response to CTX in mice.

1987 ecosystem view of management research in the Myakka River: review of Phase I and Phase II reports

This memorandum has four parts. The first is a review and partial synthesis of Phase 1 and Phase 2 Reports by Dr. Ernest Estevez of the Mote Marine Laboratory to the Board of County Commissioners of Sarasota County, Florida. The review and synthesis emphasizes identification of the most important aspects of the structure of the Myakka system in terms of forcing functions, biological components, and major energy flows. In this context, the dominant primary producers, dominant fish species and food habits, and major environmental variables were of articular interest. A major focus of the review and synthesis was on the river zonations provided in the report and based on salinity and various biological indicators. The second part of this memorandum is a review of a draft report by Mote Marine Laboratory on evaluation of potential water quality impacts on the Myakka River from proposed activities in the watershed. This Memorandum's third part is a review of resource-management related ecosystem models in the context of possible future models of the Myakka River Ecosystem. The final part of this memorandum is proposed future work as an extension of the initial reports.

Influence of dioxin and metal-contaminated sediment on phase I and II biotransformation enzymes in silver crucian carp

Several biochemical responses were measured in silver crucian carp (Carassius auratus gibelio) after exposure to sediments obtained from contaminated Ya-Er Lake, No, 1 pond, and an unpolluted reference site, Honglian Lake. After 1 week of exposure, a significant induction of the phase I biotransformation enzyme (ethoxylresorufin-o-deethylase, EROD) was found (83-fold of control), whereas the phase II biotransformation enzyme (glutathione S-transferase, GST) exhibited a slight, but significant induction (1,4-fold of control) after 4 weeks of exposure. The level of cellular glutathione in the liver was also slightly elevated after 4 weeks of exposure. The delayed response of GST to the contaminants indicates that the phase I and phase II biotransformation enzymes are regulated differently in fish. The results suggest that EROD is a sensitive bioindicator to assess the toxicity of dioxin-contamined sediment in the laboratory, (C) 1998 Academic Press.

Physical modeling of localized scour for the Yangtze Estuary Waterway Improvement Project, Phase I

In order to examine the effectiveness of engineering protection against localized scour in front of the south groin-group of the Yangtze Estuary Waterway Improvement Project, Phase I, an undistorted physical model on a geometric scale of 1:250 is built in this study, covering two groins and their adacent estuarine areas. By use of rinsing fix-bed model as well as localized mobile-bed model the experiment is undertaken under bi-directional steady flow. According to the experimental results, waterway dredging leads to the increase in steram velocity, the increase being larger during the ebb than during the flood. Construction of the upstream groin has some influence on the flow patterns near the downstream groin. Localized scour in front of the groin-heads is controlled mainly by ebb flow. In the case of a riverbed composed entirely of silt, the depths of localized scour in front of the two groin-heads are 27 m and 29 m, respectively. In reality, the underneath sediment of the prototype riverbed is clay whose threshold velocity is much higher than the stream velocity in the Yangtze Estuary; therefore, the depths of localized scour will not be much larger than the thickness of the silt layer, i. e. 7.4 m and 4.7 m, respectively. The designed aprons covering the riverbed in fron of the groin-heads are very effective in scour control. Aprons of slightly smaller size can also fulfill the task of protection, but the area of localized scour increases significantly.

Levantamento pedológico de uma área-piloto relacionada ao Projeto BiosBrasil (Conservation and Sustainable Management of Below-Ground Biodiversity: Phase I), município de Benjamin Constant (AM): janela 6.

2005

Solos das áreas-piloto do Projeto BiosBrasil (Conservation and Sustainable Management of Below-Ground Biodiversity: Phase I), Município de Benjamin Constant, Estado do Amazonas.

2005