| 1. |
- Bergmann, Troels K., et al.
(author)
-
Retrospective study of the impact of pharmacogenetic variants on paclitaxel toxicity and survival in patients with ovarian cancer
- 2011
-
In: European Journal of Clinical Pharmacology. - : Springer Science Business Media. - 0031-6970 .- 1432-1041. ; 67:7, s. 693-700
-
Journal article (peer-reviewed)abstract
- Paclitaxel has a broad spectrum of anti-tumor activity and is useful in the treatment of ovarian, breast, and lung cancer. Paclitaxel is metabolized in the liver by CYP2C8 and CYP3A4 and transported by P-glycoprotein. The dose-limiting toxicities are neuropathy and neutropenia, but the interindividual variability in toxicity and also survival is large. The main purpose of this study was to investigate the impact of genetic variants in CYP2C8 and ABCB1 on toxicity and survival. The 182 patients previously treated for ovarian cancer with carboplatin and paclitaxel in either the AGO-OVAR-9 or the NSGO-OC9804 trial in Denmark or Sweden were eligible for this study. Genotyping was carried out on formalin-fixed tissue. The patients toxicity profiles and survival data were derived from retrospective data. CYP2C8*3, ABCB1 C1236T, G2677T/A, and C3435T were chosen a priori for primary analysis; a host of other variants were entered into an exploratory analysis. Clinical data and tissue were available from a total of 119 patients. Twenty-two single nucleotide polymorphisms (SNPs) in 10 genes were determined. Toxicity registration was available from 710 treatment cycles. In the primary analysis, no statistically significant correlation was found between CYP2C8*3, ABCB1 C1236T, G2677T/A, and C3435T and neutropenia, sensoric neuropathy, and overall survival. CYP2C8*3 and the ABCB1 SNPs C1236T, G2677T/A, and C3435T were not statistically significantly correlated to overall survival, sensoric neuropathy, and neutropenia in 119 patients treated for ovarian cancer with paclitaxel/carboplatin.
|
|
| 2. |
- Eising, Stefanie, et al.
(author)
-
Type 1 diabetes risk analysis on dried blood spot samples from population-based newborns: design and feasibility of an unselected case-control study
- 2007
-
In: Paediatric and Perinatal Epidemiology. - : Wiley. - 0269-5022 .- 1365-3016. ; 21:6, s. 507-517
-
Journal article (peer-reviewed)abstract
- Development of type 1 diabetes mellitus (T1D) may be triggered pre- or perinatally by multiple factors. Identifying new predisposing T1D markers or combinations of markers in a large, well-characterised case-control collection may be important for future T1D prevention. The present work describes the design and feasibility of a large and unselected case-control study, which will define and evaluate prediction criteria for T1D at the time of birth. Danish registries (Biological Specimen Bank for Neonatal Screening, and the National Discharge Registry) made it possible to identify and collect dried blood spots (DBS) from newborns who later developed T1D (cases) born 1981-2002. DBS samples from 2086 cases and two matching control subjects per case were analysed for genetic and immune factors that are associated with T1D: (a) candidate genes (HLA, INS and CTLA4), (b) cytokines and inflammatory markers, (c) islet auto-antibodies (GAD65A, IA-2A). The objective of the study was to define reliable prediction tools for T1D using samples available at the time of birth. In a unique approach, the study linked a large unselected and population-based sample resource to well-ascertained clinical databases and advanced technology. It combined genetic, immunological and demographic data to develop prediction algorithms. It also provided a resource for future studies in which new genetic markers can be included as they are identified.
|
|
| 3. |
- Grontved, Anders, et al.
(author)
-
Association between plasma leptin and blood pressure in two population-based samples of children and adolescents
- 2011
-
In: Journal of Hypertension. - 1473-5598. ; 29:6, s. 1093-1100
-
Journal article (peer-reviewed)abstract
- Objectives In this study we examined the association between leptin and blood pressure in a population-based study of Danish and Norwegian children and adolescents. Because of the putative bidirectional relationship between leptin and adiposity we formally tested (i) the mediating effect of body mass index in the association between leptin and blood pressure, and (ii) the mediating effect of leptin in the association between body mass index and blood pressure. Methods To examine these aims we used a cross-sectional random sample of children and adolescents from Denmark and Norway (n=1993) who had measures of leptin, anthropometry, blood pressure and other personal and biological risk factors for raised blood pressure available. Results Both body mass index and leptin were positively associated with blood pressure (P<0.001). The association with leptin was stronger in pre- and early-pubertal children compared to late-and post-pubertal adolescents (P<0.01 for interaction). The association between leptin and blood pressure was almost completely mediated by body mass index, whereas the association between body mass index and blood pressure was modestly mediated by leptin. Conclusion Leptin was strongly associated with blood pressure, a relationship that to a large extent was mediated by body mass index. Conversely, the association between body mass index and blood pressure was only modestly mediated by leptin. This indicates that the influence of adiposity on blood pressure is also driven by other biological risk factors beyond leptin. Such factors could include insulin, glucose, and triglycerides although residual confounding also could account for the observed relationships. J Hypertens 29:1093-1100 (C) 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.
|
|
| 4. |
- Moros, Matthias, et al.
(author)
-
Towards an event stratigraphy for Baltic Sea sediments deposited since AD 1900 : approaches and challenges
- 2017
-
In: Boreas. - : Wiley. - 0300-9483 .- 1502-3885. ; 46:1, s. 129-142
-
Journal article (peer-reviewed)abstract
- Reconstructions of environmental changes at sub-decadal to decadal resolution based on central Baltic Sea sediments rely on accurate and precise high-resolution sediment depth/age relationships. A model chronology for Baltic Sea sediments is presented here based on established historical records of anthropogenic radionuclides (Cs-137/Am-241/bomb(14)C), polychlorinated biphenyls (PCBs), lead (Pb) and stable lead isotope (Pb-206/207 ratios), and radionuclide Pb-210 and C-14 decay dating methods. Marker horizons consisting of chemical precipitates formed by documented Major Baltic Inflow (MBIs) events and an extended diatom bloom period were also integrated into the model. The main time markers in Baltic Sea sediments that formed during the last 120years were the following: (i) the deepest observation of Pb-210(unsupp.) (marking the Pb-210 dating horizon) and departure of Hg from natural background levels at c.AD 1900; (ii) first detectable presence of PCBs at AD 1935; (iii) radionuclide production (i.e. Am-241) due to nuclear weapons testing between AD 1954 and AD 1975, with a peak in AD 1963; (iv) maximum heavy metal and PCB concentrations in the AD 1960s/1970s; (v) the Chernobyl nuclear accident in AD 1986 as a sharp Cs-137 increase; (vi) exceptionally strong diatom blooms with a massive diatom layer found in the Eastern Gotland Basin in AD 1988-1990; and (vii) characteristic manganese-carbonate layers in the deeper central basins formed by MBIs in AD 1993 and AD 2003. A precise and accurate sediment depth/age relationship can only be achieved in restricted areas of the Baltic Sea where continuous sedimentation has prevailed and there has been limited postdepositional disturbance. We demonstrate that parallel Hg and Cs-137 measurements can be used to assess the quality of sediment sequences for high-resolution environmental reconstructions. We show examples of sediment profiles that conform to the historical record, and examples from Western Baltic Sea areas where it appears to be impossible to establish accurate geochronologies.
|
|
| 5. |
- Ostergaard, Henrik, et al.
(author)
-
Prolonged half-life and preserved enzymatic properties of factor IX selectively PEGylated on native N-glycans in the activation peptide
- 2011
-
In: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 118:8, s. 2333-2341
-
Journal article (peer-reviewed)abstract
- Current management of hemophilia B entails multiple weekly infusions of factor IX (FIX) to prevent bleeding episodes. In an attempt to make a longer acting recombinant FIX (rFIX), we have explored a new releasable protraction concept using the native N-glycans in the activation peptide as sites for attachment of polyethylene glycol (PEG). Release of the activation peptide by physiologic activators converted glycoPEGylated rFIX (N9-GP) to native rFIXa and proceeded with normal kinetics for FXIa, while the Km for activation by FVIIa-tissue factor (TF) was increased by 2-fold. Consistent with minimal perturbation of rFIX by the attached PEG, N9-GP retained 73%-100% specific activity in plasma and whole-blood-based assays and showed efficacy comparable with rFIX in stopping acute bleeds in hemophilia B mice. In animal models N9-GP exhibited up to 2-fold increased in vivo recovery and a markedly prolonged half-life in mini-pig (76 hours) and hemophilia B dog (113 hours) compared with rFIX (16 hours). The extended circulation time of N9-GP was reflected in prolonged correction of coagulation parameters in hemophilia B dog and duration of effect in hemophilia B mice. Collectively, these results suggest that N9-GP has the potential to offer efficacious prophylactic and acute treatment of hemophilia B patients at a reduced dosing frequency. (Blood. 2011; 118(8): 2333-2341)
|
|
| 6. |
- Rosendahl, Mikkel, et al.
(author)
-
The risk of amenorrhoea after adjuvant chemotherapy for early stage breast cancer is related to inter-individual variations in chemotherapy-induced leukocyte nadir in young patients : Data from the randomised SBG 2000-1 study
- 2009
-
In: European Journal of Cancer. - : Elsevier BV. - 0959-8049 .- 1879-0852. ; 45:18, s. 3198-3204
-
Journal article (peer-reviewed)abstract
- Study aim: Amenorrhoea is a common side-effect to chemotherapy of premenopausal women. We examine the association between chemotherapy-induced leucopaenia and the development of amenorrhoea in premenopausal women with breast cancer. Materials and methods: in a multi-centre, randomised, controlled study, 1016 premenopausal women received seven series of FEC (F: fluorouracil, E: epirubicin and C: Cyclophosphamide) for early stage breast cancer. In the first series, all patients received standard dose (F: 600 mg/m(2), E: 60 mg/m(2) and C: 600 mg/m(2)). Patients with leukocyte nadir 1.0-1.9 x 10(9)/l continued with standard dose for the remaining six series (STANDARD(REGISTERED), n = 279). Patients with leukocyte nadir >= 2 x 10(9)/l were randomised to standard (STANDARD(RANDOMISED), n = 373) or increased (TAILORED, n = 364) dose of E and C. After each series, leukocyte nadir was evaluated. Absent bleeding after the 5th-7th series of FEC was interpreted as amenorrhoea. Results: The risk of amenorrhoea increased with age. In age-stratified analysis of the STANDARD groups (equal dose, different initial leukocyte nadir) low leukocyte nadir was associated with amenorrhoea for patients in the age-group 25-39 years (P = 0.010). In age-stratified analysis in the randomised groups (different doses, same initial leukocyte nadir) a dose related increased risk of amenorrhoea was found for age-groups 25-39 (RR: 1.15, 95% confidence interval (CI): 1.06-1.24) and 40 44 years (RR:1.21, 95% CI: 1.001-1.47). Conclusion: Age is the most important risk factor of amenorrhoea after FEC chemotherapy. However, for younger patients, lower leukocyte nadir in response to STANDARD FEC treatment or increased doses of C and E were associated with increased risk of amenorrhoea. (C) 2009 Elsevier Ltd. All rights reserved.
|
|
