| 1. |
- Andersson, Patiyan, 1978-, et al.
(författare)
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Genome-wide analysis of penile cancer using high-density single nucleotide polymorphism arrays
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The availability of genome-wide high-density single nucleotide polymorphism (SNP) arrays makes it possible to in a structured manner study chromosome aberrations in penile cancer where little is known of disruptive genetic events. In this study 19 penile squamous cell carcinomas were analyzed using the 250k NspI SNP array from Affymetrix. We find major regions of frequent copy number gain in chromosome arms 3q, 5p and 8q, and slightly less frequent in 1p, 16q and 20q. The chromosomal regions of most frequent copy number losses were 3p, 4q, 11p and 13q. We identified four candidate genes residing in the major chromosomal regions of aberration. Eight tumours showed copy number gain of the PIK3CA gene located to 3q26.3. Five of the remaining tumours carried an activating mutation of the PIK3CA gene and these tumours showed very few chromosomal aberrations. Collectively, disruption of the PIK3CA gene was found in 13/19 samples, and presence of active phosphorylated AKT was confirmed immunohistochemically in these tumours indicating an active signalling pathway. We found copy number gain of the hTERT gene (5p15.33) in 7 samples and of the Myc gene (8q24.21) in 7 samples. Copy number loss of the tumoursuppressor gene FHIT (3p14.2) was observed in 8 samples, the same 8 samples that showed copy number gain of the PIK3CA gene. In total the PI3K/AKT and RAS/MAPK pathways were found to be activated through mutation or amplification in 64% of the cases, indicating the significance of these pathways in the aetiology of penile cancer.
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| 2. |
- Andersson, Patiyan, 1978-, et al.
(författare)
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PIK3CA, HRAS and KRAS gene mutations in human penile cancer
- 2008
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Ingår i: Journal of Urology. - New York, USA : Ovid Technologies (Wolters Kluwer Health). - 0022-5347 .- 1527-3792. ; 179:5, s. 2030-2034
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The knowledge of somatic mutations that arise in penile cancer is limited. We examined the dysregulation of components in the phosphatidylinositol 3-kinase and Ras pathways. Materials and Methods: Using single stranded conformational analysis and direct sequencing we performed mutational analysis of the PIK3CA, PTEN, HRAS, KRAS, NRAS and BRAF genes in 28 penile tumors. Results: We identified somatic missense mutations in 11 of the 28 penile cancer samples (39%). In the PIK3CA gene 8 mutations (29%) were identified that were E542K or E545K. In the HRAS gene a G12S and a Q61L mutation were found (7%). The KRAS gene contained 1 mutation (3%), that is a G12S change. PIK3CA mutations were found in all grades and stages, whereas HRAS and KRAS mutations were found in larger and more advanced tumors. The mutations were mutually exclusive, suggesting that dysregulation of either pathway is sufficient for the development and progression of penile carcinoma. Conclusions: The high frequency of mutations in the PIK3CA, HRAS and KRAS genes leads us to believe that dysregulation of the phosphatidylinositol 3-kinase or Ras pathway is significant for the development and progression of penile carcinoma.
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| 3. |
- Eklund, Lena K., et al.
(författare)
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Mutation analysis of the human homologue of drosophila patched and the xeroderma pigmentosum complementation group A genes in squamous cell carcinomas of the skin
- 1998
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Ingår i: Molecular Carcinogenesis. - 0899-1987 .- 1098-2744. ; 21:2, s. 87-92
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Tidskriftsartikel (refereegranskat)abstract
- The human homologue of Drosophila patched (PTCH), located at chromosome 9q22.3, was recently identified as a candidate tumor suppressor gene for familial and sporadic basal cell carcinomas. Squamous cell carcinomas (SCCs) of the skin display allelic loss in this chromosomal region, which, in addition to the PTCH gene, contains the DNA repair gene xeroderma pigmentosum complementation group A (XPA). Patients with xeroderma pigmentosum are predisposed to non-melanoma skin tumors because of deficient excision repair of ultraviolet-induced DNA damage. Mutation analysis by single-strand conformation analysis and direct DNA sequencing of all 23 exons of the PTCH gene and all six exons of the XPA gene in 14 SCCs did not reveal structural alterations in any of these genes. Additionally, analysis of PTCH expression by in situ hybridization in SCCs revealed no evidence of upregulation of PTCH mRNA, confirming the lack of mutations in this gene. These findings suggest that another, yet to be identified gene or genes on chromosome 9q are involved in SCC tumorigenesis.
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| 4. |
- Eklund, Lena K., et al.
(författare)
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Over-expression of coronin 2a and lack of alterations in transforming growth factor ß receptor I in squamous cell carsinomas of the skin
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Allelic losses in several regions of chromosome 9q have been connected to the development of squamous cell carcinoma (SCC) of the skin. We have studied two candidate genes in the 9q22 region using mutational analysis of genomic DNA as well as immunohistochemistry for assessment of changes in protein expression. The coronin 2A (CORO2A) protein shows strong resemblance to actin-binding proteins, implying a role in cytokinesis or cell motility. It has also been found to be part of the nuclear receptor co-repressor complex involved in transcriptional regulation. We elucidated the exon-intron structure by sequence alignment of the mRNA to a "high-throughput genomic sequence" entry in GenBank. By using single strand conformation analysis and DNA sequencing we found eight silent mutations in tumor DNA, one of which was found in a subset of a normal control population. Surprisingly, immunostaining revealed over-expression in 4/40 tumors. This cannot explain the high frequency of allelic loss in cutaneous secs, but is yet indicating a possible involvement of CORO2A in cutaneous SCC development. The gene for transforming growth factor ß receptor 1 (TßR-I) has previously been positioned to the 9q22 region. TßR-I is part of a protein complex necessary for binding of the TGFß ligand initiating a signaling cascade, which affects downstream targets important for cell cycle regulation. We could not identify any alterations at either protein or DNA level and therefore exclude TßR-I as candidate for cutaneous sec development.
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| 5. |
- Heenkenda, Menikae Kanchena, et al.
(författare)
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Assessment of genetic and non-genetic risk factors for venous thromboembolism in glioblastoma - The predictive significance of B blood group
- 2019
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Ingår i: Thrombosis Research. - : PERGAMON-ELSEVIER SCIENCE LTD. - 0049-3848 .- 1879-2472. ; 183, s. 136-142
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Venous thromboembolism (VTE) is a common problem among patients with glioblastoma multi-forme (GBM) and with some other cancers. Here, we evaluated genetic and non-genetic potential risk factors for VTE among GBM patients. Materials and methods: A cohort of 139 patients treated with concomitant radiotherapy and temozolomide were included in the study. Next generation sequencing and genotyping approaches were applied to assess genetic risk factors in the haemostatic system. Clinical data including surgery, reoperation as well as blood group and patient information such as age and gender were available from patient records. Logistic regression analysis was performed to asses VTE risk. Results: In the study 47 patients (34%) were diagnosed for VTE during the course of their disease. When genetic and non-genetic potential risk factors were evaluated, only B blood group was found to be significantly associated with VTE incidence (odds ratio [OR] = 6.91; confidence interval [CI] = 2.19-24.14; P = 0.001). In contrast, A and O blood groups did not correlate with VTE risk. Frontal lobe tumor location also seemed to slightly increase VTE risk compared to other brain sites (OR = 3.14; CI = 1.1-10.7) although the significance level was at borderline (P = 0.05). Current study identified B blood group as the component in non-O blood groups that is responsible for increased VTE risk. Conclusion: In conclusion, these results suggest for the first time that B blood group is predictive for VTE incidence among patients with glioblastoma, information that may be potentially valuable when selecting GBM patients who are at risk for VTE for anticoagulant prophylaxis.
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| 6. |
- Lysiak, Malgorzata, et al.
(författare)
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Deletions on Chromosome Y and Downregulation of the SRY Gene in Tumor Tissue Are Associated with Worse Survival of Glioblastoma Patients
- 2021
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Ingår i: Cancers. - : MDPI. - 2072-6694. ; 13:7
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Biological causes of sex disparity seen in the prevalence of cancer, including glioblastoma (GBM), remain poorly understood. One of the considered aspects is the involvement of the sex chromosomes, especially loss of chromosome Y (LOY).METHODS: Tumors from 105 isocitrate dehydrogenase (IDH) wild type male GBM patients were tested with droplet digital PCR for copy number changes of ten genes on chromosome Y. Decreased gene expression, a proxy of gene loss, was then analyzed in 225 IDH wild type GBM derived from TCGA and overall survival in both cohorts was tested with Kaplan-Meier log-rank analysis and maximally selected rank statistics for cut-off determination.RESULTS: LOY was associated with significantly shorter overall survival (7 vs. 14.6 months, p = 0.0016), and among investigated individual genes survival correlated most prominently with loss of the sex-determining region Y gene (SRY) (10.8 vs. 14.8 months, p = 0.0031). Gene set enrichment analysis revealed that epidermal growth factor receptor, platelet-derived growth factor receptor, and MYC proto-oncogene signaling pathways are associated with low SRY expression.CONCLUSION: Our data show that deletions and reduced gene expression of chromosome Y genes, especially SRY, are associated with reduced survival of male GBM patients and connected to major susceptibility pathways of gliomagenesis.
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| 7. |
- Malmström, Annika, 1957-, et al.
(författare)
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ABCB1 single-nucleotide variants and survival in patients with glioblastoma treated with radiotherapy concomitant with temozolomide
- 2020
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Ingår i: The Pharmacogenomics Journal. - : Nature Publishing Group. - 1470-269X .- 1473-1150. ; 20:2, s. 213-219
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Tidskriftsartikel (refereegranskat)abstract
- Standard treatment for glioblastoma (GBM) patients is surgery and radiochemotherapy (RCT) with temozolomide (TMZ). TMZ is a substrate for ABCB1, a transmembrane drug transporter. It has been suggested that survival for GBM patients receiving TMZ is influenced by different single-nucleotide variants (SNV) of ABCB1. We therefore examined SNV:s of ABCB1, namely 1199Gamp;gt;A, 1236Camp;gt;T, 2677Gamp;gt;T/A, and 3435Camp;gt;T and correlated to survival for GBM patients receiving RCT. In a pilot cohort (97 patients) a significant correlation to survival was found for SNV 1199Gamp;gt;A, with median OS for variant G/G patients being 18.2 months versus 11.5 months for A/G (p = 0.012). We found no correlation to survival for the other SNV:s. We then expanded the cohort to 179 patients (expanded cohort) and also included a confirmatory cohort (49 patients) focusing on SNV 1199Gamp;gt;A. Median OS for G/G versus A/G plus A/A was 15.7 and 11.5 months, respectively (p = 0.085) for the expanded cohort and 13.8 versus 16.8 months (p = 0.19) for the confirmatory. In conclusion, in patients with GBM receiving RCT with TMZ, no correlation with survival was found for the SNV:s 1236Camp;gt;T, 2677Gamp;gt;T/A, and 3435Camp;gt;T of ABCB1. Although the SNV 1199Gamp;gt;A might have some impact, a clinically significant role could not be confirmed.
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| 8. |
- Mosrati, Mohamed Ali, et al.
(författare)
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TERT promoter mutations and polymorphisms as prognostic factors in primary glioblastoma
- 2015
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Ingår i: Oncotarget. - : IMPACT JOURNALS LLC. - 1949-2553. ; 6:18, s. 16663-16673
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Tidskriftsartikel (refereegranskat)abstract
- Telomerase reverse transcriptase (TERT) activity is up-regulated in several types of tumors including glioblastoma (GBM). In the present study, 128 primary glioblastoma patients were examined for single nucleotide polymorphisms of TERT in blood and in 92 cases for TERT promoter mutations in tumors. TERT promoter mutations were observed in 86% of the tumors and of these, C228T (-124 bp upstream start codon) was detected in 75% and C250T (-146 bp) in 25% of cases. TERT promoter mutations were associated with shorter overall survival (11 vs. 20 months p = 0.002 and 12 vs. 20, p = 0.04 for C228T and C250T, respectively). The minor alleles of rs2736100 and rs10069690 SNPs, located in intron 2 and the promotor regions, respectively, were associated with an increased risk of developing GBM (p = 0.004 and 0.001). GBM patients having both TERT promoter mutations and being homozygous carriers of the rs2853669 C-allele displayed significantly shorter overall survival than those with the wild type allele. The rs2853669 SNP is located in a putative Ets2 binding site in the promoter (-246 bp upstream start codon) close to the C228T and C250T mutation hot spots. Interleukin-6 (IL-6) expression regulated by TERT promoter status and polymorphism, what leads us to think that TERT and IL-6 plays a significant role in GBM, where specific SNPs increase the risk of developing GBM while the rs2853669 SNP and specific mutations in the TERT promoter of the tumor lead to shorter survival.
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| 9. |
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| 10. |
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| 11. |
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| 12. |
- Shahzad, Khurrum, et al.
(författare)
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Nlrp3-inflammasome activation in non-myeloid-derived cells aggravates diabetic nephropathy
- 2015
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Ingår i: Kidney International. - : Nature Publishing Group: Open Access Hybrid Model Option A. - 0085-2538 .- 1523-1755. ; 87:1, s. 74-84
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Tidskriftsartikel (refereegranskat)abstract
- Diabetic nephropathy is a growing health concern with characteristic sterile inflammation. As the underlying mechanisms of this inflammation remain poorly defined, specific therapies targeting sterile inflammation in diabetic nephropathy are lacking. Intriguingly, an association of diabetic nephropathy with inflammasome activation has recently been shown, but the pathophysiological relevance of this finding remains unknown. Within glomeruli, inflammasome activation was detected in endothelial cells and podocytes in diabetic humans and mice and in glucose-stressed glomerular endothelial cells and podocytes in vitro. Abolishing Nlrp3 or caspase-1 expression in bone marrow-derived cells fails to protect mice against diabetic nephropathy. Conversely, Nlrp3-deficient mice are protected against diabetic nephropathy despite transplantation of wild-type bone marrow. Pharmacological IL-1R antagonism prevented or even reversed diabetic nephropathy in mice. Mitochondrial reactive oxygen species (ROS) activate the Nlrp3 inflammasome in glucose or advanced glycation end product stressed podocytes. Inhibition of mitochondrial ROS prevents glomerular inflammasome activation and nephropathy in diabetic mice. Thus, mitochondrial ROS and Nlrp3-inflammasome activation in non-myeloid-derived cells aggravate diabetic nephropathy. Targeting the inflammasome may be a potential therapeutic approach to diabetic nephropathy.
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| 13. |
- Abate Waktola, Ebba Abate, et al.
(författare)
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Polymorphisms in CARD8 and NLRP3 are associated with extrapulmonary TB and poor clinical outcome in active TB in Ethiopia
- 2019
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Innate immunity is a first line defense against Mycobacterium tuberculosis infection where inflammasome activation and secretion of the pro-inflammatory cytokine IL-1beta, plays a major role. Thus, genetic polymorphisms in innate immunity-related genes such as CARD8 and NLRP3 may contribute to the understanding of why most exposed individuals do not develop infection. Our aim was to investigate the association between polymorphisms in CARD8 and NLRP3 and active tuberculosis (TB) as well as their relationship to treatment outcome in a high-endemic setting for TB. Polymorphisms in CARD8 (C10X) and NLRP3 (Q705K) were analysed in 1190 TB patients and 1990 healthy donors (HD). There was a significant association between homozygotes in the CARD8 polymorphism and extrapulmonary TB (EPTB), which was not the case for pulmonary TB or HDs. Among TB-patients, there was an association between poor treatment outcome and the NLRP3 (Q705K) polymorphism. Our study shows that inflammasome polymorphisms are associated with EPTB and poor clinical outcome in active TB in Ethiopia. The practical implications and determining causal relationships on a mechanistic level needs further study.
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| 14. |
- Ahmadi, Ahmad, et al.
(författare)
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Association of a protective paraoxonase 1 (PON1) polymorphism in Parkinson's disease
- 2012
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Ingår i: Neuroscience Letters. - : Elsevier BV. - 0304-3940 .- 1872-7972. ; 522:1, s. 30-35
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Tidskriftsartikel (refereegranskat)abstract
- Pesticide exposure has been suggested to increase the risk to develop Parkinson's disease (PD). The arylesterase paraoxonase 1 (PON1) is mainly expressed in the liver and hydrolyzes organophosphates such as pesticides. The polymorphism Leu54Met (rs854560) in PON1, impairing enzyme activity and leading to decreased PON1 expression levels, has been reported to be associated with Parkinson's disease (PD). PON1 is part of a cluster on chromosome 7q21.3 together with PON2 and PON3. We investigated the occurrence of four additional polymorphisms in PON1 and two in PON2 in a Swedish PD case-control material. We found a significant association (p = 0.007) with a PON1 promoter polymorphism, rs854571. The minor allele was more common among controls than PD cases which suggest a protective effect. This is strengthened by the fact that rs854571 is in strong linkage disequilibrium with another PON1 promoter polymorphism, rs854572, reported to increase PON1 gene expression. Our findings support the hypothesis that PON1 is involved in the etiology of PD and that higher PON1 levels are reducing the risk for PD. (C) 2012 Elsevier Ireland Ltd. All rights reserved.
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| 15. |
- Ahmadi, Ahmad, 1964-, et al.
(författare)
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GSTM1 and mEPHX polymorphisms in Parkinson's disease and age of onset
- 2000
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Ingår i: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 269:3, s. 676-680
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Tidskriftsartikel (refereegranskat)abstract
- Both environmental and genetic factors are involved in the development of PD and biotransformation of exogenous and endogenous compounds and may play a role in inter-individual susceptibility. Therefore, we investigated the presence of null genotypes of GSTM1, GSTT1, and two polymorphisms of mEPHX in subjects with Parkinson's disease and in a reference population. The study included 35 male PD patients and a male control group including 283 subjects. Homozygosity of the histidine (H) 113 isoform of mEPHX was significantly increased in PD patients (odds ratio = 3.8 CI 95% 1.2–11.8) and analysis of allele frequencies displayed an increased frequency of the H-allele among PD patients (odds ratio = 1.9 CI 95% 1.1–3.3). However, a significantly elevated median age for the onset of PD was found among GSTM1 gene carriers (median age = 68 years) compared to PD patients being GSTM1 null genotypes (median age = 57 years). Our observations suggest that (H) 113 isoform of mEPHX, which has been suggested as a low activity isoform, is overrepresented in PD patients and that inherited carriers of the GSTM1 gene postpone the onset of PD. These detoxification pathways may represent important protective mechanisms against reactive intermediates modifying the susceptibility and onset of PD.
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| 16. |
- Ahmadi, Ahmad, et al.
(författare)
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Interaction between smoking and glutathione S-transferase polymorphisms in solvent-induced chronic toxic encephalopathy
- 2002
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Ingår i: Toxicology and industrial health. - : SAGE Publications. - 0748-2337 .- 1477-0393. ; 18:6, s. 289-296
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Tidskriftsartikel (refereegranskat)abstract
- Exposure to organic solvents is still common in industrial and other work environments, and increases the risk of chronic toxic encephalopathy (CTE). Genetic variation in metabolic enzymes for solvents and other xenobiotics may modify the risk of developing toxic effects. Therefore, we investigated the presence of null genotypes for glutathione S-transferases M1 and T1 (GSTM1, GSTT1) and two genetic polymorphisms of microsomal epoxide hydrolase (mEPHX) in relation to the risk for chronic toxic encephalopathy (CTE) when exposed to solvents and smoking. We genotyped 115 patients who were classified into three categories: CTE (n = 56), incipient CTE (n = 27) and non-CTE (n = 32) patients. DNA was isolated from leucocytes and the GSTM 1 and GSTT1 null genotypes were determined by multiplex-polymerase chain reaction. The two polymorphisms of mEPHX were analysed by PCR-RFLP (restriction fragment length polymorphism) based assays. All analyses were performed blindly with regard to both exposure and disease status. An increased binomial regression risk ratio = 2.5, 95% confidence interval (CI) 1.5-4.2, of the GSTM1 null genotype for CTE was found in smokers and for the GSTT1 null genotype (binomial regression risk ratio 1.5, 95% CI 1.0-2.0). In nonsmokers, the GSTM1 null genotype did not confer any risk for CTE. None of the studied mEPHX polymorphisms were associated with an increased risk for CTE. We suggest that the GSTM1 null genotype in smokers is a possible risk for solvent-induced CTE.
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| 17. |
- Ahmadi, Ahmad, et al.
(författare)
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Manganese superoxide dismutase and NDUFV2 polymorphisms and susceptibility to Parkinson's disease
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Mitochondrial dysfunction has been hypothesized to contribute to the pathogenesis of Parkinson's disease (PD). Oxidative stress and production of oxygen radicals is produced in mitochondria. The superoxide dismutases (SOD) potentially play an important role in PD by detoxifying superoxide radicals. Oxidative stress has also an important role to decrease Complex I activity in the mitochondria. In addition, Complex I contains several subunits, where one, NDUFV2, plays a major role in the electron transport pathway of Complex I in substantia nigra.The aim of this project was to study polymorphisms in MTS-SOD2 and the Complex I subunit, NDUFV2 as predisposing factors for the development of idiopathic PD.Blood samples from 200 PD and 404 population controls were collected from the Southeastern part of Sweden. DNA was isolated and the polymorphisms were analyzed by pyrosequencing and direct dideoxy termination sequencing.Genotypes and allele frequencies were compared for the patient and control groups with Χ2 statistics. No statistical significant difference was evident for any of the polymorphisms neither in MTS-SOD2 (OR=0<85, 95% CI, 0<52-1.38) nor NDUFV2 (OR=0.64, 95% CI, 0.24-1.64) genes and PD.These results indicate that the MTS-SOD2 and NDUFV2 gene variants do not contribute to PD pathogenesis.
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| 18. |
- Ahmadi, Ahmad, et al.
(författare)
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Monoamine oxidase A and B genes polymorphisms in Parkinson's disease
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Parkinson's disease (PD) is a common progressive neurodegenerative disorder characterized by degeneration of nig:rostriatal dopaminergic neurons including the loss of cell bodies in the pars compacta of substantia nigra (SN). The mechanism for neurodegeneration is unknown, but the pathogenesis is considered to be multifactorial involving exposure for toxins, genetic inheritance, age, oxidative stress and mitochondrial electron transport chain defects. This study has been focused on polymorphisms in the genes for the enzymes monoamine oxidase A and B (MAO-A, MAO-B) and relation to smoking for the development of idiopathic Parkinson's disease. MAO enzymes are important in the dopamine metabolism and in the detoxification of neurotoxins. During metabolism of dopamine, MAO generates large amounts of free radicals and hydrogen peroxide, and may damage the neurons in substantia nigra, which has been suggested as a pathologic mechanism for PD.Blood samples were collected from 256 PD patients, age 30-80 years, and 582 unrelated control individuals, age 31 - 78 years, from southeastern Sweden.Two polymorphisms (exon 8 and exon 14) located in the MAO-A gene and one polymorphism located in the MA O-B gene were examined, with denatming HPLC, PCR-RFLP or DNA sequencing. Genotype and allele frequencies were determined for patients and controls. No statistical significant difference was revealed between any of the polymorphisms in the MAO-A and MAO-B genes and Parkinson's disease. Smoking displayed an enviromnental exposure with a strong decreased risk for both male (OR=0.40, 95% CI 0.25 - 0.63) and female (OR=0.48, 95% CI 0.25-0.89) PD without any interaction with MAO genotype.The polymorphisms in MAO genes might therefore not be acting as modifiers of risk for developing of PD either by itself or by interacting with smoking. With respect to the size of the study (256 PD patients and 582 controls) MAO polymorphisms do not represent any predisposing factor or a weak PD susceptibility factor.
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| 19. |
- Aljabery, Firas
(författare)
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Staging and tumor biological mechanisms of lymph node metastasis in invasive urinary bladder cancer
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Aim: To study the possibility of detecting lymph node metastasis in locally advanced urinary bladder cancer (UBC) treated with radical cystectomy (RC) by using preoperative positron emission tomography/computed tomography (PET/CT) and peroperative sentinel node biopsy (SNB) technique. We also investigate the clinical significance of macrophage traits expression by cancer cells, M2-macrophage infiltration (MI) in tumor stroma and the immunohistochemical expression of biomarkers in cancer cells in relation to clinicopathologic data.Patients and Methods: We studied prospectively 122 patients with UBC, pathological stage pT1–pT4 treated with RC and pelvic lymph node dissection (PLND) during 2005–2011 at the Department of Urology, Linköping University Hospital. In the first study, we compared the results of preoperative PET/CT and conventional CT with the findings of postoperative histopathological evaluation of lymph nodes (LNs). In the second study we investigated the value of SNB technique for detecting pathological LNs during RC in patients with UBC. W also examined the significance of the primary tumor location in the bladder in predicting the site of LN metastases, and the prognostic significance of lympho-vascular invasion (LVI) and lymph node metastasis density (LNMD) on survival. In the third study, we investigate the clinical significance of macrophage infiltration (MI) in tumor stroma and macrophage-traits expression by tumor cells. In the fourth study, we investigate the cell cycle suppression proteins p53, p21, pRb, p16, p14 ARF as well as tumors proliferative protein Ki67 and DNA repair protein ERCC1 expression in cancer cells. The results were compared with clinical and pathological characteristics and outcome.Results: Prior to RC, PET/CT was used to detect LN metastasis in 54 patients. PET/CT had 41% sensitivity, 86% specificity, 58% PPV, and 76% NPV, whereas the corresponding figures for conventional CT were 41%, 89%, 64%, and 77%. SNB was performed during RC in 103 patients. A median number of 29 (range 7–68) nodes per patient were examined. SNs were detected in 83 out of 103 patients (81%). The sensitivity and specificity for detecting metastatic disease by SNB varied among LN stations, with average values of 67% -90%. LNMD or ≥8% and LVI were significantly related to shorter survival. In 103 patients, MI was high in 33% of cases, while moderate and low infiltration occurred in 42% and 25% of tumors respectively. Patients with tumors containing high and moderate compared to low MI had low rate of LN metastases (P=0.06) and improved survival (P=0.06), although not at significant level. The expression of different tumor suppression proteins was altered in 47-91% of the patients. There were no significant association between cancer specific survival (CSS) and any of the studied biomarkers. In case of altered p14ARF, ERCC1 or p21, CSS was low in case of low p53 immunostaining but increased in case of p53 accumulation, although not at a significant level, indicating a possible protective effect of p53 accumulation in these cases.Conclusion: PET/ CT provided no improvement over conventional CT in detection and localization of regional LN metastases in bladder cancer. It is possible to detect the SN but the technique is not a reliable for perioperative localization of LN metastases; however, LVI and LNMD at a cut-off level of 8% had significant prognostic values. MI in the tumor microenvironment but not CD163 expression in tumor cells seems to be synergistic with the immune response against urinary bladder cancer. Our results further indicate that altered p53 might have protective effect on survival in case of altered p14ARF, p21, or ERCC1 indicating an interaction between these biomarkers.
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| 20. |
- Alkaissi, Hammoudi, et al.
(författare)
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Bank1 and NF-kappaB as key regulators in anti-nucleolar antibody development
- 2018
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Ingår i: PLOS ONE. - : PUBLIC LIBRARY SCIENCE. - 1932-6203. ; 13:7
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Tidskriftsartikel (refereegranskat)abstract
- Systemic autoimmune rheumatic disorders (SARD) represent important causes of morbidity and mortality in humans. The mechanisms triggering autoimmune responses are complex and involve a network of genetic factors. Mercury-induced autoimmunity (HgIA) in mice is an established model to study the mechanisms of the development of antinuclear antibodies (ANA), which is a hallmark in the diagnosis of SARD. A.SW mice with HgIA show a significantly higher titer of antinucleolar antibodies (ANoA) than the B10.S mice, although both share the same MHC class II (H-2). We applied a genome-wide association study (GWAS) to their Hg-exposed F2 offspring to investigate the non-MHC genes involved in the development of ANoA. Quantitative trait locus (QTL) analysis showed a peak logarithm of odds ratio (LOD) score of 3.05 on chromosome 3. Microsatellites were used for haplotyping, and fine mapping was conducted with next generation sequencing. The candidate genes Bank1 (B-cell scaffold protein with ankyrin repeats 1) and Nfkbl (nuclear factor kappa B subunit 1) were identified by additional QTL analysis. Expression of the Bank1 and Nfkb1 genes and their downstream target genes involved in the intracellular pathway (Tlr9,II6, Tnf) was investigated in mercury-exposed A.SW and B10.S mice by real-time PCR. Bank1 showed significantly lower gene expression in the A.SW strain after Hg-exposure, whereas the B10.S strain showed no significant difference. Nfkb1, Tlr9, II6 and Tnf had significantly higher gene expression in the A.SW strain after Hg-exposure, while the B10.S strain showed no difference. This study supports the roles of Bank1 (produced mainly in B-cells) and Nfkbl (produced in most immune cells) as key regulators of ANoA development in HgIA.
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| 21. |
- Alkaissi, Hammoudi, et al.
(författare)
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Genome-Wide Association Study to Identify Genes Related to Renal Mercury Concentrations in Mice
- 2016
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Ingår i: Journal of Environmental Health Perspectives. - : U.S. Department of Health and Human Services * National Institute of Environmental Health Sciences. - 0091-6765 .- 1552-9924. ; 124:7, s. 920-926
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Following human mercury (Hg) exposure, the metal accumulates in considerable concentrations in kidney, liver, and brain. Although the toxicokinetics of Hg have been studied extensively, factors responsible for interindividual variation in humans are largely unknown. Differences in accumulation of renal Hg between inbred mouse strains suggest a genetic interstrain variation regulating retention or/and excretion of Hg. A. SW, DBA/2 and BALB/C mouse strains accumulate higher amounts of Hg than B10.S.OBJECTIVES: We aimed to find candidate genes associated with regulation of renal Hg concentrations.METHODS: A. SW, B10.S and their F1 and F2 offspring were exposed for 6 weeks to 2.0 mg Hg/L drinking water. Genotyping with microsatellites was conducted on 84 F2 mice for genome-wide scanning with ion pair reverse-phase high-performance liquid chromatography (IP RP HPLC). Quantitative trait loci (QTL) were established. Denaturing HPLC was used to detect single nucleotide polymorphisms for haplotyping and fine mapping in 184 and 32 F2 mice, respectively. Candidate genes (Pprc1, Btrc and Nfkb2) verified by fine mapping and QTL were further investigated by real-time polymerase chain reaction. Genes enhanced by Pprc1 (Nrf1 and Nrf2) were included for gene expression analysis.RESULTS: Renal Hg concentrations differed significantly between A. SW and B10. S mice and between males and females within each strain. QTL analysis showed a peak logarithm of odds ratio score 5.78 on chromosome 19 (p = 0.002). Haplotype and fine mapping associated the Hg accumulation with Pprc1, which encodes PGC-1-related coactivator (PRC), a coactivator for proteins involved in detoxification. Pprc1 and two genes coactivated by Pprc1 (Nrf1 and Nrf2) had significantly lower gene expression in the A. SW strain than in the B10. S strain.CONCLUSIONS: This study supports Pprc1 as a key regulator for renal Hg excretion.
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| 22. |
- Alkaissi, Hammoudi, 1983-
(författare)
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Identification of candidate genes involved in Mercury Toxicokinetics and Mercury Induced Autoimmunity
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- BACKGROUND: Autoimmune diseases require the involvement and activation of immune cells and occur when the body builds up an immune response against its own tissues. This process takes place due to the inability to distinguish self-antigen from foreign antigen. Systemic autoimmunity represents an important cause of morbidity and mortality in humans. The mechanisms triggering autoimmune responses are complex and involve a network of genetic factors. Genome wide association study (GWAS) is a powerful method, used to identify genetic risk factors in numerous diseases, such as systemic autoimmune diseases. The goal of GWAS is to identify these genetic risk factors in order to make predictions about who is at risk and investigate the biological process of disease susceptibility. There are several valuable mouse models to investigate the underlying mechanisms causing systemic autoimmune diseases in which mercury induced autoimmunity (HgIA) is a well- established and relevant model. HgIA in mice includes development of autoantibodies, immune complex glomerulonephritis, lymphocyte proliferation, hypergammaglobulinemia and polyclonal B cell activation. In humans, mercury exposure accumulates with considerable concentrations in kidney, liver, and brain. Toxicokinetics of Hg has been studied extensively but the key for inter-individual variation in humans are largely unclear. Differences in accumulation of renal Hg between inbred mouse strains suggest a genetic inter-strain variation regulating retention or/and excretion of Hg.OBJECTIVES: To find loci and candidate genes associated with phenotypes involved in the development of autoimmunity and find candidate genes involved in the regulation of renal Hg excretion.METHODS: MHC II (H-2s) mice were paired (A.SW x B10.S) to obtain F2 offspring exposed to 2.0 or 4.0 mg Hg in drinking water for 6 weeks. Mercury induced autoimmune phenotypes were studied with immunofluorescence (anti-nucleolar antibodies (ANoA)), ELISA anti-DNP/anti-ssDNA (polyclonal B cell activation), anti-chromatin antibodies (ACA) (4.0 mg Hg), and serum IgG1 concentrations. Mercury accumulation in kidney was performed previously and data was included as phenotype. F2 mice exposed to 2.0 mg Hg were genotyped with microsatellites for genome-wide scan with Ion Pair Reverse Phase High Performance Liquid Chromatography (IP RP HPLC). F2 mice exposed to 4.0 mg Hg were genotyped with single nucleotide polymorphisms for genomewide scan with SNP&SEQ technology platform. Quantitative trait loci (QTL) was established with R/QTL. Denaturing HPLC, next generation sequencing, conserved region analysis and genetic mouse strain comparison were used for haplotyping and fine mapping on QTLs associated with Hg concentration in kidney, development of ANoA and serum IgG1 hypergammaglobulinemia. Candidate genes (Pprc1, Bank1 and Nfkb1) verified by additional QTL were further investigated by real time polymerase chain reaction. Genes involved in the intracellular signaling together with candidate genes were included for gene expression analysis.RESULTS: F2 mice exposed to 2.0 mg Hg had low or no development of autoantibodies and showed no significant difference in polyclonal B cell activation in the B10.S and F2 strains. F2 mice exposed to 4.0 mg Hg developed autoantibodies and significantly increased IgG1 concentration and polyclonal B cell activation (anti-DNP). QTL analysis showed a logarithm of odds ratio (LOD) score between 2.9 – 4.36 on all serological phenotypes exposed to 4.0 mg Hg, and a LOD score of 5.78 on renal Hg concentration. Haplotyping and fine mapping associated the development of ANoA with Bank1 (B-cell scaffold protein with ankyrin repeats 1) and Nfkb1 (nuclear factor kappa B subunit 1). The serum IgG1 concentration was associated with a locus on chromosome 3, in which Rxfp4 (Relaxin Family Peptide/INSL5 Receptor 4) is a potential candidate gene. The renal Hg concentration was associated with Pprc1 (Peroxisome Proliferator-Activated Receptor Gamma, Co-activator-Related). Gene expression analysis revealed that the more susceptible A.SW strain expresses significantly higher levels of Nfkb1, Il6 and Tnf than the less susceptible B10.S strain. The A.SW strain expresses significantly lower levels of Pprc1 and cascade proteins than the B10.S strain. Development of ACA was associated with chromosomes 3, 6, 7 and 16 (LOD 3.1, 3.2, 3.4 and 6.8 respectively). Polyclonal B cell activation was associated with chromosome 2 with a LOD score of 2.9.CONCLUSIONS: By implementing a GWAS on HgIA in mice, several QTLs were discovered to be associated with the development of autoantibodies, polyclonal B cell activation and hypergammaglobulinemia. This thesis plausibly supports Bank1 and Nfkb1 as key regulators for ANoA development and HgIA seems to be initiated by B cells rather than T cells. GWAS on renal mercury excretion plausibly supports Pprc1 as key regulator and it seems that this gene has a protective role against Hg.
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| 23. |
- Andersson, Patiyan, 1978-, et al.
(författare)
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Androgen receptor and vitamin D receptor gene polymorphisms and prostate cancer risk
- 2006
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Ingår i: European Journal of Cancer. - : Elsevier. - 0959-8049 .- 1879-0852. ; 42:16, s. 2833-2837
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Tidskriftsartikel (refereegranskat)abstract
- We study the CAG repeat region in exon 1 of the androgen receptor (AR) and the TaqI polymorphism in exon 9 of the vitamin D receptor (VDR) and the association with prostate cancer. 137 incidentally discovered, histologically verified prostate cancers were analysed for CAG repeat length in AR and genotype at the TaqI site of the VDR. 124 control subjects were analysed to determine the CAG repeat length and TaqI genotype determined for 176 control subjects. An unpaired t-test shows that the mean CAG repeat length was significantly (p < 0.001) shorter among cases (20.1 repeats) compared with controls (22.5 repeats). Dividing the prostate cohort and controls into tertiles (19, 20–22, 23 repeats) shows that short repeats are significantly more common among cases (odds ratio (OR) 4.45, p = 0.00003). Genotype frequencies for the TaqI polymorphism reveals no significant differences between cases and controls. We conclude that men with a short CAG repeat in the androgen receptor gene have an increased risk of developing prostate cancer.
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| 24. |
- Andersson, Patiyan, 1978-, et al.
(författare)
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Association studies on INS and IRS1polymorphisms: IRS1 G972R is associated with increased prostate cancer risk
- 2008
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Ingår i: Prostate Cancer and Prostatic Diseases. - 1365-7852 .- 1476-5608.
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Tidskriftsartikel (refereegranskat)abstract
- We study the G972R polymorphism in the Insulin receptor substrate 1 gene (IRS1) and the +1127 PstI polymorphism of the Insulin gene (INS), in 120 and 151, respectively, incidentally discovered, histologically verified prostate cancers, and in 185 healthy control subjects. The number of IRS1 R allele was found to be significantly associated with increased risk of prostate cancer. Analysis of the INS +1127 PstI polymorphism shows no significant differences between cases and controls. We conclude that subjects carrying one or two R-alleles at the IRS1 G972R polymorphic site are at an elevated risk of developing prostate cancer.
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| 25. |
- Andersson, Patiyan, 1978-
(författare)
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Molecular Genetic Studies on Prostate and Penile Cancer
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis is comprised of two parts. In the first part we study the influence of four frequently disputed genes on the susceptibility for developing prostate cancer, and in the second part we attempt to establish a basic understanding of the molecular genetic events in penile cancer.In a prostate cancer cohort we have investigated the relation of prostate cancer risk and single nucleotide polymorphisms (SNPs) in four different genes coding for the androgen receptor (AR), the vitamin D receptor (VDR), insulin (INS) and insulin receptor substrate 1 (IRS1). Despite strong biological indications of an involvement of these genes in prostate carcinogenesis, the results from different studies are contradictory and inconclusive.The action of the AR varies between individuals in part owing to a repetitive CAG sequence (polyglutamine) in the first exon of the AR gene. The results presented in this thesis show that in our cohort of prostate cancer patients the average number of repeats is 20.1, which is significantly (p<0.001) fewer repeats compared to healthy control individuals, where the average is 22.5 repeats. We find a 4.94 fold (p=0.00003) increased risk of developing prostate cancer associated with having short repeat lengths (≤19 repeats), compared with long repeats (≥23 repeats). In paper I we also study the TaqI polymorphism in the VDR gene, and find that it does not modify the risk of prostate cancer.In the INS gene we study the +1127 PstI polymorphism and find no overall effect on the risk of prostate cancer. However, we do find that the CC genotype is associated with low grade disease defined as having a Gleason score ≤6 (OR=1.46; p=0.018). In the IRS1 gene we study the G972R polymorphism and observe that the R allele is significantly associated with a 2.44 fold increased prostate cancer risk (p=0.010).The knowledge of molecular genetic events in penile cancer is very scarce and to date very few genes have been identified to be involved in penile carcinogenesis. We chose therefore to analyse the penile cancer samples using genome-wide high-density SNP arrays. We find major regions of frequent copy number gain in chromosome arms 3q, 5p and 8q, and slightly less frequent in 1p, 16q and 20q. The chromosomal regions of most frequent copy number losses are 3p, 4q, 11p and 13q. We suggest four candidate genes residing in these areas, the PIK3CA gene (3q26.32), the hTERT gene (5p15.33), the MYC gene (8q24.21) and the FHIT gene (3p14.2).The mutational status of the PIK3CA and PTEN genes in the PI3K/AKT pathway and the HRAS, KRAS, NRAS and BRAF genes in the RAS/MAPK pathway was assessed in the penile cancer samples. We find the PIK3CA, HRAS and KRAS genes to be mutated in 29%, 7% and 3% of the cases, respectively. All mutations are mutually exclusive. In total the PI3K/AKT and RAS/MAPK pathways were found to be activated through mutation or amplification in 64% of the cases, indicating the significance of these pathways in the aetiology of penile cancer.
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