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Early Testing (early + testing)

Distribution by Scientific Domains

Medical Sciences	50%

Selected Abstracts

Fluid Mechanics, Cell Distribution, and Environment in Cell Cube Bioreactors

BIOTECHNOLOGY PROGRESS, Issue 1 2003
John G. Auni
Cultivation of MRC-5 cells and attenuated hepatitis A virus (HAV) for the production of VAQTA, an inactivated HAV vaccine ( 1), is performed in the Cell Cube reactor, a laminar flow fixed-bed bioreactor with an unusual diamond-shaped, diverging-converging flow geometry. These disposable bioreactors have found some popularity for the production of cells and gene therapy vectors at intermediate scales of operation ( 2, 3). Early testing of the Cell Cube revealed that the fluid mechanical environment played a significant role in nonuniform cell distribution patterns generated during the cell growth phase. Specifically, the reactor geometry and manufacturing artifacts, in combination with certain inoculum practices and circulation flow rates, can create cell growth behavior that is not simply explained. Via experimentation and computational fluid dynamics simulations we can account for practically all of the observed cell growth behavior, which appears to be due to a complex mixture of flow distribution, particle deposition under gravity, fluid shear, and possibly nutritional microenvironment. [source]

Clinical islet transplant: current and future directions towards tolerance

IMMUNOLOGICAL REVIEWS, Issue 1 2003
A. M. James Shapiro
Summary:, The ultimate goal of islet transplantation is to completely correct the diabetic state from an unlimited donor source, without the need for chronic immunosuppressive drug therapy. Although islet transplantation provides an opportunity to develop innovative strategies for tolerance in the clinic, both alloimmune and autoimmune barriers must be controlled, if stable graft function is to be maintained long-term. After islet extraction from the pancreas, the cellular graft may be stored in tissue culture or cryopreserved for banking, providing an opportunity not only to optimally condition the recipient but also to allow in vitro immunologic manipulation of the graft before transplantation, unlike solid organ grafts. As such, islets may be considered a ,special case.' Remarkable progress has occurred in the last three years, with dramatic improvements in outcomes after clinical islet transplantation. The introduction of a steroid-free, sirolimus-based, anti-rejection protocol and islets prepared from two (or rarely three) donors led to high rates of insulin independence. The ,Edmonton Protocol' has been successfully replicated by other centers in an international multicenter trial. A number of key refinements in pancreas transportation, processing, purification on non-ficoll-based media, storage of islets in culture for two days and newer immunological conditioning and induction therapies have led to continued advancement through extensive collaboration between key centers. This review outlines the historical development of islet transplantation over the past 30 years, provides an update on current clinical outcomes, and summarizes a series of unique opportunities for development and early testing of tolerance protocols in patients. [source]

The pediatric preclinical testing program: Description of models and early testing results,

PEDIATRIC BLOOD & CANCER, Issue 7 2007
Peter J. Houghton PhD
Abstract Background The Pediatric Preclinical Testing Program (PPTP) is an initiative supported by the National Cancer Institute (NCI) to identify novel therapeutic agents that may have significant activity against childhood cancers. The PPTP has established panels of childhood cancer xenografts and cell lines to be used for in vivo and in vitro testing. These include panels for Wilms tumor, sarcomas (rhabdomyosarcoma, Ewing sarcoma, and osteosarcoma), neuroblastoma, brain tumors (glioblastoma, ependymoma, and medulloblastoma), rhabdoid tumors (CNS and renal), and acute lymphoblastic leukemia (ALL). Here, we describe the characteristics of the in vivo tumor panels and report results for the in vivo evaluation of two standard agents, vincristine and cyclophosphamide. Procedures Solid tumors were grown subcutaneously in immune-deficient mice and tumor dimensions were measured weekly. ALL xenografts were inoculated intravenously and human CD45-positive cells were enumerated weekly. Results Vincristine-induced objective responses in 6 of 24 (25%) and cyclophosphamide-induced objective responses in 18 of 28 (64%) solid tumor models. Comparable assessments of high levels of activity for these two agents were obtained using a tumor growth delay (TGD) measure. Both agents induced regressions in each of the ALL models evaluated. Conclusions We have established 51 solid tumor and 10 ALL in vivo models. The models identify vincristine and cyclophosphamide as having broad-spectrum activity. The PPTP tumor panels appear to generally recapitulate the activity of these agents against specific childhood cancers and to have the potential for identifying novel agents having significant clinical activity. Pediatr Blood Cancer 2007;49:928,940. Published 2006 Wiley-Liss, Inc. [source]

Regression Analysis with a Misclassified Covariate from a Current Status Observation Scheme

BIOMETRICS, Issue 2 2010
Leilei Zeng
Summary Naive use of misclassified covariates leads to inconsistent estimators of covariate effects in regression models. A variety of methods have been proposed to address this problem including likelihood, pseudo-likelihood, estimating equation methods, and Bayesian methods, with all of these methods typically requiring either internal or external validation samples or replication studies. We consider a problem arising from a series of orthopedic studies in which interest lies in examining the effect of a short-term serological response and other covariates on the risk of developing a longer term thrombotic condition called deep vein thrombosis. The serological response is an indicator of whether the patient developed antibodies following exposure to an antithrombotic drug, but the seroconversion status of patients is only available at the time of a blood sample taken upon the discharge from hospital. The seroconversion time is therefore subject to a current status observation scheme, or Case I interval censoring, and subjects tested before seroconversion are misclassified as nonseroconverters. We develop a likelihood-based approach for fitting regression models that accounts for misclassification of the seroconversion status due to early testing using parametric and nonparametric estimates of the seroconversion time distribution. The method is shown to reduce the bias resulting from naive analyses in simulation studies and an application to the data from the orthopedic studies provides further illustration. [source]