Biomedical subjects

Federico Vázquez

Publications and source records attributed to Federico Vázquez.

5 recordsLinked to original sources

PubMed2005

Phase I pharmacokinetic and pharmacodynamic study of weekly 1-hour and 24-hour infusion BMS-214662, a farnesyltransferase inhibitor, in patients with advanced solid tumors.

PURPOSE: BMS-214662 is a potent, nonpeptide, small molecule inhibitor of human farnesyltransferase (FT). We have conducted a phase I pharmacokinetic (PK) and pharmacodynamic study of BMS-214662 administered intravenously weekly with 1- and 24-hour infusions. The objectives were to determine the dose-limiting toxicities and the recommended dose (RD), to describe PKs, and to evaluate the relationships between BMS-214662 exposure, FT inhibition, downstream signaling, and induction of apoptosis in tumor samples. PATIENTS AND METHODS: Patients with advanced solid tumors and adequate organ function were eligible. The dose was escalated according to a modified Fibonacci schedule. RESULTS: high (> 80%) but short-lived (< or = 6 hours) in the 1-hour infusion and moderate (> 40%) but long-lived (24 hours) in the 24-hour infusion. BMS-214662 induced apoptosis in tumors but did not inhibit MAPK signaling. CONCLUSION: BMS-214662 can be safely delivered in both the 1-hour and 24-hour infusions at biologically active doses, with the preclinical, PK, and pharmacodynamic profiles favoring the 24-hour schedule.

Adult↗

PubMed2003

HLA-DRB1 and MICA in autoimmunity: common associated alleles in autoimmune disorders.

Autoimmune disorders such as type 1 diabetes (T1DM), celiac disease (CD), and Addison's disease (ADD) develop in individuals with genetic susceptibility that are exposed to environmental triggering factors not completely defined. Patients with an autoimmune disease (and their relatives) are at increased risk of developing another disorder, and this might be caused by a common genetic origin of autoimmunity; for example, HLA class II region in 6p21 shows a very strong association with most diseases. The aim of this study was to determine whether shared susceptibility markers extend from the central (DRB1) through the telomeric (MICA) HLA region. We analyzed three independent sets of families with one autoimmune disease, T1DM, CD, or ADD, and genotyped them for HLA-DRB1 and for the exon 5 GCT polymorphism of MICA. For HLA-DRB1, allele DRB1*0301 was the only one associated with risk for all three diseases; in the case of MICA, allele A9 was found to be the common protective allele. Haplotype analysis shows that haplotype A5.1-DRB1*0301 confers risk to autoimmunity. Our results show that there are common risk and protection alleles in both loci, suggesting a core of genetic association with autoimmunity (HLA-DRB1*0301 risk; A9 protection) that could be modulated by other alleles/loci or environmental factors toward one or another disease. Some alleles are part of conserved haplotypes (A5.1-DR3, A5.1-DR2), whereas others seem to have independent effect (A9) and support the idea of two independent loci in this region.

Adolescent↗

PubMed2003

5'-Insulin gene VNTR polymorphism is specific for type 1 diabetes: no association with celiac or Addison's disease.

The VNTR region located at the 5'-end of the insulin gene on chromosome 11p15.5 is linked to susceptibility to type 1 diabetes mellitus (T1DM), and class I alleles have been associated with increased risk of disease, whereas class III alleles are considered to be protective. Although a potential effect on the expression level of thymic insulin and a consequent abnormal tolerance have been proposed as an explanation, it is still not clear whether the association is specific for T1DM or whether it is shared by other autoimmune disorders. To investigate the contribution of INS-VNTR to the genetic susceptibility to autoimmune disorders, we analyzed 102 autoantibody-positive T1DM patients, 59 patients with celiac disease (CD), and 57 patients with Addison's disease (ADD), as well as 111 unrelated healthy individuals from the general population. When analyzing the results, class I allele frequencies were 85.8% in the T1DM group, 77% among CD patients, 71% in the ADD group, and 76.1% in the general population. Association with increased risk was seen only in the T1DM group (pc = 0.015). Risk to T1DM was associated with the class I/class I homozygous genotype (RR, 1.92; 95% CI, 1.03-3.6). In conclusion, INS-VNTR does not seem to be involved in the susceptibility to autoimmune diseases other than T1DM and can be considered a diabetes-specific locus.

Addison Disease↗

PubMed2002

Coarse graining from coarse-grained descriptions.

We present a generalization of Zwanzig's method of projection operators to the case where the underlying dynamics is not deterministic. The method allows us to perform a coarse graining of an already coarse-grained level of description in which fluctuations are important. The initial level of description is described by a Fokker-Planck equation and, under suitable approximations, the final slower level of description is also described by a Fokker-Planck equation. We illustrate the method for the simple case of the diffusion of colloidal particles at two levels of descriptions.

Colloids↗

PubMedDate not supplied

No evidence of association of CTLA4 polymorphisms with Addison's disease.

BACKGROUND: Addison's disease (AD) is an autoimmune disorder caused by the destruction of the adrenal gland by the lymphocytes in genetically susceptible individuals. The contribution of HLA genes to the genetic risk to AD has been known for a long time; however, non-HLA genetic factors are likely to be required for the development of the disease. Several studies have associated the CD28/CTLA4 region on chromosome 2q33 with the disease in different populations. The cytotoxic T lymphocyte-associated antigen 4 (CTLA4) gene encodes a receptor involved in the control of T cell proliferation and mediates T cell apoptosis. AIM: To determine the contribution of two polymorphisms of the CTLA4 to the disease; the A/G dimorphism at position +49 in exon 1 and the (AT)n microsatellite in the 3' untranslated region of exon 3. PATIENTS: Fifty seven patients with autoimmune AD (autoimmunity for anti 21-hydroxylase was confirmed) and 111 unrelated healthy subjects from the general populations were analyzed as controls. METHODS: Restriction enzyme digestion of polymerase chain reaction (PCR) amplified genomic DNA for the A/G dimorphism and PCR followed by high-resolution electrophoresis for the (AT)n microsatellite. For disease association studies, the case-control approach was used. RESULTS: The frequency of the A allele of 49 A/G polymorphism was 65.79% in the patients compared with 72.07% in the control group. These differences were not significant. Analysis of the (AT)n polymorphism identified 19 different alleles, ranging from 262 to 308 bp in length, but no allele was significantly associated with the disease. CONCLUSIONS: Our results did not show any evidence of association of any of the CTLA4 gene polymorphisms with the disease. This might result from population-specific differences in genetic and environmental susceptibility to AD.

Addison Disease↗