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- Shaw, DE, et al.
(författare)
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Clinical and inflammatory characteristics of the European U-BIOPRED adult severe asthma cohort
- 2015
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Ingår i: The European respiratory journal. - : European Respiratory Society (ERS). - 1399-3003 .- 0903-1936. ; 46:5, s. 1308-1321
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Tidskriftsartikel (refereegranskat)abstract
- U-BIOPRED is a European Union consortium of 20 academic institutions, 11 pharmaceutical companies and six patient organisations with the objective of improving the understanding of asthma disease mechanisms using a systems biology approach.This cross-sectional assessment of adults with severe asthma, mild/moderate asthma and healthy controls from 11 European countries consisted of analyses of patient-reported outcomes, lung function, blood and airway inflammatory measurements.Patients with severe asthma (nonsmokers, n=311; smokers/ex-smokers, n=110) had more symptoms and exacerbations compared to patients with mild/moderate disease (n=88) (2.5 exacerbations versus 0.4 in the preceding 12 months; p<0.001), with worse quality of life, and higher levels of anxiety and depression. They also had a higher incidence of nasal polyps and gastro-oesophageal reflux with lower lung function. Sputum eosinophil count was higher in severe asthma compared to mild/moderate asthma (median count 2.99% versus 1.05%; p=0.004) despite treatment with higher doses of inhaled and/or oral corticosteroids.Consistent with other severe asthma cohorts, U-BIOPRED is characterised by poor symptom control, increased comorbidity and airway inflammation, despite high levels of treatment. It is well suited to identify asthma phenotypes using the array of “omic” datasets that are at the core of this systems medicine approach.
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- Berggren de Verdier, P. J., et al.
(författare)
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Prognostic significance of homozygous deletions and multiple duplications at the CDKN2A (p16INK4a)/ARF (p14ARF) locus in urinary bladder cancer
- 2006
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Ingår i: Scand J Urol Nephrol. - : Informa UK Limited. - 0036-5599 .- 1651-2065. ; 40:5, s. 363-9
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The 9p21 locus is a major target in the pathogenesis of human urinary bladder cancer. This locus harbours the CDKN2A/ARF tumour suppressor gene, which encodes two cell-cycle regulatory proteins: p16INK4a and p14ARF. We studied how homozygous deletions and multiple duplications at this locus affect prognosis and survival in patients with bladder cancer. MATERIAL AND METHODS: Real-time quantitative polymerase chain reaction (QPCR), based on simultaneous amplification of ARF and a reference gene, glyceraldehyde-3-phosphate dehydrogenase, was used to measure homozygous deletions and multiple duplications in a population-based material consisting of 478 patients with urinary bladder cancer. Results from real-time QPCR were compared with clinico-pathological parameters and survival curves were generated using the Kaplan-Meier method. RESULTS: Real-time QPCR analysis showed 71 (15%) homozygous deletions and 8 (2%) multiple duplications. We were unable to find any association between either stage or grade and urinary neoplasms with homozygous deletions. However, although there were only a limited number of patients with multiple duplications, 7/8 of them had highly malignant tumours (G2b-G4 or > or = T1; p = 0.02). CONCLUSIONS: Urinary bladder cancers constitute a spectrum of neoplasms with varying clinical manifestations. We were unable to establish a prognostic relevance for patients with tumours harbouring homozygous deletions at the CDKN2A/ARF locus. However, our data did indicate that patients with multiple duplications at the CDKN2A/ARF locus had poor survival. This suggests that multiple duplications, in combination with other genetic changes, have cooperative effects which have a negative outcome on urinary bladder cancer prognosis.
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- Ryk, C., et al.
(författare)
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Influence of polymorphism in DNA repair and defence genes on p53 mutations in bladder tumours
- 2006
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Ingår i: Cancer Lett. - : Elsevier BV. - 0304-3835 .- 1872-7980. ; 241:1, s. 142-9
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Tidskriftsartikel (refereegranskat)abstract
- We studied the effects of polymorphisms in nine genes involved in DNA repair and detoxification on occurrence and type of p53 mutation in 327 bladder cancer patients. The included polymorphisms are XPC(Lys939Gln), XPD(Lys751Gln), XPG(Asp1104His), XRCC1(Arg3999Gln), XRCC3(Thr241Met), NBS1(Glu185Gln), cyclin D1(Pro241Pro), MTHFR(Ala222Val and Glu429Ala) and NQO1(Arg139Trp and Pro187Ser). We found increased risk for p53 mutation among cyclin D1 variant allele homozygotes (OR 2.4 CI 0.8-6.7). Among non-smokers, 75% (3/4) with p53 mutation but only 12.5% (3/24) without p53 mutations were XRCC3 241Met homozygotes (P=0.03). Among smokers, all p53 transversions (3/3), but only 41.7% (5/12) of p53 transitions were found among carriers of the XPC 939Gln allele. Individuals carrying the NQO1 187Ser allele showed increased risk for p53 transversions (OR 4.7, CI 0.9-26.1). All (2/2) NQO1 139Trp allele carriers but only 17.5% (7/40) of the Arg139 homozygotes had p53 transversions. Our findings suggest that altered repair and detoxification due to genetic polymorphism may influence the occurrence of p53 mutations in bladder cancer.
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- Ryk, C., et al.
(författare)
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The (CCTTT)n microsatellite polymorphism in the NOS2 gene may influence lung cancer risk and long-term survival, especially in non-smokers
- 2014
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Ingår i: Tumor Biology. - : Kluwer Academic Publishers. - 1010-4283 .- 1423-0380. ; 35:5, s. 4425-4434
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Tidskriftsartikel (refereegranskat)abstract
- We analyzed the associations of the NOS2 (CCTTT)n promoter polymorphism to lung cancer risk and tumor histology in smokers and non-smokers. We also investigated lung cancer long-term survival in relation to the polymorphism, smoking data, histology, age at diagnosis, and gender. One hundred eighty-five lung-cancer patients and 164 matched controls, where non-smokers were enriched among the lung cancer cases, were genotyped by fragment analysis and sequencing. Genotypes were combined with information on histology, patient smoking status, and cancer-specific death, using a 20-year follow-up. We divided the (CCTTT)n alleles into short (n≤10), intermediate (n=11-12), and long (n≥13). Patients homozygous for short repeats had significantly increased risk of lung cancer (p=0.030) compared to carriers of two long alleles (LL). Lack of long allele was associated with a significantly increased lung cancer risk overall (p=0.011), especially among non-smokers (p=0.001). A significantly higher lung cancer survival was seen in non-smokers compared to smokers (p=0.046) and in low-dose smokers compared to high-dose smokers at the time of diagnosis (p=0.028). Moreover, non-smoking patients with squamous cell carcinoma (p=0.015) or adenocarcinoma (p=0.024) showed a significantly lower survival compared to other lung carcinomas. Nitric oxide can induce proliferation as well as apoptosis depending on cellular context. Our results suggest that the (CCTTT)n NOS2 microsatellite may influence the risk of developing lung cancer, especially in non-smokers, possibly by affecting intracellular nitric oxide levels. Our results also give additional information about the yet poorly understood etiological and prognostic differences between lung cancer in non-smokers and smokers. © International Society of Oncology and BioMarkers (ISOBM) 2014.
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- Sanyal, S., et al.
(författare)
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Polymorphisms in XPD, XPC and the risk of death in patients with urinary bladder neoplasms
- 2007
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Ingår i: Acta Oncol. - : Informa UK Limited. - 0284-186X .- 1651-226X. ; 46:1, s. 31-41
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Tidskriftsartikel (refereegranskat)abstract
- We conducted a follow-up study on 311 patients with urinary bladder neoplasms to investigate the association of polymorphisms in DNA repair and cell growth regulatory genes with the clinical outcomes of this disease. We found that patients carrying the variant allele of XPD (K751Q) polymorphism were at lower risk of death (p = 0.04) than the noncarriers. Patients that were simultaneous carriers of variant alleles from XPD (K751Q) and XPC (K939Q) polymorphisms, showed lower risk of death than the other patients (p = 0.001). The variant allele carriers of MSH6 (G39E) polymorphism showed a higher risk for highly malignant disease (TaG3 +T1) than the non-carriers (p = 0.03). The variant allele carriers of XRCC1 (R399Q) polymorphism showed lower risk for recurrence (TaG2; p = 0.05) and death (T2+; p = 0.03) after instillation and radiotherapy than the non-carriers. After radiotherapy, an inverse association of the variant allele of OGG1 (S326C) polymorphism was observed with the risk of death (T2 +; p = 0.04). A significant low-risk for stage progression (p = 0.03) was observed in patients carrying the variant allele of H-ras (H27H) polymorphism. Our results are consistent with the notion that the XPD (K751Q) polymorphism either individually or in combination with the XPC (K939Q) polymorphism modulates the risk of death in patients with urinary bladder neoplasms.
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- Wu, Xifeng, et al.
(författare)
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Genetic variation in the prostate stem cell antigen gene PSCA confers susceptibility to urinary bladder cancer.
- 2009
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 41:9, s. 991-5
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Tidskriftsartikel (refereegranskat)abstract
- We conducted a genome-wide association study on 969 bladder cancer cases and 957 controls from Texas. For fast-track validation, we evaluated 60 SNPs in three additional US populations and validated the top SNP in nine European populations. A missense variant (rs2294008) in the PSCA gene showed consistent association with bladder cancer in US and European populations. Combining all subjects (6,667 cases, 39,590 controls), the overall P-value was 2.14 x 10(-10) and the allelic odds ratio was 1.15 (95% confidence interval 1.10-1.20). rs2294008 alters the start codon and is predicted to cause truncation of nine amino acids from the N-terminal signal sequence of the primary PSCA translation product. In vitro reporter gene assay showed that the variant allele significantly reduced promoter activity. Resequencing of the PSCA genomic region showed that rs2294008 is the only common missense SNP in PSCA. Our data identify rs2294008 as a new bladder cancer susceptibility locus.
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| 10. |
- Gillberg, L., et al.
(författare)
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Effective treatment of mouse experimental colitis by alpha 2 integrin antibody : comparison with alpha 4 antibody and conventional therapy
- 2013
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Ingår i: Acta Physiologica. - : Wiley. - 1748-1708 .- 1748-1716. ; 207:2, s. 326-336
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Tidskriftsartikel (refereegranskat)abstract
- Aim To compare the therapeutic effect of a2 and a4 integrin-blocking antibodies to conventional inflammatory bowel disease drugs methotrexate, 5-aminosalicylic acid and azathioprine in the dextran sulphate sodium mouse colitis model. Methods Colitis was induced in balb/c mice with 2.53.0% dextran sulphate sodium. Treatment was given daily for 7 days after the onset of colitis, by rectal installation. Clinical signs of disease were assessed daily using a disease activity index. After 19 days, all animals were killed and colon samples collected for histological grading and mRNA/protein analysis. All treatment groups were compared with an untreated control group and a treatment group receiving dextran sulphate sodium alone to monitor the potential degree of clinical remission. Results Treatment with anti-a2 antibodies and methotrexate reduced the body weight loss. At the end of treatment, anti-a2 antibodies reduced rectal bleeding, while methotrexate reduced the disease activity index score. Histological evaluation showed that anti-a2 antibodies, methotrexate, 5-aminosalicylic acid and azathioprine treatment reduced the acute inflammation; methotrexate was the only treatment with effect on the crypt score. Compared with the dextran sulphate sodium alone group, the methotrexate group showed down-regulation of IL-1 beta at the mRNA level, while the anti-a2 antibody group displayed decreased protein expression of iNOS and IL-1 beta. Conclusions Specific blocking of extravascular trafficking of leucocytes with a2-antibodies could be a new beneficial drug target in inflammatory bowel disease.
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