| 46431. |
- Lindmark, F, et al.
(författare)
-
H6D polymorphism in macrophage-inhibitory cytokine-1 gene associated with prostate cancer
- 2004
-
Ingår i: Journal of the National Cancer Institute. - Umea Univ, Dept Radiat Sci Oncol, S-90187 Umea, Sweden. Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. Umea Univ Hosp, Dept Urol & Androl, S-90185 Umea, Sweden. Wake Forest Univ, Sch Med, Ctr Human Genomics, Winston Salem, NC 27109 USA. Johns Hopkins Med Inst, Dept Urol, Baltimore, MD 21205 USA. : OXFORD UNIV PRESS INC. - 0027-8874 .- 1460-2105. ; 96:16, s. 1248-1254
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Accumulating epidemiologic and molecular evidence suggest that inflammation is an important component in the etiology of prostate cancer. Macrophage-inhibitory cytokine-1 (MIC-1), a member of the transforming growth factor beta superfamily, is thought to play an important role in inflammation by regulating macrophage activity. We examined whether sequence variants in the MIC-1 gene are associated with the risk of prostate cancer. Methods: The study population, a population-based case-control study in Sweden, consisted of 1383 prostate cancer case patients and 780 control subjects. From 94 of the control subjects, we constructed gene-specific haplotypes of MIC-1 and identified four haplotype-tagging single-nucleotide polymorphisms (SNPs): Exon1+25 (V9L), Exon1+142 (S48T), IVS1+1809, and Exon2+2423 (H6D). All study subjects were genotyped for the four SNPs, and conditional logistic regression analysis was used to estimate odds ratios (ORs) with 95% confidence intervals (CIs). Results: A statistically significant difference (P = .006) in genotype frequency was observed for the nonsynonymous change H6D) (histidine to aspartic acid at position 6) between prostate cancer patients and control subjects. Carriers of the GC genotype, which results in the H6D change, experienced a lower risk of sporadic prostate cancer (OR = 0.80, 95% CI = 0.66 to 0.97) and of familial prostate cancer (OR = 0.61, 95% CI = 0.42 to 0.89) than the CC genotype carriers. In the study population, the proportion of prostate cancer cases attributable to the CC genotype was 7.2% for sporadic cancer and 19.2% for familial cancer. None of the other SNPs or haplotypes was associated with prostate cancer. Conclusion: This study shows an association between a nonsynonymous change (H6D) in the MIC-1 gene and prostate cancer. This finding supports the hypothesis that genetic variation in the inflammatory process contributes to prostate cancer susceptibility.
|
|
| 46432. |
- Lindmark, F, et al.
(författare)
-
Interleukin-1 receptor antagonist haplotype associated with prostate cancer risk
- 2005
-
Ingår i: British Journal of Cancer. - Umea Univ, Dept Radiat Sci Oncol, S-90187 Umea, Sweden. Wake Forest Univ, Bowman Gray Sch Med, Ctr Human Genom, Winston Salem, NC USA. Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. Johns Hopkins Med Inst, Dept Urol, Baltimore, MD 21205 USA. Orebro Univ Hosp, Dept Urol & Clin Med, Orebro, Sweden. Univ Hosp, Reg Oncol Ctr, Uppsala, Sweden. : NATURE PUBLISHING GROUP. - 0007-0920 .- 1532-1827. ; 93:4, s. 493-497
-
Tidskriftsartikel (refereegranskat)abstract
- IL1-RN is an important anti-inflammatory cytokine that modulate the inflammation response by binding to IL1 receptors, and as a consequence inhibits the action of proinflammatory cytokines IL1 alpha and IL1 beta. In this study, we hypothesise that sequence variants in the IL1-RN gene are associated with prostate cancer risk. The study population, a population-based case - control study in Sweden, consisted of 1383 prostate cancer case patients and 779 control subjects. We first selected 18 sequence variants covering the IL1-RN gene and genotyped these single-nucleotide polymorphisms ( SNPs) in 96 control subjects. Gene-specific haplotypes of IL1-RN were constructed and four haplotype-tagging single-nucleotide polymorphisms (htSNPs) were identified (rs878972, rs315934, rs3087263 and rs315951) that could uniquely describe 495% of the haplotypes. All study subjects were genotyped for the four htSNPs. No significant difference in genotype frequencies between cases and controls were observed for any of the four SNPs based on a multiplicative genetic model. Overall there was no significant difference in haplotype frequencies between cases and controls; however, the prevalence of the most common haplotype (ATGC) was significantly higher among cases (38.7%) compared to controls (33.5%) ( haplotype-specific P = 0.009). Evaluation of the prostate cancer risk associated with carrying the 'ATGC' haplotype revealed that homozygous carriers were at significantly increased risk ( odds ratio (OR) = 1.6, 95% confidence interval (CI) = 1.2 - 2.2), compared to noncarriers, while no significant association was found among subjects heterozygous for the haplotype ( OR = 1.0, 95% CI = 0.8 - 1.2). Restricting analyses to advanced prostate cancer strengthened the association between the 'ATGC' haplotype and disease risk (OR for homozygous carriers vs noncarriers 1.8, 95% CI = 1.3 - 2.5). In conclusion, the results from this study support the hypothesis that inflammation has a role of in the development of prostate cancer, but further studies are needed to identify the causal variants in this region and to elucidate the biological mechanism for this association.
|
|
| 46433. |
- Lindmark, Fredrik, 1973-
(författare)
-
Prostate cancer and inflammatory genes
- 2005
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Prostate cancer remains a significant health concern for men throughout the world. Accumulating epidemiologic and molecular evidence suggests that inflammation is an important component in the aetiology of prostate cancer. Supporting this hypothesis, population studies have found an increased risk of prostate cancer in men with a prior history of certain sexually transmitted infections or prostatitis. More general evidence of a relationship between inflammation and prostate cancer has been provided by reports indicating that daily use of non steroidal anti-inflammatory drugs (NSAIDs) may be associated with a lower incidence of prostate cancer. The exact mechanism whereby inflammation might act in tumour development and progression remains to be elucidated, but is likely to be complex. The genetic contribution to inflammatory responses involved in the development of prostate cancer has not yet been extensively or systematically studied. However, this thesis evaluates the role of various inflammation-related genes in the pathogenesis of prostate cancer. The macrophage scavenger receptor 1 (MSR1) is a transmembrane protein that is mainly expressed by macrophages. This receptor mediates the binding, internalization and processing of a wide range of macromolecules, and is suggested to play a major role in the recognition and clearance of pathogenic and damaged cells. Recent reports have suggested MSR1 to be a candidate gene for hereditary prostate cancer. Therefore, we screened the MSR1 gene among men with hereditary prostate cancer and identified 18 sequence variants. One previously reported truncation mutation was found more frequently in men with prostate cancer than in unaffected men, in accordance with previously published results. However, the difference in frequencies we found between these groups was not statistically significant. In addition, we genotyped five common polymorphisms in MSR1 in 215 men with unselected prostate cancer and 425 controls. No association between any of the five common variants and prostate cancer were found. We then performed a comprehensive genetic study using extensive populationbased case-control material to evaluate possible associations between sequence variants in inflammation-related genes and prostate cancer. The first gene to be examined was interleukin-1 receptor antagonist (IL-1-RN), encoding a cytokine that plays an important role in regulation of the inflammatory response by binding to the IL-1 receptor and thus inhibiting the binding of the pro-inflammatory cytokines IL-1α and IL-1β. Collectively, these three cytokines exert a central role in the protection against diverse lesions, ranging from microbial colonisation to infection and malignant transformation. The genetic analysis of IL-1RN revealed that the most common haplotype was significantly associated with prostate cancer risk for patients with prostate cancer, and further this association appears to be stronger in cases with advanced disease. The macrophage inhibitory cytokine-1 (MIC-1), a member of the transforming growth-factor-β superfamily has been shown to exert diverse biological functions, including regulation of macrophage activity in the inflammatory response and both growth inhibition and induction of apoptosis in epithelial and other tumour cell lines. The genetic analysis of MIC-1 revealed that a seuqence variant (H6D) appears to be associated with a decreased prostate cancer risk. We also performed measurements of MIC-1 serum levels among patients with prostate cancer and healthy controls. These data indicate that serum MIC-1 levels are associated with an increased risk for prostate cancer. Further, the clear relation between clinical stage and MIC-1 level also suggest that MIC-1 may be useful as a prognostic factor, where high serum concentration is associated with a poor prognosis. In summary, our results provide further support for the assumption that polymorphisms in inflammatory genes play critical roles in prostate cancer susceptibility. Additional studies are needed to elucidate the mechanisms whereby the demonstrated variations contribute to prostate cancer development.
|
|
| 46434. |
|
|
| 46435. |
- Lindmark, Gudrun, et al.
(författare)
-
qRT-PCR analysis of CEACAM5, KLK6, SLC35D3, MUC2 and POSTN in colon cancer lymph nodes : An improved method for assessment of tumor stage and prognosis
- 2024
-
Ingår i: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 154:3, s. 573-584
-
Tidskriftsartikel (refereegranskat)abstract
- One fourth of colorectal cancer patients having curative surgery will relapse of which the majority will die. Lymph node (LN) metastasis is the single most important prognostic factor and a key factor when deciding on postoperative treatment. Presently, LN metastases are identified by histopathological examination, a subjective method analyzing only a small LN volume and giving no information on tumor aggressiveness. To better identify patients at risk of relapse we constructed a qRT-PCR test, ColoNode, that determines levels of CEACAM5, KLK6, SLC35D3, MUC2 and POSTN mRNAs. Combined these biomarkers estimate the tumor cell load and aggressiveness allocating patients to risk categories with low (0, −1), medium (1), high (2) and very high (3) risk of recurrence. Here we present result of a prospective, national multicenter study including 196 colon cancer patients from 8 hospitals. On average, 21 LNs/patient, totally 4698 LNs, were examined by both histopathology and ColoNode. At 3-year follow-up, 36 patients had died from colon cancer or lived with recurrence. ColoNode identified all patients that were identified by histopathology and in addition 9 patients who were undetected by histopathology. Thus, 25% of the patients who recurred were identified by ColoNode only. Multivariate Cox regression analysis proved ColoNode (1, 2, 3 vs 0, −1) as a highly significant risk factor with HR 4.24 [95% confidence interval, 1.42-12.69, P =.01], while pTN-stage (III vs I/II) lost its univariate significance. In conclusion, ColoNode surpassed histopathology by identifying a significantly larger number of patients with future relapse and will be a valuable tool for decisions on postoperative treatment.
|
|
| 46436. |
- Lindmark, H, et al.
(författare)
-
Enteric bacteria counteract lipopolysaccharide induction of antimicrobial peptide genes.
- 2001
-
Ingår i: J Immunol. - 0022-1767. ; 167, s. 6920-6923
-
Tidskriftsartikel (refereegranskat)abstract
- The humoral immunity of Drosophila involves the production of antimicrobial peptides, which are induced by evolutionary conserved microbial molecules, like LPS. By using Drosophila mbn-2 cells, we found that live bacteria, including E. coli, Salmonella typhimurium, Erwinia carotovora, and Pseudomonas aeruginosa, prevented LPS from inducing antimicrobial peptide genes, while Micrococcus luteus and Streptococcus equi did not. The inhibitory effect was seen at bacterial levels from 20 per mbn-2 cell, while antimicrobial peptides were induced at lower bacterial concentrations (< or =2 bacteria per cell) also in the absence of added LPS. Gel shift experiment suggests that the inhibitory effect is upstream or at the level of the activation of the transcription factor Relish, a member of the NF-kappaB/Rel family. The bacteria have to be in physical contact with the cells, but not phagocytosed, to prevent LPS induction. Interestingly, the inhibiting mechanism is, at least for E. coli, independent of the type III secretion system, indicating that the inhibitory mechanism is unrelated to the one earlier described for YopJ from Yersinia.
|
|
| 46437. |
- Lindmark, Krister, et al.
(författare)
-
Epidemiology of heart failure and trends in diagnostic work-up : a retrospective, population-based cohort study in Sweden
- 2019
-
Ingår i: Clinical Epidemiology. - : Dove medical press. - 1179-1349 .- 1179-1349. ; 11, s. 231-244
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose: The purpose of this study was to examine the trends in heart failure (HF) epidemiology and diagnostic work-up in Sweden.Methods: Adults with incident HF (>= 2 ICD-10 diagnostic codes) were identified from linked national health registers (cohort 1, 2005-2013) and electronic medical records (cohort 2, 2010-2015; primary/secondary care patients from Uppsala and Vasterbotten). Trends in annual HF incidence rate and prevalence, risk of all-cause and cardiovascular disease (CVD)-related 1-year mortality and use of diagnostic tests 6 months before and after first HF diagnosis (cohort 2) were assessed.Results: Baseline demographic and clinical characteristics were similar for cohort 1 (N=174,537) and 2 (N=8,702), with mean ages of 77.4 and 76.6 years, respectively; almost 30% of patients were aged >= 85 years. From 2010 to 2014, age-adjusted annual incidence rate of HF/1,000 inhabitants decreased (from 3.20 to 2.91, cohort 1; from 4.34 to 3.33, cohort 2), while age-adjusted prevalence increased (from 1.61% to 1.72% and from 2.15% to 2.18%, respectively). Age-adjusted 1-year all-cause and CVD-related mortality was higher in men than in women among patients in cohort 1 (all-cause mortality hazard ratio [HR] men vs women 1.07 [95% CI 1.06-1.09] and CVD-related mortality subdistribution HR for men vs women 1.04 [95% CI 1.02-1.07], respectively). While 83.5% of patients underwent N-terminal pro-B-type natriuretic peptide testing, only 36.4% of patients had an echocardiogram at the time of diagnosis, although this increased overtime. In the national prevalent HF population (patients with a diagnosis in 1997-2004 who survived into the analysis period; N=273,999), death from ischemic heart disease and myocardial infarction declined between 2005 and 2013, while death from HF and atrial fibrillation/flutter increased (P<0.0001 for trends over time).Conclusion: The annual incidence rate of HF declined over time, while prevalence of HF has increased, suggesting that patients with HF were surviving longer over time. Our study confirms that previously reported epidemiological trends persist and remain to ensure proper diagnostic evaluation and management of patients with HF.
|
|
| 46438. |
|
|
| 46439. |
- Lindmark, Krister, et al.
(författare)
-
Long-term follow-up of mitral valve regurgitation : importance of mitral valve pathology and left ventricular function on survival
- 2009
-
Ingår i: International Journal of Cardiology. - : Elsevier BV. - 0167-5273 .- 1874-1754. ; 137:2, s. 145-150
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Timing of surgery for mitral regurgitation (MR) is one of the more difficult decisions for the practicing cardiologist. METHODS AND RESULTS: In order to determine useful clinical cut-offs, we investigated the influence of baseline echocardiographic predictors for survival in a long-time follow-up cohort. Data from 144 patients with MR were collected between 1989 and 1993. Five-year mortality for MR patients was 30% compared to 13% for age- and sex matched controls (p<0.001). Each mm increase in left ventricular end systolic diameter (LVESD increased mortality with 2.5% (p<0.05) and each percent decrease in ejection fraction (EF) increased mortality with 1.8% (p<0.05). These effects were not linear and this material suggests cut-off points for LVESD to be 40 mm and EF 50%. Degree of MR did not correlate with survival, but patients with severe MR were operated more often than those with moderate MR. Patients with functional MR had reduced survival compared to patients with structural MR (p<0.01). CONCLUSIONS: MR is a disease with greatly increased mortality and these data suggest a more aggressive approach to surgery.
|
|
| 46440. |
- Lindmark, Krister, et al.
(författare)
-
Natriuretic Peptides
- 2010
-
Ingår i: Heart Failure in Clinical Practice. - London : Springer London. - 9781849961523 - 9781849961530 ; , s. 309-318
-
Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- Natriuretic peptides are clinically used as biomarkers of heart failure and have in recent years become more and more valuable in the diagnosis of heart failure. B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-pro-BNP) have become commercially available, their accurate assays have been made, and their most widespread use has been achieved, although other natriuretic peptides can be of interest as well. The body of data supporting the use of BNP and NT-pro-BNP is steadily increasing. Low levels of BNP and NT-pro-BNP can, because of their high negative predictive values, be used to rule out heart failure, and high levels of these peptides predict a poor prognosis. There are, however, several pitfalls in the use of natriuretic peptides that one has to be aware of when using them in routine clinical practice. Many unanswered questions also remain to be resolved
|
|
