Zevalin ibritumomab

ABSTRACT Therapeutic success of anti-HIV therapies is limited by the development of drug resistant viruses. These genetic variants display complex mutational patterns in their pol gene, which codes for protease and reverse transcriptase, the molecular targets of current antiretroviral therapy. Genotypic resistance testing depends on the ability to interpret such sequence data, whereas phenotypic resistance testing directly measures relative in vitro susceptibility to a drug. From a set of 650 matched genotypephenotype pairs we construct regression models for the prediction of phenotypic drug resistance from genotypes. Since the range of resistance factors varies considerably between different drugs, two scoring functions are derived from different sets of predicted phenotypes. Firstly, we compare predicted values to those of samples derived from 178 treatment-naive patients and report the relative deviance. Secondly, estimation of the probability density of 2000 predicted phenotypes gives rise to an intrinsic definition of a susceptible and a resistant subpopulation. Thus, for a predicted phenotype, we calculate the probability of membership in the resistant subpopulation. Both scores provide standardized measures of resistance that can be calculated from the genotype and are comparable between drugs. The geno2pheno system makes these genotype interpretations available via the Internet : genafor ; . INTRODUCTION A panel of 17 approved antiretroviral agents is currently available for treating infections with human immunodeficiency.
P-glycoprotein drug efflux pump 18 ; . In addition structural and functional alternations in the - and -tubulins of tumor cells, resulting from either genetic mutations or post-translational modifications, are associated with acquired resistance to taxenes and vinca alkaloids 4 ; . Identification of natural and synthetic compounds with therapeutic effects on multiple-drug resistant tumors remains an attractive goal. Evodiamine is one of the major bioactive compounds that have been isolated and purified from the traditional Chinese herbal medicine, Wu-Chu-Yu. Evodiamine has been shown to possess anti-inflammatory 19 ; , anti-obesity 20 ; and anti-nociceptive effects 21 ; . Furthermore evodiamine is documented to inhibit tumor cell proliferation, cell migration with invasion, and lung metastasis 22, 23 ; . In this study, evodiamine was found to possess inhibitory activity against multiple-drug resistant human breast cancer NCI ADR-RES cells. The mechanism whereby evodiamine produces this inhibition was also explored in these cells.

Reached a peak at day 21, and declined to baseline at day 28, reflecting a similar time course and pattern of gene expression Figure 2d ; . These data further indicate that there is a close temporal relation between SAR and -globin mRNA expression in primary bone marrow cells, and strongly suggest that the SAR and -globin genes coexist in cells of this erythroid lineage. A growing body of basic and clinical data points to fundamental gender-related differences in the nature and extent of myocardial hypertrophy and adaptation, which might account for the survival advantage for women.12, 13 Early studies of.

Annual Conference of the Society for Glycobiology mannosyltransferase, a member of the GT-15 retaining glycosyltransferase family. The crystal structures of the catalytic domain of Kre2p and its binary and ternary complexes with the donor substrate GDP-mannose Mn2 + and acceptor methyl--mannoside have been determined at 2.0 resolution. The protein has a fold, similar to glycosyltransferases of the GT-A family despite the absence of sequence homology, with a central seven-stranded mixed -sheet and a three-stranded anti-parallel -sheet forming a wedge-like sandwich flanked by -helices. Manganese is bound by a modified DxD motif EPD ; with only the glutamate involved. The GDP moiety of the donor is tightly bound to the active site, but the mannose moiety is not visible in the electron density. The O2 of the acceptor mannoside forms a hydrogen bond with the hydroxyl of Tyr 220 that, in turn, coordinates a -phosphate oxygen of GDP to which the presumably cleaved mannose moiety was bound. The donor mannose was modeled using binary complex structures of other GT-A enzymes. The C1 of the modeled donor mannose is within hydrogen-bond distance of the Tyr 220 hydroxyl and its -linked hydrogen points roughly towards the tyrosine. Combined with modeling, the structures suggest that the hydroxyl of Tyr 220 is the potential nucleophile which may form the covalent -linked intermediate with the donor mannose before the nucleophilic attack by the acceptor, thereby supporting a double-displacement mechanism of retention for these mannosyltransferases. The Y220F mutation yielded an enzyme with a very low residual activity thus confirming the important role of Tyr 220 in catalysis. Supported by NIH grant GM31265. 185 ; Decreased Monoclonal IgG1 Galactosylation at Reduced Dissolved Oxygen Concentration Is Not A Result of Lowered Galactosyltransferase Activity In Vitro Jeremy P. Kunkel1, 3, William Y. Yan2, Michael Butler2 and James C. Jamieson1 [1] Department of Chemistry, University of Manitoba, Winnipeg, MB, R3T 2N2, [2] Department of Microbiology, University of Manitoba, Winnipeg, MB, R3T 2N2, [3] Present address: Wadsworth Center, New York State Department of Health, Albany, NY, 12201-0509. Monoclonal antibodies mAbs ; are exceptionally important as in vitro and in vivo diagnostic reagents, therapeutic pharmaceuticals, and ligands for affinity purification techniques. The majority of mAbs are of the immunoglobulin G IgG ; class and are produced in hybridoma or recombinant cell cultures. Many different aspects of cell culture have been shown to influence glycosylation of mAbs and recombinant glycoproteins, and, thus, their physicochemical, structural, and functional properties. We have previously reported that the N-linked glycosylation of a monoclonal IgG1 produced by a hybridoma grown in serum-free continuous culture is dependent upon both the steady-state dissolved oxygen DO ; concentration and the configuration of the bioreactor. More specifically, the level of galactosylation was reduced above and below 100% DO, producing an optimum DO concentration for maximum galactosylation and dropped considerably between 50 and 10% DO. This effect was more pronounced in one bioreactor than the other, probably due to differences in bioreactor configuration and DO monitoring and supply strategies. The level of galactosylation of the Fc N-glycans at Asn-297 of each of the two heavy chains has particular structural and functional relevance for IgG. To further investigate the decrease in galactosylation between 50 and 10% DO setpoints, and to determine whether the decrease occured at a specific %DO threshold or as a gradient, we examined N-glycans of the same mAb produced in 1, 2, 5, and 50% DO. A gradual but steep decline in galactosylation was confirmed, which became even more pronounced below 10% DO. We also measured 1, 4-galactosyltransferase 1, ; activities of the respective hybridomal cell homogenate supernatants by Gal transfer from UDP-3H-Gal donor to GlcNAc acceptor. The 1, 4Gal-T specific activities were remarkably similar in all six cultures and not correlated to the DO concentrations. The overall mean specific activity compared extremely well with activities determined for other B-lymphocyte cell lines using both GlcNAc and macromolecular acceptors. In rheumatoid arthritis, reductions in galactosylated IgG have been attributed to decreases in 1, 4Gal-T activities in peripheral B cells, but not to levels of 1, 4Gal-T mRNA or protein. Unlike rheumatoid arthritis, this work has disqualified alterations in in vitro 1, 4Gal-T activity as the cause of the observed DO effect on galactosylation. This implies that the activity of 1, 4Gal-T may be regulated post-translationally by reversible serine phosphorylation, or altered glycosylation, disulfide bond formation, or protein folding. Other physicochemical or biochemical for the observed effect must be explored. We have suggested that the DO effect may reflect a perturbation in the redox state of the ER and or Golgi, affecting both the rate and timing of and idarubicin.