| 1. |
- Olsson, Marie, et al.
(författare)
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Effects of extracts of apple peel from organically and integrated production cultivated apples and ursolic acid on cancer cell proliferation
- 2014
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Ingår i: Acta Horticulturae. - 0567-7572 .- 2406-6168. - 9789462610286 ; 1040, s. 227-230
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Konferensbidrag (refereegranskat)abstract
- The effects of extract of apple peel, 'Aroma', organically cultivated or cultivated according to integrated production, on cell proliferation in vitro of colon cancer HT29 cells and breast cancer MCF-7 cells, were investigated. Different sequences of solvents were used, and the inhibiting effect on cancer cell proliferation of the different extracts was investigated. The solvents used were ethanol, methanol, DMSO and hexane in different sequences. The extracts decreased the proliferation of both HT29 and MCF-7 cells, the effect was different for the different extracts, and ethanol showed the highest inhibition effect. The inhibiting effect of the extracts also varied between both apple production methods, and extracts from peels of organically produced apples showed in some cases higher inhibition effects, while sometimes no differences were found. In addition, as ursolic acid, a component of apple peel, has been proposed to inhibit cancer cell proliferation, the inhibiting effect of pure ursolic acid on cancer cell proliferation was compared with the effect of the apple peel solvent fraction with the highest ursolic acid concentration. The inhibiting effect was higher in the apple fraction extract than in pure ursolic acid. Further, a range of different apple cultivars, integrated production and organically cultivated, were analysed by HPLC for their content of ursolic acid to investigate possible differences in concentrations.
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| 2. |
- Hansen, Louise, et al.
(författare)
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Intake of dietary fiber, especially from cereal foods, is associated with lower incidence of colon cancer in the HELGA cohort
- 2012
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Ingår i: International Journal of Cancer. - Geneve : International union against cancer. - 0020-7136 .- 1097-0215. ; 131:2, s. 469-478
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Tidskriftsartikel (refereegranskat)abstract
- The role of dietary fiber on the risk of colon and rectal cancer has been investigated in numerous studies, but findings have been inconsistent. The purpose of this study was to examine associations between intake of dietary fiber and risk of incident colon (including distal and proximal colon) and rectal cancer in the prospective Scandinavian HELGA cohort and to determine if fiber source (vegetables, fruits, potatoes, cereals) impacted the association. We included 1,168 incident cases (691 colon, 477 rectal cancer), diagnosed during a median of 11.3 years, among 108,081 cohort members. Sex-specific incidence rate ratios (IRRs) of colon and rectal cancer were related to intake of total or specific fiber source using Cox proportional hazards models. For men, an inverse association was observed between intake of total fiber and the risk of colon cancer per an incremental increase of 10 g day(-1) , IRR (95% CI): 0.74 (0.64-0.86). Intake of cereal fiber per 2 g day(-1) was associated with an IRR of 0.94 (0.91-0.98), which was also seen for intake of cereal fiber from foods with high fiber content (≥5 g per 100 g product), where the IRR per 2 g day(-1) was 0.94 (0.90-0.98). In women, intake of cereal fiber per 2 g day(-1) was also associated with lower risk of colon cancer, 0.97 (0.93-1.00). No clear associations were seen for rectal cancer. Our data indicate a protective role of total and cereal fiber intake, particularly from cereal foods with high fiber content, in the prevention of colon cancer.
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| 3. |
- Lindahl, Pernilla, et al.
(författare)
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Copy number variants in the kallikrein gene cluster.
- 2013
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:7
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Tidskriftsartikel (refereegranskat)abstract
- The kallikrein gene family (KLK1-KLK15) is the largest contiguous group of protease genes within the human genome and is associated with both risk and outcome of cancer and other diseases. We searched for copy number variants in all KLK genes using quantitative PCR analysis and analysis of inheritance patterns of single nucleotide polymorphisms. Two deletions were identified: one 2235-bp deletion in KLK9 present in 1.2% of alleles, and one 3394-bp deletion in KLK15 present in 4.0% of alleles. Each deletion eliminated one complete exon and created out-of-frame coding that eliminated the catalytic triad of the resulting truncated gene product, which therefore likely is a non-functional protein. Deletion breakpoints identified by DNA sequencing located the KLK9 deletion breakpoint to a long interspersed element (LINE) repeated sequence, while the deletion in KLK15 is located in a single copy sequence. To search for an association between each deletion and risk of prostate cancer (PC), we analyzed a cohort of 667 biopsied men (266 PC cases and 401 men with no evidence of PC at biopsy) using short deletion-specific PCR assays. There was no association between evidence of PC in this cohort and the presence of either gene deletion. Haplotyping revealed a single origin of each deletion, with most recent common ancestor estimates of 3000-8000 and 6000-14 000 years for the deletions in KLK9 and KLK15, respectively. The presence of the deletions on the same haplotypes in 1000 Genomes data of both European and African populations indicate an early origin of both deletions. The old age in combination with homozygous presence of loss-of-function variants suggests that some kallikrein-related peptidases have non-essential functions.
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| 4. |
- Palm, Maria E, et al.
(författare)
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Cisplatin binds human copper chaperone Atox1 and promotes unfolding in vitro.
- 2011
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 108:17, s. 6951-6
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Tidskriftsartikel (refereegranskat)abstract
- Cisplatin (cisPt), Pt(NH(3))(2)Cl(2), is a cancer drug believed to kill cells via DNA binding and damage. Recent work has implied that the cellular copper (Cu) transport machinery may be involved in cisPt cell export and drug resistance. Normally, the Cu chaperone Atox1 binds Cu(I) via two cysteines and delivers the metal to metal-binding domains of ATP7B; the ATP7B domains then transfer the metal to the Golgi lumen for loading on cuproenzymes. Here, we use spectroscopic methods to test if cisPt interacts with purified Atox1 in solution in vitro. We find that cisPt binds to Atox1's metal-binding site regardless of the presence of Cu or not: When Cu is bound to Atox1, the near-UV circular dichroism signals indicate Cu-Pt interactions. From NMR data, it is evident that cisPt binds to the folded protein. CisPt-bound Atox1 is however not stable over time and the protein begins to unfold and aggregate. The reaction rates are limited by slow cisPt dechlorination. CisPt-induced unfolding of Atox1 is specific because this effect was not observed for two unrelated proteins that also bind cisPt. Our study demonstrates that Atox1 is a candidate for cisPt drug resistance: By binding to Atox1 in the cytoplasm, cisPt transport to DNA may be blocked. In agreement with this model, cell line studies demonstrate a correlation between Atox1 expression levels, and cisplatin resistance.
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| 5. |
- Jiang, Lin, et al.
(författare)
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Constitutive activation of the ERK pathway in melanoma and skin melanocytes in Grey horses
- 2014
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407 .- 1471-2407. ; 14, s. 857-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Constitutive activation of the ERK pathway, occurring in the vast majority of melanocytic neoplasms, has a pivotal role in melanoma development. Different mechanisms underlie this activation in different tumour settings. The Grey phenotype in horses, caused by a 4.6 kb duplication in intron 6 of Syntaxin 17 (STX17), is associated with a very high incidence of cutaneous melanoma, but the molecular mechanism behind the melanomagenesis remains unknown. Here, we investigated the involvement of the ERK pathway in melanoma development in Grey horses.METHODS: Grey horse melanoma tumours, cell lines and normal skin melanocytes were analyzed with help of indirect immunofluorescence and immunoblotting for the expression of phospho-ERK1/2 in comparison to that in non-grey horse and human counterparts. The mutational status of BRAF, RAS, GNAQ, GNA11 and KIT genes in Grey horse melanomas was determined by direct sequencing. The effect of RAS, RAF and PI3K/AKT pathways on the activation of the ERK signaling in Grey horse melanoma cells was investigated with help of specific inhibitors and immunoblotting. Individual roles of RAF and RAS kinases on the ERK activation were examined using si-RNA based approach and immunoblotting.RESULTS: We found that the ERK pathway is constitutively activated in Grey horse melanoma tumours and cell lines in the absence of somatic activating mutations in BRAF, RAS, GNAQ, GNA11 and KIT genes or alterations in the expression of the main components of the pathway. The pathway is mitogenic and is mediated by BRAF, CRAF and KRAS kinases. Importantly, we found high activation of the ERK pathway also in epidermal melanocytes, suggesting a general predisposition to melanomagenesis in these horses.CONCLUSIONS: These findings demonstrate that the presence of the intronic 4.6 kb duplication in STX17 is strongly associated with constitutive activation of the ERK pathway in melanocytic cells in Grey horses in the absence of somatic mutations commonly linked to the activation of this pathway during melanomagenesis. These findings are consistent with the universal importance of the ERK pathway in melanomagenesis and may have valuable implications for human melanoma research.
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| 6. |
- Behrens, Thomas, et al.
(författare)
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Pesticide exposure in farming and forestry and the risk of uveal melanoma
- 2012
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Ingår i: Cancer Causes and Control. - : Springer. - 0957-5243 .- 1573-7225. ; 23:1, s. 141-151
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Tidskriftsartikel (refereegranskat)abstract
- Since pesticides are disputed risk factors for uveal melanoma, we studied the association between occupational pesticide exposure and uveal melanoma risk in a case-control study from nine European countries.Incident cases of uveal melanoma and population as well as hospital controls were included and frequency-matched by country, 5-year age groups and sex. Self-reported exposure was quantified with respect to duration of exposure and pesticide application method. We calculated the exposure intensity level based on application method and use of personal protective equipment. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated by unconditional logistic regression analyses and adjusted for several potential confounders.293 case and 3,198 control subjects were interviewed. We did not identify positive associations with activities in farming or forestry, pesticide application or pesticide mixing. No consistent positive associations were seen with exposure intensity level scores either. The only statistically significantly raised association in this study was for exposure to chemical fertilizers in forestry (OR = 8.93; 95% CI 1.73-42.13), but this observation was based on only six exposed subjects. Results did not change when we restricted analyses to morphologically verified cases and excluded proxy interviews as well as cancer controls. We did not observe effect modification by sex or eye color.Risk estimates for pesticide exposures and occupational activities in agriculture and forestry were not increased and did not indicate a hormonal mechanism due to these exposures.
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| 7. |
- Lindqvist, Breezy Malakkaran, 1978-, et al.
(författare)
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Whole genome DNA methylation signature of HER2-positive breast cancer
- 2014
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Ingår i: Epigenetics. - Austin, USA : Landes Bioscience. - 1559-2294 .- 1559-2308. ; 9:8, s. 1149-1162
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Tidskriftsartikel (refereegranskat)abstract
- In order to obtain a comprehensive DNA methylation signature of HER2-positive breast cancer (HER2+ breast cancer), we performed a genome-wide methylation analysis on 17 HER2+ breast cancer and compared with ten normal breast tissue samples using the Illumina Infinium HumanMethylation450 BeadChip (450K). In HER2+ breast cancer, we found altered DNA methylation in genes involved in multicellular development, differentiation and transcription. Within these genes, we observed an overrepresentation of homeobox family genes, including several genes that have not been previously reported in relation to cancer (DBX1, NKX2-6, SIX6). Other affected genes included several belonging to the PI3K and Wnt signaling pathways. Notably, HER2, AKT3, HK1, and PFKP, genes for which altered methylation has not been previously reported, were also identified in this analysis. In total, we report 69 candidate biomarker genes with maximum differential methylation in HER2+ breast cancer. External validation of gene expression in a selected group of these genes (n = 13) revealed lowered mean gene expression in HER2+ breast cancer. We analyzed DNA methylation in six top candidate genes (AKR1B1, INA, FOXC2, NEUROD1, CDKL2, IRF4) using EpiTect Methyl II Custom PCR Array and confirmed the 450K array findings. Future clinical studies focusing on these genes, as well as on homeobox-containing genes and HER2, AKT3, HK1, and PFKP, are warranted which could provide further insights into the biology of HER2+ breast cancer.
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| 8. |
- Betsholtz, Christer, et al.
(författare)
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PDGF, Pericytes and the Pathogenesis of Idiopathic Basal Ganglia Calcification (IBGC)
- 2014
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Ingår i: Brain Pathology. - : Wiley. - 1015-6305 .- 1750-3639. ; 24:4, s. 387-395
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Tidskriftsartikel (refereegranskat)abstract
- Platelet-derived growth factors (PDGFs) are important mitogens for various types of mesenchymal cells, and as such, they exert critical functions during organogenesis in mammalian embryonic and early postnatal development. Increased or ectopic PDGF activity may also cause or contribute to diseases such as cancer and tissue fibrosis. Until recently, no loss-of-function (LOF) mutations in PDGF or PDGF receptor genes were reported as causally linked to a human disease. This changed in 2013 when reports appeared on presumed LOF mutations in the genes encoding PDGF-B and its receptor PDGF receptor-beta (PDGF-R) in familial idiopathic basal ganglia calcification (IBGC), a brain disease characterized by anatomically localized calcifications in or near the blood microvessels. Here, we review PDGF-B and PDGF-R biology with special reference to their functions in brain-blood vessel development, pericyte recruitment and the regulation of the blood-brain barrier. We also discuss various scenarios for IBGC pathogenesis suggested by observations in patients and genetically engineered animal models of the disease.
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| 9. |
- Degerman, Sofie, et al.
(författare)
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Immortalization of T-Cells Is Accompanied by Gradual Changes in CpG Methylation Resulting in a Profile Resembling a Subset of T-Cell Leukemias
- 2014
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Ingår i: Neoplasia. - : Elsevier BV. - 1522-8002 .- 1476-5586. ; 16:7, s. 606-615
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Tidskriftsartikel (refereegranskat)abstract
- We have previously described gene expression changes during spontaneous immortalization of T-cells, thereby identifying cellular processes important for cell growth crisis escape and unlimited proliferation. Here, we analyze the same model to investigate the role of genome-wide methylation in the immortalization process at different time points pre-crisis and post-crisis using high-resolution arrays. We show that over time in culture there is an overall accumulation of methylation alterations, with preferential increased methylation close to transcription start sites (TSSs), islands, and shore regions. Methylation and gene expression alterations did not correlate for the majority of genes, but for the fraction that correlated, gain of methylation close to TSS was associated with decreased gene expression. Interestingly, the pattern of CpG site methylation observed in immortal T-cell cultures was similar to clinical T-cell acute lymphoblastic leukemia (T-ALL) samples classified as CpG island methylator phenotype positive. These sites were highly overrepresented by polycomb target genes and involved in developmental, cell adhesion, and cell signaling processes. The presence of non-random methylation events in in vitro immortalized T-cell cultures and diagnostic T-ALL samples indicates altered methylation of CpG sites with a possible role in malignant hematopoiesis.
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| 10. |
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