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Viable Strategy (viable + strategy)
Selected AbstractsViable strategies to facilitate liver transplantation for human immunodeficiency virus coinfection,LIVER TRANSPLANTATION, Issue 9 2009Peter G. Stock [source] A Chemical Approach Towards Understanding the Mechanism and Reversal of Drug Resistance in Plasmodium falciparum: Is it Viable?IUBMB LIFE, Issue 4-5 2002Kelly Chibale Abstract Genetic and biochemical approaches to studies of drug resistance mechanisms in Plasmodium falciparum have raised controversies and contradictions over the past several years. A different and novel chemical approach to this important problem is desirable at this point in time. Recently, the molecular basis of drug resistance in P. falciparum has been associated with mutations in the resistance genes, Chloroquine Resistance Transporter (PfCRT) and the P-glycoprotein homologue (Pgh1). Although not the determinant of chloroquine resistance in P. falciparum, mutations in Pgh1 have important implications for resistance to other antimalarial drugs. Because it is mutations in the aforementioned resistance genes rather than overexpression that has been associated with drug resistance in malaria, studies on mechanisms of drug resistance and its reversal by chemosensitisers should benefit from a chemical approach. Target-oriented organic synthesis of chemosensitisers against proteins implicated in drug resistance in malaria should shed light on mechanism of drug resistance and its reversal in this area. The effect of structurally diverse chemosensitisers should be examined on several putative resistance genes in P. falciparum to deal with antimalarial drug resistance in the broadest sense. Therefore, generating random mutations of these resistance proteins and subsequent screening in search of a specific phenotype followed by a search for mutations and/or chemosensitisers that affect a specific drug resistance pathway might be a viable strategy. This diversity-oriented organic synthesis approach should offer the means to simultaneously identify resistance proteins that can serve as targets for therapeutic intervention (therapeutic target validation) and chemosensitisers that modulate the functions of these proteins (chemical target validation). [source] Refuge habitats modify impact of insecticide disturbance on carabid beetle communitiesJOURNAL OF APPLIED ECOLOGY, Issue 2 2001Jana C. Lee Summary 1Carabid beetles are polyphagous predators that can act as biological control agents of insect pests and weeds. While current agricultural practices often create a harsh environment, habitat management such as the establishment of within-field refuges has been proposed to enhance carabid beetle abundance and impact. We examined the joint effects of refuge habitats and insecticide application on carabid activity density (parameter of population density and relative activity) and species composition in a cornfield. 2Our 2-year study comprised four treatments: (i) ,refuge/,insecticide; (ii) +refuge/,insecticide; (iii) ,refuge/+insecticide; (iv) +refuge/+insecticide. Refuge strips consisted of grasses, legumes and perennial flowering plants. ,,Refuge' strips were planted with corn and not treated with insecticide. 3Before planting and insecticide application, carabid activity density in the crop areas was similar across all treatments. Insecticide application immediately reduced carabid activity density and altered community composition in the crop area. 4Refuge strips had significantly higher activity density of beetles than ,refuge strips before planting and during the summer. 5During summer, as new carabids emerged and insecticide toxicity declined, the presence of refuge strips influenced carabids in the adjacent crop area. Carabid activity density within crop areas previously treated with insecticide was significantly higher when adjacent to refuge strips. Also, carabid communities within insecticide-treated crop areas were affected by the presence or absence of a refuge strip. 6The presence of refuge strips did not consistently augment carabid numbers in crop areas where insecticide was not applied. One explanation may be that insecticides decreased the quality of crop habitat to carabids by depletion of prey and direct mortality. However, subsequent rebounds in prey density and the absence of competing predators may make these areas relatively more attractive than unperturbed crop habitats to carabid colonization from refuges. 7This study demonstrates that refuges may buffer the negative consequences of insecticide application on carabids in adjacent fields. Diversifying agro-ecosystems with refuge habitats may be a viable strategy for maintaining carabid populations in disturbed agricultural landscapes to keep pests below outbreak levels. [source] A solid-state approach to enable early development compounds: Selection and animal bioavailability studies of an itraconazole amorphous solid dispersionJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 9 2010David Engers Abstract A solid-state approach to enable compounds in preclinical development is used by identifying an amorphous solid dispersion in a simple formulation to increase bioavailability. Itraconazole (ITZ) was chosen as a model crystalline compound displaying poor aqueous solubility and low bioavailability. Solid dispersions were prepared with different polymers (PVP K-12, K29/32, K90; PVP VA S-630; HPMC-P 55; and HPMC-AS HG) at varied concentrations (1:5, 1:2, 2:1, 5:1 by weight) using two preparation methods (evaporation and freeze drying). Physical characterization and stability data were collected to examine recommended storage, handling, and manufacturing conditions. Based on generated data, a 1:2 (w/w) ITZ/HPMC-P dispersion was selected for further characterization, testing, and scale-up. Thermal data and computational analysis suggest that it is a possible solid nanosuspension. The dispersion was successfully scaled using spray drying, with the materials exhibiting similar physical properties as the screening samples. A simple formulation of 1:2 (w/w) ITZ/HPMC-P dispersion in a capsule was compared to crystalline ITZ in a capsule in a dog bioavailability study, with the dispersion being significantly more bioavailable. This study demonstrated the utility of using an amorphous solid form with desirable physical properties to significantly improve bioavailability and provides a viable strategy for evaluating early drug candidates. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:3901,3922, 2010 [source] Gene Transfer in Human Vestibular Epithelia and the Prospects for Inner Ear Gene Therapy,,THE LARYNGOSCOPE, Issue 5 2008Bradley W. Kesser MD Abstract Transfer of exogenous genetic material into the mammalian inner ear using viral vectors has been characterized over the last decade. A number of different viral vectors have been shown to transfect the varying cell types of the nonprimate mammalian inner ear. Several routes of delivery have been identified for introduction of vectors into the inner ear while minimizing injury to existing structures and at the same time ensuring widespread distribution of the agent throughout the cochlea and the rest of the inner ear. These studies raise the possibility that gene transfer may be developed as a potential strategy for treating inner ear dysfunction in humans. Furthermore, a recent report showing successful transfection of excised human vestibular epithelia offers proof of principle that viralgene transfer is a viable strategy for introduction andexpression of exogenous genetic material to restore function to the inner ear. Human vestibular epithelia were harvested from patients undergoing labyrinthectomy, either for intractable Ménière's disease or vestibular schwannoma resection, and cultured for as long as 5 days. In those experiments, recombinant, multiply-deleted, replication-deficient adenoviral vectors were used to transfect and express a reporter gene as well as the functionally relevant gene, wild-type KCNQ4, a potassium channel gene that when mutated causes the autosomal dominant HL DFNA2. Here, we review the current state of viral-mediated gene transfer in the inner ear and discuss different viral vectors, routes of delivery, and potential applications of gene therapy. Emphasis is placed on experiments demonstrating viral transfection of human inner ear tissue and implications of these findings and for the future of gene therapy in the human inner ear. [source] An Anti-CD103 Immunotoxin Promotes Long-Term Survival of Pancreatic Islet AllograftsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 9 2009L. Zhang Previous studies using knockout mice document a key role for the integrin CD103 in promoting organ allograft rejection and graft-versus-host disease. However, a determination of whether blockade of the CD103 pathway represents a viable therapeutic strategy for intervention in these processes has proven problematic due to the lack of reagents that efficiently deplete CD103+ cells from wild type hosts. To circumvent this problem, we conjugated the nondepleting anti-CD103 monoclonal antibody, M290, to the toxin, saporin, to produce an immunotoxin (M290-SAP) that efficiently depletes CD103+ cells in vivo. Herein, we show that M290-SAP dramatically reduces the frequency and absolute numbers of CD103-expressing leukocytes in the blood, spleen, mesenteric lymph nodes and intestinal epithelium of treated mice. We further demonstrate that M290-SAP promotes indefinite islet allograft survival in a fully MHC mismatched mouse model. The prolonged islet allograft survival resulting from M290-SAP treatment was associated with multiple effects in the host immune system including not only depletion of CD103-expressing leukocytes, but also an increase in CD4+CD25+FoxP3+ T regulatory cells and a predominance of effector-memory CD8 T cells. Regardless of the underlying mechanisms, these data document that depletion of CD103-expressing cells represents a viable strategy for therapeutic intervention in allograft rejection. [source] MLN3897 plus methotrexate in patients with rheumatoid arthritis: Safety, efficacy, pharmacokinetics, and pharmacodynamics of an oral CCR1 antagonist in a phase IIa, double-blind, placebo-controlled, randomized, proof-of-concept study,ARTHRITIS & RHEUMATISM, Issue 12 2009Clarissa E. Vergunst Objective To assess the efficacy, safety, pharmacokinetics, and pharmacodynamics of the CC chemokine receptor CCR1 antagonist MLN3897 in patients with rheumatoid arthritis (RA) receiving methotrexate (MTX). Methods In this phase IIa, proof-of-concept study, patients meeting the American College of Rheumatology (ACR) criteria for RA who had been taking MTX for ,6 months with evidence of active disease were randomly assigned to receive either 10 mg oral MLN3897 or matching placebo once daily for 12 weeks (days 1,83) while continuing to receive MTX once a week. Clinical assessments, safety monitoring, and sampling for pharmacokinetic and pharmacodynamic analyses were performed throughout the study. The primary efficacy end point was the difference in the percentage of patients meeting the ACR 20% improvement criteria (achieving an ACR20 response) on day 84 in the MLN3897-treated group compared with that in the placebo-treated group. Results MLN3897 was well tolerated, with no evidence of systemic immunosuppression. In the intent-to-treat population, there was no significant difference in day 84 ACR20 response rates between MLN3897-treated patients and placebo-treated patients (35% versus 33%, respectively; P = 0.72). Results were similar for the per-protocol population. Pharmacokinetic analyses demonstrated no interactions between MLN3897 and MTX. MLN3897 was associated with a high degree of CCR1 occupancy (,90% on days 28, 56, and 84 in 82% of patients, by macrophage inflammatory protein 1, internalization assay). Conclusion MLN3897 at a concentration of 10 mg once daily had no discernible activity in patients with RA who were also receiving MTX. The results suggest that CCR1 antagonism is unlikely to be a viable strategy for the treatment of RA when used in isolation at the receptor occupancy levels reached in this study. [source] Foundation for problem-based gamingBRITISH JOURNAL OF EDUCATIONAL TECHNOLOGY, Issue 3 2007Kristian Kiili Educational games may offer a viable strategy for developing students' problem-solving skills. However, the state of art of educational game research does not provide an account for that. Thus, the aim of this research is to develop an empirically allocated model about problem-based gaming that can be utilised to design pedagogically meaningful games. The proposed model was evaluated through a business simulation game. The interviews indicated that authenticity, collaboration and learning by doing were found to be the most important characteristics of effective educational games. Results also showed that the proposed model describes well the problem-based gaming process in which the reflection phase seems to be a vital factor. The outcome of the reflection phase may be personal synthesis of knowledge, validation of hypothesis laid or a new playing strategy to be tested. However, because of the small sample size of this study, more research on the topic is recommended. Especially, ways to support reflection in games needs to be studied. [source] | |||||||||||||