| 1. |
- Ashley, S. F., et al.
(författare)
-
Lifetime determination of excited states in Cd-106
- 2007
-
Ingår i: Acta Physica Polonica B. - 0587-4254 .- 1509-5770. ; 38:4, s. 1385-1388
-
Tidskriftsartikel (refereegranskat)abstract
- Two separate experiments using the Differential Decay Curve Method have been performed to extract mean lifetimes of excited states in 106 Cd. The inedium-spin states of interest were populated by the Mo-98(C-12, 4n) Cd-106 reaction performed at the Wright Nuclear Structure Lab., Yale University. From this experiment, two isomeric state mean lifetimes have been deduced. The low-lying states were populated by the Mo-96(C-13, 3n)Cd-106 reaction performed at the Institut fur Kernphysik, Universitat zu Koln. The mean lifetime of the I-pi = 2(1)(+) state was deduced, tentatively, as 16.4(9) ps. This value differs from the previously accepted literature value from Coulomb excitation of 10.43(9) ps.
|
|
| 2. |
- Elander, Nils
(författare)
-
Inflammation-associated genes and genetic variations in colorectal cancer
- 2009
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Colorectal cancer is a major cause of morbidity and mortality around the world, each year affecting about one million individuals worldwide. The disease is characterized by an accumulation of genetic alterations, and a sequence of events leading to the development of an invasive and metastasising tumour. Chronic or dysregulated inflammation may contribute to tumour initiation and progression via the release and activity of various mediators – e.g. cytokines, prostaglandins, inducible nitric oxide synthase (NOS2), matrix metalloproteinases (MMPs), and vascular endothelial growth factors (VEGF). In the present thesis, genes and genetic alterations controlling these events were analysed and discussed within the context of colorectal cancer.Prostaglandins, being generated from arachidonic acid in reactions dependent on cyclooxygenases (COX-1, COX-2), have been implicated in carcinogenesis of many organs. Since the quite recent characterization of the terminal and specific prostaglandin synthases, which act downstream of COX enzymes, the search for molecular targets which selectively suppress individual prostanoids has been intensified. In papers I-II, the role and regulation of inducible prostaglandin E2 (PGE2) synthase - mPGES-1 - were explored within the context of intestinal cancer. mPGES-1 was genetically deleted in the ApcMin/+ mouse - yielding marked suppression of PGE2 generation in intestinal and tumour tissue. However, a shift towards enhanced generation of non-PGE2 prostanoids was observed in mPGES-1 knock out mice, and these mice developed more and larger instestinal tumours. These results therefore indicate that targeting mPGES-1 may paradoxically promote tumourigenesis, most likely by secondary effects on other potentially pro-tumoural mediators. We also explored the relation of the commonly mutated APC gene and mPGES-1 in colon tumour cells, and found that high expression of mPGES-1 was associated with the presence of wild type APC. Rather than by regulating putative β-catenin/Tcf binding sites of the mPGES-1 promoter, APC seems to influence the stabilisation of mPGES-1 mRNA.In papers III-V, the possible contribution of variations in regulatory regions of genes encoding NOS2, MMPs, and VEGF, was assessed in populations of colorectal cancer patients and healthy control individuals. A single nucleotide insertion (1G/2G) at -1607 upstream the transcription start site of the MMP-1 gene was identified to be a susceptibility factor for colorectal cancer development, although no relation with disease characteristics was observed. Except for a rather uncommon combination of two individual polymorphisms of the VEGF gene, investigated genetic variations of VEGF, other MMPs, and NOS2, were not associated with colorectal cancer susceptibility or clinicopathological characteristics. We therefore suggest that other molecular events play more significant roles for the dysregulation of these genes in colorectal tumours.In summary, accumulating evidence, including the results here presented, suggest significant albeit complex roles of inflammation-induced genes and mediators in colorectal tumourigenesis. The present results may aid in identifying or excluding potential biomarkers and drug targets within cancer-related inflammation.
|
|
| 3. |
- Elander, Nils, 1980-, et al.
(författare)
-
Matrix metalloproteinase (MMP) -1, -2, -3 and -9 promoter polymorphisms in colorectal cancer
- 2006
-
Ingår i: Anticancer Research. - : International Institute of Anticancer Research. - 0250-7005 .- 1791-7530. ; 26:1B, s. 791-795
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Matrix metalloproteinases (MMPs) are a group of matrix-degrading proteins implicated in several pathological processes, e.g., invasion and metastasis in malignant diseases such as colorectal cancer (CRC). Materials and methods: One hundred and twenty-seven CRC patients and 208 controls were genotyped for MMP-1, -2, -3 and -9 promoter polymorphisms. The genotyping was performed with PCR/primer-extension/DHPLC or PCR/RFLP. Results: The MMP-1 2G allele was significantly associated with CRC (p=0.037). No significant association between CRC and MMP-2, -3 or -9 polymorphisms was evident. The analysis of polymorphisms in the clinicopathological subgroups displayed no significant associations. Conclusion: The MMP-1 promoter polymorphism seems to affect the susceptibility to CRC, while MMP-2, -3 and -9 polymorphisms appear less likely to have any impact on CRC.
|
|
| 4. |
- Fransén, Karin, 1973-, et al.
(författare)
-
Association between ulcerative growth and hypoxia inducible factor-1alpha polymorphisms in colorectal cancer patients
- 2006
-
Ingår i: Molecular Carcinogenesis. - : John Wiley & Sons. - 0899-1987 .- 1098-2744. ; 45:11, s. 833-840
-
Tidskriftsartikel (refereegranskat)abstract
- The hypoxia inducible factor-1alpha (HIF-1alpha) has been found to be involved in several different physiological mechanisms, such as blood-vessel formation, apoptosis, and erythropoiesis. HIF-1alpha is hydroxylated at normoxia and rapidly degraded via the von Hippel-Lindau (VHL)/ubiquitin-proteasome degradation system to prevent angiogenesis. In a previous study, the C1772T (P582S) and the G1790A (A588T) polymorphisms were identified in the human HIF-1alpha gene, which was shown to have a higher transactivating capability in vitro compared to the wild type allele. However, the role for these polymorphisms in vivo is still unclear. In the present investigation, we have therefore studied the role of the two polymorphic variants in the development of colorectal cancer (CRC) with PCR/RFLP (restriction fragment length polymorphism), single strand conformation analysis (SSCA), and immunohistochemistry (IHC). A significant higher-risk was identified between patients heterozygous for the C1772T polymorphism and the more severe ulcerative growth pattern compared to homozygous C1772C wild type tumors (RR = 5.2; 95% CI 1.26-21.6; P = 0.006). This was also verified on the allelic level (RR = 6.5; 95% CI 1.58-26.8; P = 0.001). In addition, patients carrying one or more polymorphic alleles in either the HIF-1alpha C1772T or the G1790A polymorphisms display significant higher risk for the development of ulcerative CRCs (RR = 4.17; 95% CI = 1.33-13.08; P = 0.004). These results suggest that the HIF-1alpha polymorpisms are an important factor for development of a subset of ulcerative intestinal tumors. Future screening of the polymorphic HIF-1alpha allele may therefore be of importance in the selection of treatment strategies of CRC.
|
|
| 5. |
- Fransén, Karin, 1973-, et al.
(författare)
-
Association between ulcerative growth and hypoxia inducible factor-1α polymorphisms in colorectal cancer patients
- 2006
-
Ingår i: Molecular Carcinogenesis. - : Wiley. - 0899-1987 .- 1098-2744. ; 45:11, s. 833-840
-
Tidskriftsartikel (refereegranskat)abstract
- The hypoxia inducible factor-1α (HIF-1α) has been found to be involved in several different physiological mechanisms, such as blood-vessel formation, apoptosis, and erythropoiesis. HIF-1α is hydroxylated at normoxia and rapidly degraded via the von Hippel–Lindau (VHL)/ubiquitin-proteasome degradation system to prevent angiogenesis. In a previous study, the C1772T (P582S) and the G1790A (A588T) polymorphisms were identified in the human HIF-1α gene, which was shown to have a higher transactivating capability in vitro compared to the wild type allele. However, the role for these polymorphisms in vivo is still unclear. In the present investigation, we have therefore studied the role of the two polymorphic variants in the development of colorectal cancer (CRC) with PCR/RFLP (restriction fragment length polymorphism), single strand conformation analysis (SSCA), and immunohistochemistry (IHC). A significant higher-risk was identified between patients heterozygous for the C1772T polymorphism and the more severe ulcerative growth pattern compared to homozygous C1772C wild type tumors (RR = 5.2; 95% CI 1.26–21.6; P = 0.006). This was also verified on the allelic level (RR = 6.5; 95% CI 1.58–26.8; P = 0.001). In addition, patients carrying one or more polymorphic alleles in either the HIF-1α C1772T or the G1790A polymorphisms display significant higher risk for the development of ulcerative CRCs (RR = 4.17; 95% CI = 1.33–13.08; P = 0.004). These results suggest that the HIF-1α polymorpisms are an important factor for development of a subset of ulcerative intestinal tumors. Future screening of the polymorphic HIF-1α allele may therefore be of importance in the selection of treatment strategies of CRC.
|
|
| 6. |
- Fransén, Karin, 1973-
(författare)
-
Molecular genetic aspects of colorectal cancer development
- 2005
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Colorectal cancer (CRC) is one of the most common cancer diseases in the world after lung and female breast cancer and approximately 945 000 new cases are diagnosed every year. CRC is caused by genetic alterations in the DNA, which results in cell cycle acceleration, escape from apoptosis, senescence, angiogenesis, invasion and metastasis. In this thesis, we have investigated molecular genetic alterations for the development of CRC and focused on the MAPK pathway, HIF-1 α and NOS2 genes.Alterations in the MAPK pathway have been found in several different cancer forms, including CRe. In the present study, we found somatic mutations in the MAPK pathway in 50% of the CRCs; 40% of the tumors carried mutations in the KRAS gene and 10% carried BRAF mutations. No genetic alterations were found in the ARAF or RAF-1 genes. B&4F gene mutations were present only in exon 15 and were associated with micro satellite instability. Three mutation types were identified; V599E, D593G and K600N, whereof the latter has not previously been described.The hypoxia inducible factor (HIF)-la protein is involved in the oxygen sensing mechanism and several tumor types show HIF-la overexpression due to hypoxia. At normoxia, HIF-la is degraded by interaction with the von Hippel-Lindau (VHL) tumor suppressor protein followed by an ubiquitin-proteasome dependent degradation mechanism, which prevents HIF-l a from nuclear translocation and transcription of downstream target genes. Fifteen percent of CRC patients and normal healthy population was found to carry the P582S polymorphism in the HIF-1 α gene, which previously has been associated to higher transactivating capacity. In the present study, the polymorphism was associated to ulcerative tumor development. In addition, loss of heterozygosity of the wild type P582 allele in heterozygotes may contribute to the development of ulcerative CRCs. However, the overall mechanism for ulcerative tumor development is still unclear.Nitric oxide (NO) is involved in several physiological processes, such as apoptosis, neurotransmission, angiogenesis and immune defence and is produced by three nitric oxide synthases; NOSl-3. In the present study, NOS2 upregulation was identified in CRCs compared to normal intestinal mucosa. Moreover, the contribution of NOS2 in CRC development was investigated in APCMin/+ and APCMin/+ NOS2-/- mice. The APCMin/+ NOS-/- mice developed a higher polyp frequency compared to APCMin/+ mice, indicating a protective role for the presence of NOS2 in intestinal cancer development. The elevated polyp formation in the APCMin/+ NOS-/- mice was independent of the expression of Notch-l and p21. We also investigated whether polymorphisms in the NOS2 promoter affected the onset of CRC, but no differences in allele or genotype frequencies were observed in normal healthy population compared to CRC patients.
|
|
| 7. |
- Fransén, Karin, 1973-, et al.
(författare)
-
Nitric oxide synthase 2 (NOS2) promoter polymorphisms in colorectal cancer
- 2005
-
Ingår i: Cancer Letters. - : Elsevier. - 0304-3835 .- 1872-7980. ; 225:1, s. 99-103
-
Tidskriftsartikel (refereegranskat)abstract
- Previously, increased expression of nitric oxide synthase 2 (NOS2) in colorectal cancer (CRC) has been identified. The NOS2 gene is transcriptionally regulated, which suggests that polymorphisms in the NOS2 promoter may have a role for CRC development and progression. The genotyping was performed with PCR/RFLP, single strand conformation analysis or MegaBACE genotyping of normal blood DNA from CRC patients and normal healthy controls. However, no significant association between NOS2 polymorphisms and CRC onset or clinical outcome was evident. In conclusion, these results, therefore, suggest that NOS2 promoter polymorphisms have a limited effect on the onset or progression of CRC.
|
|
| 8. |
- Grahn, Niclas, et al.
(författare)
-
Molecular identification of Helicobacter DNA present in human colorectal adenocarcinomas by 16S rDNA PCR amplification and pyrosequencing analysis
- 2005
-
Ingår i: Journal of Medical Microbiology. - : Microbiology Society. - 0022-2615 .- 1473-5644. ; 54:11, s. 1031-1035
-
Tidskriftsartikel (refereegranskat)abstract
- Seroepidemiological studies have indicated that Helicobacter pylori infection might be a possible risk factor for colorectal adenocarcinoma (CRC) development. However, limited information is available as to whether or not Helicobacter species are present in CRC tissues. In this study the presence of Helicobacter DNA in 77 CRC biopsies was investigated by means of a Helicobacter species-specific 16S rDNA PCR assay and real-time DNA pyrosequencing of the 16S rDNA variable V3 region. Pyrosequencing revealed the presence of Helicobacter DNA sequences in 21 of 77 biopsy specimens (27%). 16S rDNA sequences corresponding to H. pylori 26695 and H. pylori J99 were most commonly found. Intriguingly, one sequence belonged to Helicobacter mustelae, previously identified in ferrets. No significant correlations were found in the prevalence of Helicobacter DNA between colon and rectum tumour biopsies (P = 0.815), nor between Dukes' classes A/B and C/D (P = 0.262). 16S rDNA PCR amplification combined with pyrosequencing analysis of 16S rDNA variable V3 regions provides a powerful molecular tool to identify Helicobacter species in human biopsy specimens. © 2005 SGM.
|
|
