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- Magliulo, Laura, et al.
(författare)
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Do CYP3A and ABCB1 genotypes influence the plasma concentration and clinical outcome of donepezil treatment?
- 2011
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Ingår i: European Journal of Clinical Pharmacology. - : Springer Science and Business Media LLC. - 0031-6970 .- 1432-1041. ; 67:1, s. 47-54
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Tidskriftsartikel (refereegranskat)abstract
- Purpose The aim of our study was to evaluate the impact of CYP3A4, CYP3A5, and ABCB1 polymorphisms on donepezil disposition and clinical outcome. Methods Fifty-four Italian patients diagnosed with probable mild to moderate Alzheimer's disease, treated with donepezil (37 patients 5 mg/day, 17 patients 10 mg/day) were genotyped for CYP3A4 (*1B, *3, and *4), CYP3A5 (*2, *3, and *6) and ABCB1 (3435C>T, 2677G>T/A, and 1236C>T) polymorphisms. All patients were evaluated for the degree of cognitive impairment with Mini Mental State Examination (MMSE) screening test at baseline (before treatment) and after at least 3 months of donepezil treatment at stable dose, when the drug plasma levels were measured. Results Three patients carried one detrimental CYP3A4 allelic variant, and 12 carried one functional CYP3A5*1 allele. No statistically significant association was found between CYP3A4 or CYP3A5 genotypes and plasma donepezil concentrations, or between genotypes and clinical response (as measured by change in MMSE score). Nine ABCB1 haplotypes were observed, the most common being 1236C/2677G/3435C (46%) and 1236T/2677T/3435T (41%). Patients homozygous for the T/T/T haplotype had slightly though not significantly lower plasma donepezil concentration-to-dose ratios than those carrying other genotypes [median (95% CI) 0.18 (0.13-0.45) vs. 0.31 (0.30-0.44) mg/l/mg/kg, respectively]. These patients also showed a slightly better clinical response (as measured by change in MMSE score) than the other genotype groups [median (95% CI) 0 (-1.3 to 3.3) vs. -1.0 (-2.1 to 0.0), respectively]. Conclusions Our data suggest that the CYP3A4 and CYP3A5 polymorphisms are unlikely to influence donepezil metabolism and/or clinical outcome. On the other hand, the ABCB1 polymorphisms may play a role in donepezil disposition and clinical outcome.
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| 3. |
- Maxwell, Christopher A., et al.
(författare)
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Interplay between BRCA1 and RHAMM Regulates Epithelial Apicobasal Polarization and May Influence Risk of Breast Cancer
- 2011
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Ingår i: PLoS Biology. - : Public Library of Science (PLoS). - 1545-7885 .- 1544-9173. ; 9:11
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Tidskriftsartikel (refereegranskat)abstract
- Differentiated mammary epithelium shows apicobasal polarity, and loss of tissue organization is an early hallmark of breast carcinogenesis. In BRCA1 mutation carriers, accumulation of stem and progenitor cells in normal breast tissue and increased risk of developing tumors of basal-like type suggest that BRCA1 regulates stem/progenitor cell proliferation and differentiation. However, the function of BRCA1 in this process and its link to carcinogenesis remain unknown. Here we depict a molecular mechanism involving BRCA1 and RHAMM that regulates apicobasal polarity and, when perturbed, may increase risk of breast cancer. Starting from complementary genetic analyses across families and populations, we identified common genetic variation at the low-penetrance susceptibility HMMR locus (encoding for RHAMM) that modifies breast cancer risk among BRCA1, but probably not BRCA2, mutation carriers: n = 7,584, weighted hazard ratio ((w)HR) = 1.09 (95% CI 1.02-1.16), p(trend) = 0.017; and n = 3,965, (w)HR = 1.04 (95% CI 0.94-1.16), p(trend) = 0.43; respectively. Subsequently, studies of MCF10A apicobasal polarization revealed a central role for BRCA1 and RHAMM, together with AURKA and TPX2, in essential reorganization of microtubules. Mechanistically, reorganization is facilitated by BRCA1 and impaired by AURKA, which is regulated by negative feedback involving RHAMM and TPX2. Taken together, our data provide fundamental insight into apicobasal polarization through BRCA1 function, which may explain the expanded cell subsets and characteristic tumor type accompanying BRCA1 mutation, while also linking this process to sporadic breast cancer through perturbation of HMMR/RHAMM.
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| 4. |
- Trzonkowski, Piotr, et al.
(författare)
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Hurdles in therapy with regulatory T cells
- 2015
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 7:304
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Tidskriftsartikel (refereegranskat)abstract
- Improper activation of the immune system contributes to a variety of clinical conditions, including autoimmune and allergic diseases as well as solid organ and bone marrow transplantation. One approach to counteract this activation is through adoptive therapy with regulatory T cells (T-regs). Efforts to manufacture these cells have led to good maunfacturing practice-compliant protocols, and T-reg products are entering early clinical trials. Here, we report the stance of the European Union Cooperation in Science and Technology Action BM1305, "Action to Focus and Accelerate Cell-based Tolerance-inducing Therapies-A FACTT," which identifies hurdles hindering T-reg clinical applications in Europe and provides possible solutions.
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| 5. |
- Varsaldi, Federica, et al.
(författare)
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Impact of the CYP2D6 polymorphism on steady-state plasma concentrations and clinical outcome of donepezil in Alzheimer's disease patients
- 2006
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Ingår i: European Journal of Clinical Pharmacology. - : Springer Science and Business Media LLC. - 0031-6970 .- 1432-1041. ; 62:9, s. 721-726
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The aims of this study were to evaluate the impact of the CYP2D6 polymorphism on both the steady-state plasma concentrations (Cp) and the clinical outcome of donepezil, a selective acetylcholinesterase inhibitor used in the treatment of Alzheimer's disease (AD). Methods: Forty-two patients of Caucasian ethnicity affected by probable AD were included in the study. All had been receiving therapy with donepezil for at least 3 months: 31 patients with 5 mg/day and 11 patients with 10 mg/day. The CYP2D6 genotype was analysed, and donepezil Cp was measured by using high-performance liquid chromatography. Results: On the basis of their CYP2D6 genotype, 30 patients could be classified as homozygous extensive metabolizers (EM), 10 as heterozygous EM and 2 as ultrarapid metabolizers (UM). No poor metabolizer was found. The dose and body weight-corrected median donepezil Cp were slightly, though not significantly, lower in homozygous than in heterozygous EM (0.33 vs. 0.41 ng/ml/mg/kg, respectively). The latter group consistently showed a better clinical response to treatment, as measured by change in Mini-Mental State Examination score (median: 1.40 vs. -1.30, respectively). UM patients had lower Cp than EM patients and showed no clinical improvement. Conclusions: Our preliminary data suggest that the CYP2D6 polymorphism influences both donepezil metabolism and therapeutic outcome and that a knowledge of a patient's CYP2D6 genotype together with donepezil concentration measurements might be useful in the context of improving the clinical efficacy of donepezil therapy.
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