| 1. |
- Einarsdottir, Berglind Osk, 1979, et al.
(författare)
-
Melanoma patient-derived xenografts accurately model the disease and develop fast enough to guide treatment decisions.
- 2014
-
Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 5:20, s. 9609-18
-
Tidskriftsartikel (refereegranskat)abstract
- The development of novel therapies against melanoma would benefit from individualized tumor models to ensure the rapid and accurate identification of biomarkers of therapy response. Previous studies have suggested that patient-derived xenografts (PDXes) could be useful. However, the utility of PDXes in guiding real-time treatment decisions has only been reported in anecdotal forms. Here tumor biopsies from patients with stage III and IV metastatic malignant melanoma were transplanted into immunocompromised mice to generate PDXes. 23/26 melanoma biopsies generated serially transplantable PDX models, and their histology, mutation status and expression profile resembled their corresponding patient biopsy. The potential treatment for one patient was revealed by an in vitro drug screen and treating PDXes with the MEK inhibitor trametinib. In another patient, the BRAF mutation predicted the response of both the patient and its corresponding PDXes to MAPK-targeted therapy. Importantly, in this unselected group of patients, the time from biopsy for generation of PDXes until death was significantly longer than the time required to reach the treatment phase of the PDXes. Thus, it could be clinically meaningful to use this type of platform for melanoma patients as a pre-selection tool in clinical trials.
|
|
| 2. |
|
|
| 3. |
- Baumgart, Juliane, 1978-, et al.
(författare)
-
Androgen levels during adjuvant endocrine therapy in postmenopausal breast cancer patients
- 2014
-
Ingår i: Climacteric. - London, United Kingdom : Informa Healthcare. - 1369-7137 .- 1473-0804. ; 17:1, s. 48-54
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: To investigate plasma steroid hormone levels in postmenopausal breast cancer patients with and without adjuvant endocrine therapy and in healthy postmenopausal women.Methods: Steroid hormone levels in postmenopausal breast cancer patients treated with aromatase inhibitors (n = 32) were compared with breast cancer patients treated with tamoxifen (n = 34), breast cancer patients without adjuvant endocrine therapy (n = 15), and healthy postmenopausal women (n = 56). Pregnenolone, 17-hydroxypregnenolone, 17-hydroxyprogesterone, 11-deoxycortisol, cortisol, cortisone, dehydroepiandrosterone (DHEA), androstenedione, total testosterone, dihydrotestosterone, estrone and estradiol were measured using liquid chromatography-tandem mass spectrometry. Sex hormone binding globulin was measured by solid-phase chemiluminescent immunometric assays, and the free androgen index was calculated.Results: Aromatase inhibitor users did not differ in dihydrotestosterone, total testosterone, androstenedione, DHEA, or free androgen index levels from healthy controls or untreated breast cancer patients. The highest total testosterone levels were found in tamoxifen-treated women, who had significantly higher plasma concentrations than both women treated with aromatase inhibitors and breast cancer patients without adjuvant treatment. Concentrations of cortisol and cortisone were significantly greater in aromatase inhibitor users as well as tamoxifen users, in comparison with healthy controls and untreated breast cancer patients. Aromatase inhibitor users had lower estrone and estradiol plasma concentrations than all other groups.Conclusion: Adjuvant treatment with aromatase inhibitors or tamoxifen was associated with increased cortisol and cortisone plasma concentrations as well as decreased estradiol concentrations. Androgen levels were elevated in tamoxifen-treated women but not in aromatase inhibitor users.
|
|
| 4. |
- DuttaRoy, Smita, 1971, et al.
(författare)
-
The effects of age on circulating vascular markers and cardiac prognostic markers, before and after 2 months home-based high-frequency exercise training in patients with stable coronary artery disease
- 2014
-
Ingår i: European Heart Journal. European Society of Cardiology, 30 August - 3 September 2014, Barcelona. - 0195-668X .- 1522-9645. ; 35:Supplement: 1
-
Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Purpose: Vascular endothelial growth factor (VEGF) and stromal derived factor (SDF-1) play an important role in angiogenesis. Relaxin-2 (Rlx-2) has both angiogenic and vasodilatory properties, while endothelin-1 (ET-1) is a potent vasocontrictor.VEGF, SDF-1 and Rlx-2-levels have shown to be positively modulated by exercise training, while the effect of exercise on (Rlx-2) is not known. Age is a known risk factor for morbidity and mortality in coronary artery disease (CAD). We wanted to investigate how age affects levels of these vascular factors and known prognostic cardiac markers before and after high frequency exercise training (HFE), in patients with CAD. Methods: Patients with stable CAD (age 48-80 years) were randomized to HFE (aerobic exercise 70% of max, 30 minutes, 5 times/week and resistance exercise 3 times/week), performed at home for 8 weeks, or usual lifestyle (ctrl). Serum and plasma was collected from 21 controls and 24 HFE-patients and analyzed at baseline and after 8 weeks. VEGF, SDF-1, Rlx-2 and ET-1were analyzed with enzymelinked immunoadsorbent assay (ELISA). TnT and NT-pro-BNP were analyzed on Cobas e602 (Roche). Correlation was calculated using the statistical software Graph Pad Prism 6. Pearson’s r was calculated to determine correlation between the factors prior to exercise, while Spearman’s r was used for the analysis on the exercise induced effects of the HFE-group. The exercise-induced effect on cardiac biomarkers was determined by comparing % change (from baseline to 8 weeks) between HFE and Ctrl using Mann-Whitney U-test. Results: At baseline, there was a significant positive correlation between age and TnT (r=0.38, p<0.05) and a non-significant positive correlation between age and NT-proBNP (r=0.36, p=0.06), while no correlation was found between age and levels of vascular markers (VEGF r=-0,14, SDF-1 r=-0,13, ET-1 r=0,08, Rlx-2 r=0,06, p=ns for all). As we have previously shown, home-based HFE decreased VEGF (2,6+29% (ctrl) and -3,9 +13% (HFE), p<0,05), but the other studied factors were not significantly affected. We found no correlation between age and changes in cardiac markers after exercise. Conclusions: Elderly patients with stable CAD have higher levels of TnT and NT-proBNP, indicating a higher degree of underlying CAD. This may also reflect their higher mortality in CAD. HFE-training may lower VEGF in patients with stable CAD. Interestingly, there seems to be no difference in the respone response to exercise in cardiac biomarkers, between younger and older CAD patients
|
|
| 5. |
- Emilsson, Gustav, 1989, et al.
(författare)
-
Identifying bacteria using DNA binding maps
- 2013
-
Ingår i: 17th International Conference on Miniaturized Systems for Chemistry and Life Sciences, MicroTAS 2013; Freiburg; Germany; 27 October 2013 through 31 October 2013. - 9781632666246 ; 1, s. 473-475
-
Konferensbidrag (refereegranskat)abstract
- We have developed an assay, based on nanofluidic channels and fluorescence microscopy, for optical mapping of DNA based on competitive binding between two molecules - one fluorescent and one sequence selective. From the experimental data we can extract binding constants for the two competing DNA binders, which may be subsequently used to calculate a theoretical reference map of any DNA with known sequence. The goal is to create a method for fast identification of bacteria from single DNA molecules without the need for additional cultivation or amplification. We here demonstrate a proof-of-principle experiment on phage DNA and furthermore show that the method can be used to distinguish between two strains of E. coli DNA and to map pieces of DNA onto the full genome.
|
|
| 6. |
- Gad, Helge, et al.
(författare)
-
MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool
- 2014
-
Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 508:7495, s. 215-221
-
Tidskriftsartikel (refereegranskat)abstract
- Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bindin the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.
|
|
| 7. |
- Hedner, Margareta, et al.
(författare)
-
Age-Related Olfactory Decline is Associated with the BDNF Val66met Polymorphism : Evidence from a Population-Based Study
- 2010
-
Ingår i: Frontiers in Aging Neuroscience. - : Frontiers Media SA. - 1663-4365. ; 2:7, s. 24-
-
Tidskriftsartikel (refereegranskat)abstract
- The present study investigates the effect of the brain-derived neurotrophic factor (BDNF) val66met polymorphism on change in olfactory function in a large scale, longitudinal population-based sample (n = 836). The subjects were tested on a 13 item force-choice odor identification test on two test occasions over a 5-year-interval. Sex, education, health-related factors, and semantic ability were controlled for in the statistical analyses. Results showed an interaction effect of age and BDNF val66met on olfactory change, such that the magnitude of olfactory decline in the older age cohort (70–90years old at baseline) was larger for the val homozygote carriers than for the met carriers. The older met carriers did not display larger age-related decline in olfactory function compared to the younger group. The BDNF val66met polymorphism did not affect the rate of decline in the younger age cohort (45–65years). The findings are discussed in the light of the proposed roles of BDNF in neural development and maintenance.
|
|
| 8. |
- Jansson, Johan, 1973-, et al.
(författare)
-
Commitment to sustainability in small and medium-sized enterprises: The influence of market and entrepreneurial orientations
- 2014
-
Ingår i: 43rd European Marketing Academy Conference (EMAC), Valencia, Spain, June 3-6. - : EMAC; Universitat de Valencia. - 9788437094533
-
Konferensbidrag (refereegranskat)abstract
- During the last few decades, ecosystem degradation has grown to become a major topic among several actors in society. While larger companies are generally incorporating environmental practices to varying degrees, small and medium-sized enterprises (SMEs) are often argued to be lagging. Given this development, this study examines the role of two important strategic orientations, market orientation (MO) and entrepreneurial orientation (EO), and their contribution to commitment to sustainability. Questionnaire responses from 450 SMEs were analyzed showing that both MO as well as EO significantly impacts commitment to sustainability, but in different ways. Theoretical and practical implications of findings are discussed.
|
|
| 9. |
- Kallak, Theodora Kunovac, 1985-, et al.
(författare)
-
Higher than expected estradiol levels in aromatase inhibitor-treated, postmenopausal breast cancer patients
- 2012
-
Ingår i: Climacteric. - London, United Kingdom : Informa Healthcare. - 1369-7137 .- 1473-0804. ; 15:5, s. 473-480
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: Vaginal estradiol is considered contraindicated in aromatase inhibitor (AI)-treated patients because of the risk of elevated estrogen levels. This leaves limited treatment options for patients experiencing gynecological symptoms. However, in clinical practice, no precise estimation has been performed of circulating estrogens and aromatase index in postmenopausal breast cancer patients on long-lasting AI or tamoxifen treatment.Methods: Steroid hormones were measured using liquid chromatography tandem mass spectrometry (LC-MS/MS) and extraction radioimmunoassay (RIA). Postmenopausal AI-treated patients (n =33) were compared with tamoxifen-treated patients (n =34) and controls without vaginal treatment (n =56), with vaginal estradiol (n =25), or with estriol (n =11) treatment.Results: By use of LC-MS/MS, median (range) estradiol plasma concentrations were 16.7 (2.4-162.6), 31.0 (13.4-77.1), 27.2 (7.8-115.8) and 33.3 (20.3-340.1) pmol/l in AI-treated breast cancer patients, tamoxifen-treated breast cancer patients, postmenopausal controls and postmenopausal controls on vaginal estradiol, respectively. The AI-treated group and subgroups had significantly lower estradiol and estrone concentrations than all other groups (p <0.05). There was extensive interindividual variation in estradiol concentration within the AI-treated group, measured using both LC-MS/MS (2.3-182.0 pmol/l) and extraction RIA (2.4-162.6 pmol/l). The AI-treated group had lower aromatase index compared to all other groups (p <0.05-0.001).Conclusion: Circulating estrogen levels may have been underestimated in previous longitudinal studies of AI-treated breast cancer patients. Additional studies are required to further evaluate the role of circulating estrogens in breast cancer patients suffering from gynecological symptoms.
|
|
| 10. |
- Lindh, Magnus, 1960, et al.
(författare)
-
IL28B polymorphisms determine early viral kinetics and treatment outcome in patients receiving peginterferon/ribavirin for chronic hepatitis C genotype 1
- 2011
-
Ingår i: Journal of Viral Hepatitis. - : Wiley. - 1352-0504 .- 1365-2893. ; 18:7
-
Tidskriftsartikel (refereegranskat)abstract
- Single nucleotide polymorphisms (SNPs) upstream of IL28B predict the outcome of treatment in chronic hepatitis C virus (HCV) infection, but their impact on viral kinetics and relation to other predictors are not well known. Here, two SNPs, rs12979860 and rs8099917, were analysed and related to early viral kinetics during treatment in 110 patients with HCV genotype 1 infection. The reduction of HCV RNA after 7days of therapy was more pronounced (P<0.0001) in patients with CC(rs12979860) or TT(rs8099917) than in patients carrying TT(rs12979860) or GG(rs8099917), respectively. The two SNPs were in linkage disequilibrium (d' =1, r2 = 0.44), but CC(rs12979860) was less common (43% vs. 71%) than TT(rs8099917). Patients carrying both CC(rs12979860) and TT(rs8099917) genotypes achieved lower levels of HCV RNA at week 4 than those with CT or TT at rs12979860 and TT(rs8099917) (P=0.0004). The viral elimination was significantly influenced by rs12979860 independently of baseline viral load, age or fibrosis. This translated into high rates of sustained viral response (SVR) among patients carrying CC(rs12979860) despite the presence of high viral load at baseline (SVR 74%), high age (SVR 79%) or severe liver fibrosis (SVR 83%). We conclude that the IL28B variability influences the antiviral efficiency of interferon/ribavirin therapy and has a strong impact on SVR, independently of traditional response predictors. A combined assessment of these SNPs in conjunction with other response predictors may better predict outcome in difficult-to-treat patients.
|
|
