2,982 research outputs found
A multi-factorial genetic model for prognostic assessment of high risk melanoma patients receiving adjuvant interferon
Purpose: IFNa was the first cytokine to demonstrate anti-tumor activity in advanced melanoma. Despite the ability of high-dose IFNa reducing relapse and mortality by up to 33%, large majority of patients experience side effects and toxicity which outweigh the benefits. The current study attempts to identify genetic markers likely to be associated with benefit from IFN-a2b treatment and predictive for survival. Experimental design: We tested the association of variants in FOXP3 microsatellites, CTLA4 SNPs and HLA genotype in 284 melanoma patients and their association with prognosis and survival of melanoma patients who received IFNa adjuvant therapy. Results: Univariate survival analysis suggested that patients bearing either the DRB1*15 or HLA-Cw7 allele suffered worse OS while patients bearing either HLA-Cw6 or HLA-B44 enjoyed better OS. DRB1*15 positive patients suffered also worse RFS and conversely HLA-Cw6 positive patients had better RFS. Multivariate analysis revealed that a five-marker genotyping signature was prognostic of OS independent of disease stage. In the multivariate Cox regression model, HLA-B38 (p = 0.021), HLA-C15 (p = 0.025), HLA-C3 (p = 0.014), DRB1*15 (p = 0.005) and CT60*G/G (0.081) were significantly associated with OS with risk ratio of 0.097 (95% CI, 0.013-0.709), 0.387 (95% CI, 0.169-0.889), 0.449 (95% CI, 0.237-0.851), 1.948 (95% CI, 1.221-3.109) and 1.484 (95% IC, 0.953-2.312) respectively. Conclusion: These results suggest that gene polymorphisms relevant to a biological occurrence are more likely to be informative when studied in concert to address potential redundant or conflicting functions that may limit each gene individual contribution. The five markers identified here exemplify this concept though prospective validation in independent cohorts is needed
Natalizumab affects T-cell phenotype in multiple sclerosis: implications for JCV reactivation
The anti-CD49d monoclonal antibody natalizumab is currently an effective therapy against the relapsing-remitting form of multiple sclerosis (RRMS). Natalizumab therapeutic efficacy is limited by the reactivation of the John Cunningham polyomavirus (JCV) and development of progressive multifocal leukoencephalopathy (PML). To correlate natalizumab-induced phenotypic modifications of peripheral blood T-lymphocytes with JCV reactivation, JCV-specific antibodies (serum), JCV-DNA (blood and urine), CD49d expression and relative abundance of peripheral blood T-lymphocyte subsets were longitudinally assessed in 26 natalizumab-treated RRMS patients. Statistical analyses were performed using GraphPad Prism and R. Natalizumab treatment reduced CD49d expression on memory and effector subsets of peripheral blood T-lymphocytes. Moreover, accumulation of peripheral blood CD8+ memory and effector cells was observed after 12 and 24 months of treatment. CD4+ and CD8+ T-lymphocyte immune-activation was increased after 24 months of treatment. Higher percentages of CD8+ effectors were observed in subjects with detectable JCV-DNA. Natalizumab reduces CD49d expression on CD8+ T-lymphocyte memory and effector subsets, limiting their migration to the central nervous system and determining their accumulation in peripheral blood. Impairment of central nervous system immune surveillance and reactivation of latent JCV, can explain the increased risk of PML development in natalizumab-treated RRMS subjects
On the Origin of the Inner Structure of Halos
We calculate by means of the Press-Schechter formalism the density profile
developed by dark-matter halos during accretion, i.e., the continuous
aggregation of small clumps. We find that the shape of the predicted profile is
similar to that shown by halos in high-resolution cosmological simulations.
Furthermore, the mass-concentration relation is correctly reproduced at any
redshift in all the hierarchical cosmologies analyzed, except for very large
halo masses. The role of major mergers, which can cause the rearrangement of
the halo structure through violent relaxation, is also investigated. We show
that, as a result of the boundary conditions imposed by the matter continuously
infalling into the halo during the violent relaxation process, the shape of the
density profile emerging from major mergers is essentially identical to the
shape the halo would have developed through pure accretion. This result
explains why, according to high-resolution cosmological simulations, relaxed
halos of a given mass have the same density profile regardless of whether they
have had a recent merger or not, and why both spherical infall and hierarchical
assembly lead to very similar density profiles. Finally, we demonstrate that
the density profile of relaxed halos is not affected either by the capture of
clumps of intermediate mass.Comment: 14 pages, 8 figures, accepted for publication in ApJ. Minor changes,
matches the published version. To appear in the ApJ August 10, 2003 issu
- âŠ