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61.
  • Isaksson-Mettävainio, Martin, et al. (författare)
  • c-Met expression in primary tumors and their corresponding distant metastases
  • 2009
  • Ingår i: Molecular Medicine Reports. - Umeå. - 1791-2997. ; 1:6, s. 787-790
  • Tidskriftsartikel (refereegranskat)abstract
    • c-Met is a receptor tyrosine kinase that has beenimplicated in the pathogenesis and growth of a wide variety ofhuman malignancies, including CRC, but its role in metastasisis largely unknown. We compared c-Met expression in primaryhuman colorectal carcinomas and distant metastases from thesame patients. Formalin-fixed paraffin-embedded tissuesamples from 69 colorectal cancer patients were obtained. Theprotein expression of c-Met was evaluated immunohistochemicallyusing a commercial antibody. The difference inexpression between primary tumors and their correspondingdistant metastases was analyzed using the Wilcoxon signedranktest. c-Met expression was statistically significantlylower in the distant metastases compared to their correspondingprimary tumors (p<0.001), whereas no difference was foundbetween lymph node metastases and their correspondingprimary tumors (p=0.957). The degree of c-Met expressionwas not related to clinicopathological characteristics such astumor grade and Dukes' stage at the time of primary tumordiagnosis, or to the location of the distant metastases. Wedemonstrated that c-Met expression is often reduced in distantmetastases compared to their corresponding primary colorectaltumors. Additional studies of c-Met activation and signaltransduction will increase our knowledge about the role ofc-Met in colorectal cancer metastasis.
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62.
  • Isaksson-Mettävainio, Martin, et al. (författare)
  • High SMAD4 levels appear in MSI and hypermethylated colon cancers, and indicate a better prognosis
  • 2012
  • Ingår i: International Journal of Cancer. - Geneve : International union against cancer. - 0020-7136. ; 131, s. 779-788
  • Tidskriftsartikel (refereegranskat)abstract
    • Colorectal cancer (CRC) is one of the most common causes of cancer related deaths in western countries. CRC are commonly divided in cancers showing microsatellite stability (MSS) or microsatellite instability (MSI). A more novel classification is dependent on promoter hypermethylation of CpG islands (the CpG island methylator phenotype, CIMP), where cancers show high, low or negative methylation status. SMAD4, located on chromosome 18q, has been thoroughly investigated during the last years. Loss of SMAD4 expression has been reported to correlate with poor CRC patient prognosis. In this study we analyze the impact of SMAD4 expression on prognosis in relation to MSI screening status and CIMP status. 479 paraffin-embedded specimens of CRC were examined for nuclear SMAD4 expression using immunohistochemistry. The tumors were scored loss (-), moderate (+) and high (++) expressing tumors. Loss of SMAD4 correlated significantly with decreased survival in all colon cancer patients. High SMAD4 expression, on the other hand, was significantly associated with increased survival, especially in colon cancer patients which has undergone potential curative surgery. In addition, in MSI tumors and CIMP-high tumors, high SMAD4 expression was significantly related to increase in survival, while loss of SMAD4 resulted in a significantly poorer prognosis. SMAD4 expression was not correlated to prognosis in rectal cancer cases. We conclude, loss of SMAD4 indicates a poor prognosis in colon cancer patients. The novel findings that high SMAD4 expression predicts a better prognosis suggests that SMAD4 immunohistochemistry could constitute a prognostic marker in combination with CIMP and MSI screening status.
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63.
  • Jenab, Mazda, et al. (författare)
  • Association between pre-diagnostic circulating vitamin D concentration and risk of colorectal cancer in European populations : a nested case-control study
  • 2010
  • Ingår i: BMJ. British Medical Journal (International Ed.). - BMJ Publishing Group. - 0959-8146. ; 340, s. b5500
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: To examine the association between pre-diagnostic circulating vitamin D concentration, dietary intake of vitamin D and calcium, and the risk of colorectal cancer in European populations. DESIGN: Nested case-control study. Setting The study was conducted within the EPIC study, a cohort of more than 520 000 participants from 10 western European countries. PARTICIPANTS: 1248 cases of incident colorectal cancer, which developed after enrolment into the cohort, were matched to 1248 controls MAIN OUTCOME MEASURES: Circulating vitamin D concentration (25-hydroxy-vitamin-D, 25-(OH)D) was measured by enzyme immunoassay. Dietary and lifestyle data were obtained from questionnaires. Incidence rate ratios and 95% confidence intervals for the risk of colorectal cancer by 25-(OH)D concentration and levels of dietary calcium and vitamin D intake were estimated from multivariate conditional logistic regression models, with adjustment for potential dietary and other confounders. RESULTS: 25-(OH)D concentration showed a strong inverse linear dose-response association with risk of colorectal cancer (P for trend <0.001). Compared with a pre-defined mid-level concentration of 25-(OH)D (50.0-75.0 nmol/l), lower levels were associated with higher colorectal cancer risk (<25.0 nmol/l: incidence rate ratio 1.32 (95% confidence interval 0.87 to 2.01); 25.0-49.9 nmol/l: 1.28 (1.05 to 1.56), and higher concentrations associated with lower risk (75.0-99.9 nmol/l: 0.88 (0.68 to 1.13); >or=100.0 nmol/l: 0.77 (0.56 to 1.06)). In analyses by quintile of 25-(OH)D concentration, patients in the highest quintile had a 40% lower risk of colorectal cancer than did those in the lowest quintile (P<0.001). Subgroup analyses showed a strong association for colon but not rectal cancer (P for heterogeneity=0.048). Greater dietary intake of calcium was associated with a lower colorectal cancer risk. Dietary vitamin D was not associated with disease risk. Findings did not vary by sex and were not altered by corrections for season or month of blood donation. CONCLUSIONS: The results of this large observational study indicate a strong inverse association between levels of pre-diagnostic 25-(OH)D concentration and risk of colorectal cancer in western European populations. Further randomised trials are needed to assess whether increases in circulating 25-(OH)D concentration can effectively decrease the risk of colorectal cancer.
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64.
  • Jenab, Mazda, et al. (författare)
  • Association of nut and seed intake with colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition.
  • 2004
  • Ingår i: Cancer Epidemiology Biomarkers & Prevention. - 1055-9965. ; 13:10, s. 1595-603
  • Tidskriftsartikel (refereegranskat)abstract
    • A link between unsaturated fatty acids or phytonutrients and reduced risk of colorectal cancer has been suggested. However, the effects of higher intake of dietary sources of these nutrients, such as the nuts and seeds food group, are less clear. The objective of this study was to determine the effects of nut and seed intake on colorectal cancer risk within the European Prospective Investigation into Cancer and Nutrition study, a large prospective cohort study involving 10 European countries. Total nut and seed intake was determined from country-specific dietary questionnaires. The data set included 478,040 subjects (141,988 men, 336,052 women) with a total of 855 (327 men, 528 women) colon and 474 (215 men, 259 women) rectal cancer cases. A multivariate Cox proportional hazards model, stratified by center and controlled for fruit intake, dietary fiber, energy, height, weight, sex, age, physical activity, and smoking, was used. The data show no association between higher intake of nuts and seeds and risk of colorectal, colon, and rectal cancers in men and women combined, but a significant inverse association was observed in subgroup analyses for colon cancer in women at the highest (>6.2 g/d) versus the lowest (nonconsumers; hazard ratio, 0.69;, 95% confidence interval, 0.50-0.95) category of intake and for the linear effect of log-transformed intake (hazard ratio, 0.89; 95% confidence interval, 0.80-0.98), with no associations in men. It is not evident from this data why there may be a stronger association in women or why it may be limited to the colon, suggesting that much, further research is necessary.
65.
  • Jenab, Mazda, et al. (författare)
  • Consumption and portion sizes of tree nuts, peanuts and seeds in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohorts from 10 European countries
  • 2006
  • Ingår i: British Journal of Nutrition. - Cambridge : Cambridge University Press. - 0007-1145. ; 96:S2, s. 12-23
  • Tidskriftsartikel (refereegranskat)abstract
    • Tree nuts, peanuts and seeds are nutrient dense foods whose intake has been shown to be associated with reduced risk of some chronic diseases. They are regularly consumed in European diets either as whole, in spreads or from hidden sources (e.g. commercial products). However, little is known about their intake profiles or differences in consumption between European countries or geographic regions. The objective of this study was to analyse the population mean intake and average portion sizes in subjects reporting intake of nuts and seeds consumed as whole, derived from hidden sources or from spreads. Data was obtained from standardised 24-hour dietary recalls collected from 36 994 subjects in 10 different countries that are part of the European Prospective Investigation into Cancer and Nutrition (EPIC). Overall, for nuts and seeds consumed as whole, the percentage of subjects reporting intake on the day of the recall was: tree nuts=4 center dot 4%, peanuts=2 center dot 3 % and seeds=1 center dot 3 %. The data show a clear northern (Sweden: mean intake=0 center dot 15 g/d, average portion size=15 center dot 1 g/d) to southern (Spain: mean intake=2 center dot 99 g/d, average portion size=34 center dot 7 g/d) European gradient of whole tree nut intake. The three most popular tree nuts were walnuts, almonds and hazelnuts, respectively. In general, tree nuts were more widely consumed than peanuts or seeds. In subjects reporting intake, men consumed a significantly higher average portion size of tree nuts (28 center dot 5 v. 23 center dot 1 g/d, P < 0 center dot 01) and peanuts (46 center dot 1 v. 35 center dot 1 g/d, P < 0 center dot 01) per day than women. These data may be useful in devising research initiatives and health policy strategies based on the intake of this food group.
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66.
  • Jenab, Mazda, et al. (författare)
  • Serum C-peptide, IGFBP-1 and IGFBP-2 and risk of colon and rectal cancers in the European Prospective Investigation into Cancer and Nutrition.
  • 2007
  • Ingår i: International Journal of Cancer. - 0020-7136. ; 121:2, s. 368-76
  • Tidskriftsartikel (refereegranskat)abstract
    • Western style diets and lifestyles are associated with increasing rates of obesity, diabetes and insulin resistance. Higher circulating insulin levels may modulate cell proliferation and apoptosis either directly or indirectly by increasing the bioactivity of IGF-I and decreasing the bioactivity of some of its binding proteins. The objective of this study was to determine the association of increasing levels of serum C-peptide, a biomarker of pancreatic insulin secretion, and IGF binding proteins (IGFBP) -1 and -2 with colorectal cancer risk in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC), a large cohort involving 10 Western European countries. A total of 1,078 colorectal cancer cases were matched (age, date of blood donation, fasting status, gender, study center) to an equal number of control subjects. Relative cancer risks were estimated using conditional logistic regression models. Serum C-peptide concentration was positively associated with an increased colorectal cancer risk for the highest versus the lowest quintile (OR = 1.56, 95% CI = 1.16-2.09, p(trend) < 0.01), which was slightly attenuated after adjustment for BMI and physical activity (OR = 1.37, 95% CI = 1.00-1.88, p(trend) = 0.10). When stratified by anatomical site, the cancer risk was stronger in the colon (OR 1.67, 95% CI = 1.14-2.46, p(trend) < 0.01) than in the rectum (OR 1.42, 95% CI = 0.90-2.25, p(trend) = 0.35). The cancer risk estimates were not heterogeneous by gender or fasting status. No clear colorectal cancer risk associations were observed for IGFBP-1 or -2. This large prospective study confirms that hyperinsulinemia, as determined by C-peptide levels, is associated with an increased colorectal cancer risk. (C) 2007 Wiley-Liss, Inc.
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67.
  • Jenab, Mazda, et al. (författare)
  • Vitamin D receptor and Calcium sensing receptor Polymorphisms and the risk of Colorectal Cancer in European populations
  • 2009
  • Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - American Association for Cancer Research. - 1055-9965. ; 18, s. 2485-2491
  • Tidskriftsartikel (refereegranskat)abstract
    • Increased levels of vitamin D and calcium may play a protective role in colorectal cancer (CRC) risk. It has been suggested that these effects may be mediated by genetic variants of the vitamin D receptor (VDR) and the calcium sensing receptor (CASR). However, current epidemiologic evidence from European populations for a role of these genes in CRC risk is scarce. In addition, it is not clear whether these genes may modulate CRC risk independently or by interaction with blood vitamin D concentration and level of dietary calcium intake. A case-control study was conducted nested within the European Prospective Investigation into Cancer and Nutrition. CRC cases (1,248) were identified and matched to 1,248 control subjects. Genotyping for the VDR (BsmI: rs1544410; Fok1: rs2228570) and CASR (rs1801725) genes was done by Taqman, and serum vitamin D (25OHD) concentrations were measured. Conditional logistic regression was used to estimate the incidence rate ratio (RR). Compared with the wild-type bb, the BB genotype of the VDR BsmI polymorphism was associated with a reduced risk of CRC [RR, 0.76; 95% confidence interval (CI), 0.59-0.98). The association was observed for colon cancer (RR, 0.69; 95% CI, 0.45-0.95) but not rectal cancer (RR, 0.97; 95% CI, 0.62-1.49). The Fok1 and CASR genotypes were not associated with CRC risk in this study. No interactions were noted for any of the polymorphisms with serum 25OHD concentration or level of dietary calcium. These results confirm a role for the BsmI polymorphism of the VDR gene in CRC risk, independent of serum 25OHD concentration and dietary calcium intake. (Cancer Epidemiol Biomarkers Prev 2009;18(9):2485-91).
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68.
  • Jones, Dylan T, et al. (författare)
  • Albumin activates the AKT signaling pathway and protects B-chronic lymphocytic leukemia cells from chlorambucil- and radiation-induced apoptosis.
  • 2003
  • Ingår i: Blood. - 0006-4971. ; 101:8, s. 3174-80
  • Tidskriftsartikel (refereegranskat)abstract
    • Activation of the phosphatidylinositol 3- kinase/AKT pathway antagonizes apoptosis in diverse cellular systems. We previously showed that human plasma activated AKT and potently blocked the ability of chlorambucil or gamma radiation to induce apoptosis of B-chronic lymphocytic leukemia (CLL) cells. Here we report experiments that identify albumin as the major component of plasma that blocks CLL cell killing by chlorambucil or radiation. Intact plasma depleted of albumin by chromatography on Cibacron blue-Sepharose or plasma from a subject with analbuminemia failed either to activate AKT or to protect CLL cells from chlorambucil-induced apoptosis. Both functions were restored by re-addition of albumin. The protective action of albumin as well as AKT activation was compromised by the binding of lipids. Fluorescence-activated cell sorter (FACScan) analysis demonstrated the uptake of fluoresceinated albumin by CLL cells. Accumulation of albumin in intracellular vesicles was also shown by confocal microscopy. Indirect inhibition of AKT activation by the phosphatidylinositol 3-kinase inhibitor LY294002 reversed the blockade of chlorambucil-induced killing by plasma albumin. The data suggest that activation of AKT consequent to binding of albumin by CLL cells blocks chlorambucil- and radiation-induced apoptosis. Strategies designed to block albumin-induced antiapoptotic signaling may, therefore, be of value in enhancing cytotoxic drug action on CLL cells.
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69.
  • Kaaks, Rudolf, et al. (författare)
  • Insulin-like Growth Factor-II Methylation Status in Lymphocyte DNA and Colon Cancer Risk in the Northern Sweden Health and Disease Cohort
  • 2009
  • Ingår i: Cancer Research. - 0008-5472. ; 69:13, s. 5400-5405
  • Tidskriftsartikel (refereegranskat)abstract
    • Loss of imprinting (LOI) of the insulin-like growth factor II (IGFII) gene is a frequent phenomenon in colorectal tumor tissues. Previous reports indicated that subjects with colorectal neoplasias show LOI of IGFII in circulating lymphocytes. Furthermore, LOI of IGFII is strongly related to the methylation of a differentially methylated region (DMR) in intron 2 of IGFII, suggesting that the methylation status could serve as a biomarker for early detection. Thus, hypermethylation of this DMR, even at a systemic level, e.g., in lymphocyte DNA, could be used for screening for colon cancer. To validate this, we performed a case-control study of 97 colon cancer cases and 190 age-matched and gender-matched controls, nested within the prospective Northern Sweden Health and Disease Study cohort. Methylation levels of the IGFII-DMR in lymphocyte DNA were measured at two specific CpG sites of the IGFII-DMR using a mass-spectrometric method called short oligonucleotide mass analysis, the measurements of which showed high reproducibility between replicate measurements for the two CpG sites combined and showed almost perfect validity when performed on variable mixtures of methylated and unmethylated standards. Mean fractions of CpG methylation, for the two CpG sites combined, were identical for cases and controls (0.47 and 0.46, respectively; Pdifference = 0.75), and logistic regression analyses showed no relationship between colon cancer risk and quartile levels of CpG methylation. The results from this study population do not support the hypothesis that colon cancer can be predicted from the different degrees of methylation of DMR in the IGFII gene from lymphocyte DNA. [Cancer Res 2009;69(13):5400-5].
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70.
  • Karling, Pontus, et al. (författare)
  • Improved monitoring of inflammatory activity in patients with ulcerative colitis by combination of faecal tests for haemoglobin and calprotectin
  • 2019
  • Ingår i: Scandinavian Journal of Clinical and Laboratory Investigation. - Taylor & Francis. - 0036-5513. ; 79:5, s. 341-346
  • Tidskriftsartikel (refereegranskat)abstract
    • Faecal calprotectin (FC) tests and faecal immunological tests (FIT) for haemoglobin have been used to monitor disease activity in patients with ulcerative colitis (UC) but used alone they have some limitation concerning the predictive ability. We aimed to test if an FC test used in combination with FIT could improve the predictive ability. Consecutive out-patients with UC (n = 93) who were admitted for colonoscopy completed a single faecal sample before the start of bowel preparation. A quantitative CALPRO (R) calprotectin ELISA test and a qualitative FIT (cut-off &lt; 40 ng/mL) were analyzed. An estimated Mayo score and a score of histological inflammation was performed blinded to the result of the faecal tests. The sensitivity, specificity, negative predictive value and positive predictive value for endoscopic inflammation (Mayo score &gt; 1) was for FIT 85%, 83%, 96%, 57% and for FC &gt; 186 mu g/g 73%, 87%, 87%, 54%. Corresponding results for FIT*FC &gt; 186 mu g/g (at least one test positive) were 92%, 69%, 97%, 43%. For detecting moderate/severe histological inflammation the results were for FIT 69%, 79%, 92%, 43%, for FC &gt; 75 mu g/g 95%, 62%, 98%, 41%, and for FIT*FC &gt; 75 mu g/g 100%, 60%, 100%, 36%. None of the markers alone or in combination were useful to predict deep remission (Mayo score = 0 and no histological inflammation). We conclude that using the combination of an FC test and FIT shows minor improvement in predictive ability for inflammatory activity and remission in patients with UC.
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