| 1. |
- Bjursten, Malin, 1976, et al.
(författare)
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Long-term treatment with anti-alpha 4 integrin antibodies aggravates colitis in G alpha i2-deficient mice.
- 2005
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Ingår i: European journal of immunology. - : Wiley. - 0014-2980 .- 1521-4141. ; 35:8, s. 2274-83
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Tidskriftsartikel (refereegranskat)abstract
- Targeted deletion of the heterotrimeric G protein, Galphai2, in mice induces lethal colitis closely resembling ulcerative colitis. In chronic colitis, migration of circulating leukocytes into the intestinal mucosa is partially dependent on alpha4 integrins. In previous studies, short-term administration of anti-alpha4 integrin antibodies has been shown to attenuate intestinal inflammation, and here we elucidate the effect of long-term administration of anti-alpha4 integrin antibodies on colitis in Galphai2(-/- )mice. Long-term blockade of alpha4 integrin significantly increased the severity of colitis in Galphai2(-/-) mice. The inflammation was confined to the colon, associated with increased cancer in situ, destruction of crypt architecture, and increased production of IL-1beta, TNF-alpha and IFN-gamma. Blockade of alpha4 integrin reduced the recruitment of activated T cells to the small intestine. In strong contrast, there were significantly higher numbers of activated T cells in the colonic lamina propria and epithelium, most probably due to in situ proliferation. Furthermore, treatment with alpha4 integrin antibodies induced decreased levels of total IgA and IgG in sera, whereas total IgM levels were unchanged. These new findings may have implications in the understanding of the progression of chronic intestinal inflammation.
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| 2. |
- Bjursten, Malin, 1976, et al.
(författare)
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Transfer of colitis by Galphai2-deficient T lymphocytes: impact of subpopulations and tissue origin.
- 2005
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Ingår i: Inflammatory bowel diseases. - 1078-0998. ; 11:11, s. 997-1005
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Tidskriftsartikel (refereegranskat)abstract
- To elucidate the potential cell population(s) involved in the induction of colitis in inhibitory G protein Galphai2(-/-) mice, Galphai2-deficient or competent bone marrow or splenic and mesenteric lymph node (MLN) T cells were transferred into immunodeficient mice. The mice were followed up to 23 weeks after transfer, recording changes in body weight. Colitis was graded on hematoxylin and eosin-stained colonic tissue, and production of serum interleukin-18 and colon-derived interferon-gamma was measured using ELISA. After adoptive transfer of Galphai2(-/-) bone marrow, severe colitis developed in irradiated wild type recipients, whereas irradiated Galphai2(-/-) mice increased their life span more than 3 times after transfer of wild type bone marrow, accompanied by significant amelioration of colitis. Neither purified Galphai2(-/-) CD4(+), nor CD8(+) splenic or MLN-derived T cells could induce colitis in recombination-activating gene V(RAG) 2(-/-) recipient mice, whereas transfer of splenic Galphai2(-/-) CD3(+) T cells induced severe colitis. In contrast, transfer of Galphai2(-/-) CD3(+) T cells from the MLN caused only minor histopathological changes in the intestinal mucosa. Finally, serum levels of interleukin-18 and interferon-gamma production from colonic tissue cultures correlated well with disease severity. Our results show that bone marrow transplantation can prolong the life of Galphai2(-/-) mice and ameliorate intestinal inflammation. Splenic CD4(+) or CD8(+) T cells on their own were poor inducers of colitis, whereas the combination of both was highly involved in the induction of intestinal inflammation. Furthermore, we show that the tissue origin of CD3(+) T cells is critical for their potency to induce colitis.
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| 3. |
- Block, Mattias, 1968, et al.
(författare)
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Neoplasia in the colorectal specimens of patients with ulcerative colitis and ileal pouch-anal anastomosis - need for routine surveillance?
- 2015
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Ingår i: Scandinavian journal of gastroenterology. - : Informa UK Limited. - 1502-7708 .- 0036-5521. ; 50:5, s. 528-35
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Tidskriftsartikel (refereegranskat)abstract
- Patients who undergo ileal pouch-anal anastomosis (IPAA) after colectomy for ulcerative colitis (UC) occasionally have neoplasia in the IPAA. Patients with evidence of dysplasia or carcinoma in the colorectal specimen may have an increased risk of such neoplasia. A surveillance program has been suggested. The aims of this study were to evaluate the outcomes of surveillance of a large patient cohort, and to investigate the prevalences of neoplasia in the ileal pouch mucosa and in the anal transitional zone (ATZ).
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| 4. |
- Odin, Elisabeth, 1955, et al.
(författare)
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Altered gene expression of folate enzymes in adjacent mucosa is associated with outcome of colorectal cancer patients.
- 2003
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Ingår i: Clinical cancer research : an official journal of the American Association for Cancer Research. - 1078-0432 .- 1557-3265. ; 9:16 Pt 1, s. 6012-9
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: The purpose of this study was to analyze whether gene expression levels of folate enzymes in adjacent mucosa were associated with outcome of colorectal cancer patients. EXPERIMENTAL DESIGN: Real-time PCR was used to quantify expression levels of folate-associated genes including the reduced folate carrier (RFC-1), folylpolyglutamate synthase (FPGS), gamma-glutamyl hydrolase (GGH),and thymidylate synthase (TS) in tumor tissue and adjacent mucosa of patients with primary colorectal cancer (n=102). Furthermore, reduced folates in the tissues were measured with a binding-assay method. RESULTS: Mean gene expression levels of RFC-1, FPGS, GGH, and TS were significantly higher in tumor biopsies compared with mucosa. Univariate and multivariate analyses showed that the FPGS gene expression level in mucosa, but not in tumor, was a prognostic parameter independent of the clinicopathological factors with regard to survival. Patients with high FPGS levels (>0.92) in mucosa also showed significantly higher total folate concentrations (P=0.03) and gene expression levels of RFC-1 (P<0.01), GGH (P<0.01), and TS (P=0.04) compared with patients with low FPGS levels. The total reduced folate concentration correlated with the gene expression levels of RFC-1 and FPGS but not with TS or GGH. CONCLUSION: Our results suggest that normal-appearing colonic mucosa adjacent to primary colon cancer can show altered gene expression levels of FPGS that may have bearing on the development of aggressive metastatic behavior of the tumor and on tumor-specific survival.
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| 5. |
- Odin, Elisabeth, 1955, et al.
(författare)
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Expression and clinical significance of methylenetetrahydrofolate reductase in patients with colorectal cancer
- 2006
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Ingår i: Clin Colorectal Cancer. - 1533-0028. ; 5:5, s. 344-9
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The aim of the study was to investigate the influence of methylenetetrahydrofolate reductase (MTHFR) gene expression levels and MTHFR polymorphism C677T on the outcome of patients with colorectal cancer (CRC). Furthermore, we wanted to evaluate the interaction between MTHFR and thymidylate synthase (TS) and folylpolyglutamate synthase (FPGS) and to investigate the impact of folate concentration on patients with CRC with different MTHFR genotypes. PATIENTS AND METHODS: The frequency of MTHFR polymorphism C677T was determined (n = 147), and gene expression levels of MTHFR, TS, and FPGS were quantified with real-time polymerase chain reaction (n = 157). Reduced folates in tissue were measured with a binding assay (n = 40). RESULTS: We observed a significantly lower concentration of tetrahydrofolate (THF) in patients with CT or TT genotypes compared with patients having the CC genotype. Twenty-six patients with Dukes A to C tumors who had not been subjected to chemotherapy relapsed. Out of these, 18 had CT or TT genotypes, and only 8 had the CC genotype (P = 0.045). Furthermore, 75 patients did not relapse, and out of these, 35 had CT or TT genotypes, and 40 had the CC genotype. The relative gene expression level of MTHFR in patients subgrouped by CC and CT or TT genotypes was significantly lower in carcinomas compared with adjacent mucosa (P < 0.0001 and P < 0.0001, respectively). A significant difference in MTHFR expression level was also observed according to MTHFR genotype in the tumor but not in adjacent mucosa. The MTHFR gene expression level in mucosa was a prognostic parameter independent of the clinicopathologic factors with regard to survival for patients with MTHFR C677T mutation. CONCLUSION: Our results showed that it is possible to identify patients with CRC with a higher risk for relapse. Furthermore, patients with a mutant genotype in combination with low MTHFR expression have a poor clinical outcome.
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| 7. |
- Wettergren, Yvonne, 1957, et al.
(författare)
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Low expression of reduced folate carrier-1 and folylpolyglutamate synthase correlates with lack of a deleted in colorectal carcinoma mRNA splice variant in normal-appearing mucosa of colorectal carcinoma patients
- 2005
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Ingår i: Cancer Detect Prev. - : Elsevier BV. - 0361-090X .- 1525-1500. ; 29:4, s. 348-55
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Cellular folate deficiency leads to DNA strand breaks, mutations, and aberrant methylation and might be a risk factor for colorectal cancer (CRC). The putative tumor suppressor gene deleted in colorectal carcinoma (DCC) is one of several genes the expression of which seems to be affected by the folate concentration at the tissue level. Decreased expression of DCC may be caused by LOH or hypermethylation, i.e. by events that might be linked to folate deficiency. The purpose of this study was to analyze if the folate level and the gene expression levels of reduced folate carrier (RFC-1) and folylpolyglutamate synthase (FPGS) had impact on the expression of DCC splice variants. METHODS: Quantification of RFC-1 and FPGS expression in mucosa of 53 CRC patients was performed using real-time PCR whereas DCC splicing variants were detected by automated capillary gel electrophoresis. Total reduced folate concentration was measured with the FdUMP-binding assay (n = 22). RESULTS: Significantly higher expression levels of RFC-1 (p = 0.026) and FPGS (p = 0.05) were found in mucosa expressing the splice variant DCC342 compared to mucosa that did not. Furthermore, multivariate analysis showed that RFC-1 and FPGS (r = 0.49, p = 0.01) as well as folate and RFC-1 (r = 0.56, p = 0.023) were correlated only in mucosa expressing DCC342. CONCLUSIONS: In conclusion, the present study points to a potential influence of folates in regulating DCC expression at multiple levels involving post-transcriptional pathways. The results may provide a basis for a detailed investigation of molecular mechanisms involved in folate regulation of DCC expression.
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| 8. |
- Willén, Roger, 1939, et al.
(författare)
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Prophylactic surgery for patients with longstanding ulcerative colitis. Which option? Histopathological and clinical implications.
- 2007
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Ingår i: Upsala journal of medical sciences. - 2000-1967 .- 0300-9734. ; 112:1, s. 49-60
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Tidskriftsartikel (refereegranskat)abstract
- Patients with longstanding chronic ulcerative proctocolitis are at risk to develop colorectal cancer Conflicting views as regards surveillance, the indications for surgery and type of preventive procedure exist. For permanent prevention of cancer development complete removal of all potential malignant colorectal mucosa has to be done. Panprocto-colectomy with a conventional ileostomy or continent ileostomy removing all colorectal mucosa should therefore eliminate further risks of colorectal cancer. Colectomy and ileorectal anastomosis is a controversial issue. While many surgeons today are reluctant to use the technique, emphasising the persistent cancer risk, others consider the operation a viable alternative when used on a selective basis. The long-term risk of cancer in the rectal stump is the main strong argument . In restorative proctocolectomy, i.e. proctocolectomy with construction of an ileopouch anal anastomosis residual rectal mucosa is left behind irrespective of technique used and is therefore at risk for cancer development. Quite a few cancers have been reported to occur in these patients but controversy exists as regards the origin of these tumours but the risk for cancer development is very low. Biopsies from ileal pouches demonstrate various histopathological changes from nearly normal mucosa, to inflammation and atrophy, inflammatory cell changes, dysplasia as well as development of carcinoma. Grading of type and atypia is a challenge to reproduce and requires the participation of experienced gastrointestinal histopathologists.
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