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- Heidenblad, Markus, et al.
(författare)
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Detailed genomic mapping and expression analyses of 12p amplifications in pancreatic carcinomas reveal a 3.5-Mb target region for amplification.
- 2002
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257. ; 34:2, s. 211-223
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Tidskriftsartikel (refereegranskat)abstract
- Previous cytogenetic and comparative genomic hybridization (CGH) analyses have shown that the gain of chromosome arm 12p is frequent in pancreatic carcinomas. We investigated 15 pancreatic carcinoma cell lines using CGH, fluorescence in situ hybridization (FISH), and semiquantitative polymerase chain reaction (PCR) to characterize 12p amplifications in detail. The CGH analysis revealed gains of 12p in four of the cell lines and local amplification within 12p11-12 in six cell lines. By FISH analysis, using precisely mapped YAC clones, the commonly amplified region was found to be approximately 5 Mb. The amplified segment extended from YAC 753f12, covering the KRAS2 locus, to YAC 891f1, close to the centromere. A semiquantitative PCR methodology was used to estimate genomic copy numbers of 14 precisely mapped expressed sequence tags (ESTs) and sequence-tagged sites, located within this interval. The level of amplification ranged from two- to 12-fold. The produced gene copy profiles revealed a 3.5-Mb segment with various local amplifications. This region includes KRAS2 and ranges from D12S1617 to sts-N38796. Two of the cell lines (primary and metastatic tumor from the same patient) showed amplification peaks within the distal region of this segment, two had peaks within the proximal region, one showed subpeaks in both regions, and one displayed amplification of the entire region. Chromosome segment-specific cDNA array analysis of 29 expressed sequences within the whole interval between D12S1617 and sts-N38796 indicated overexpression of four ESTs, two corresponding to DEC2 and PPFIBP1, and two to ESTs with unknown function. Expression analysis of these and of KRAS2 showed specific overexpression in the six cell lines with local 12p amplifications. These findings indicate two target regions within the 3.5-Mb segment in 12p11-12, one proximal including PPFIBP1, and one distal including KRAS2.
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- Johansson, Markus, 1974-
(författare)
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Effects of Agriculture on Abundance, Genetic Diversity and Fitness in the Common Frog, Rana temporaria
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aims of this thesis were to evaluate the effects of agriculture on amphibians in terms of (i) population genetic consequences of agriculture-induced spatial changes of the landscape and (ii) local adaptation and tolerance to frequently used agrochemicals. The study was performed using the common frog Rana temporaria as a model. Abundance, occurrence, genetic diversity and gene flow were negatively affected by agriculture in southern Sweden, but unaffected or even positively affected by agriculture in the central and northern regions, respectively. These test parameters correlated positively with landscape diversity both in the south and in the north. Moreover, the size and occurrence of R. temporaria populations decreased towards the north i.e. the margin of the species’ distribution range. In accordance with theoretical expectations, genetic variability decreased and population substructuring increased as a negative function of (effective) population size. Southern Swedish common frogs are naturally exposed to higher levels of nitrates, and thus have a higher tolerance to high nitrate levels than their northern conspecifics. This suggests local adaptation to naturally varying nitrate levels. Consequently, increased anthropogenic supplementation of nitrate could impact more the northern than the southern Swedish common frog populations. Exposure to the pesticides azoxystrobin, cyanazine and permethrin at ecologically relevant concentrations had small or no effects on R. temporaria tadpoles. The populations with lowest microsatellite variation (fragmented populations) in southern Sweden had considerably lower fitness in terms of survival and growth as compared to those with the highest genetic variability (non-fragmented populations). The results indicate that populations with low levels of neutral genetic variability were phenotypically less differentiated than populations with higher levels of variability. One possible explanation for this is that the degree of population differentiation in low variability populations has been constrained due to lack of suitable genetic variation or inefficiency of selection relative to genetic drift.
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- Johansson, Matti, et al.
(författare)
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Integrated Assessment Modeling of Air Pollution in Four European Countries.
- 2001
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Ingår i: Water, Air and Soil Pollution. - 1573-2932. ; 130:1-4, s. 175-186
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Tidskriftsartikel (refereegranskat)abstract
- The integrated assessment modeling on acid rain has incorporated several related effects and pollutants into a multi-pollutant/multi-effect approach, resulting in complex integrated models and policy assessments. The development and implementation of effects-oriented cost-effective emission reduction strategies in Europe are based on integrated assessment models. The project on national integrated assessment modeling in Finland, Denmark, Spain and Sweden aimed to support the national evaluation of European emission reduction strategies. The tasks covered the comparison of inventories and projections for emissions of sulfur, nitrogen oxides, ammonia and volatile organic compounds, assessment of control techniques and related costs, concentration and deposition scenarios to estimate environmental effects of acidification, eutrophication and ground-level ozone and their temporal aspects, uncertainty analyses on both individual modules and whole integrated models, and dissemination of results to stakeholders. The integrated assessment modeling provided a consistent framework for the harmonization of input data and in-depth scientific research tasks on emissions, pollutant loading and impacts including comprehensive uncertainty analyses, and facilitated the dissemination of knowledge to policy-makers.
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- Jonson, Tord, et al.
(författare)
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Altered expression of TGFB receptors and mitogenic effects of TGFB in pancreatic carcinomas
- 2001
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Ingår i: International Journal of Oncology. - 1019-6439. ; 19:1, s. 71-81
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Tidskriftsartikel (refereegranskat)abstract
- Alteration of the transforming growth factor beta (TGFB) signalling pathway is important in pancreatic carcinogenesis, as shown by the frequent inactivation of the downstream target SMAD4. We recently analysed a series of pancreatic carcinoma cell lines with respect to alterations of five SMAD genes involved in TGFB signalling, and showed that SMAD4 was structurally rearranged in 42% of these. This pathway may, however, also be affected by alterations of genes whose products regulate the activation of TGFB as well as of TGFB receptor genes. We therefore studied the expression of UPA, UPAR, IGF2R, ALK5 (TGFBR1), TGFBR2, TGFBR3, ENG, ALK1, TGFB1, TGFB2, and TGFB3 in a series of 14 pancreatic carcinoma cell lines. We also analysed ALK5 and TGFBR2 for mutations, cell surface localisation of TGFBR2 and ENG, and TGFB1 response. No mutations of ALK5 or TGFBR2 were found. However, 4 cell lines were methylated within the ALK5 promoter region. ALK5 expression was strongly reduced in 9 cases, whereas TGFBR2 expression was increased in 12 of the cell lines. The TGFB signalling associated receptors ENG and ALK1 were co-expressed in 4 of the cell lines. There was no evidence for disruption of the UPAR-IGF2R TGFB activating pathway. The response to TGFB1 was analysed in 12 cell lines, and 6 of these (50%) showed increased proliferation. The cell lines stimulated by TGFB showed frequent mutations of SMAD4, KRAS2, and TP53, as well as frequent absence of CDKN2B expression. These results suggest that the ALK5-SMAD4 part of the TGFB signalling pathway is a major target for inactivation in pancreatic carcinomas, that the expression of TGFBR2, TGFBR3, and receptors involved in TGFB activation are maintained, and that alterations of components of the TGFB signalling pathway may be accompanied by a positive effect of TGFB on cell growth.
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- Pavey, S, et al.
(författare)
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Microarray expression profiling in melanoma reveals a BRAF mutation signature
- 2004
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Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 1476-5594 .- 0950-9232. ; 23:23, s. 4060-4067
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Tidskriftsartikel (refereegranskat)abstract
- We have used microarray gene expression pro. ling and machine learning to predict the presence of BRAF mutations in a panel of 61 melanoma cell lines. The BRAF gene was found to be mutated in 42 samples (69%) and intragenic mutations of the NRAS gene were detected in seven samples (11%). No cell line carried mutations of both genes. Using support vector machines, we have built a classifier that differentiates between melanoma cell lines based on BRAF mutation status. As few as 83 genes are able to discriminate between BRAF mutant and BRAF wild-type samples with clear separation observed using hierarchical clustering. Multidimensional scaling was used to visualize the relationship between a BRAF mutation signature and that of a generalized mitogen-activated protein kinase ( MAPK) activation ( either BRAF or NRAS mutation) in the context of the discriminating gene list. We observed that samples carrying NRAS mutations lie somewhere between those with or without BRAF mutations. These observations suggest that there are gene-specific mutation signals in addition to a common MAPK activation that result from the pleiotropic effects of either BRAF or NRAS on other signaling pathways, leading to measurably different transcriptional changes.
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