| 11. |
- Rostami, Elham, 1979-, et al.
(författare)
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BDNF polymorphism predicts general intelligence after penetrating traumatic brain injury
- 2011
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:11, s. e27389-
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Tidskriftsartikel (refereegranskat)abstract
- Neuronal plasticity is a fundamental factor in cognitive outcome following traumatic brain injury. Brain-derivedneurotrophic factor (BDNF), a member of the neurotrophin family, plays an important role in this process. While thereare many ways to measure cognitive outcome, general cognitive intelligence is a strong predictor of everyday decisionmaking,occupational attainment, social mobility and job performance. Thus it is an excellent measure of cognitive outcomefollowing traumatic brain injury (TBI). Although the importance of the single-nucleotide polymorphisms polymorphism oncognitive function has been previously addressed, its role in recovery of general intelligence following TBI is unknown. Wegenotyped male Caucasian Vietnam combat veterans with focal penetrating TBI (pTBI) (n = 109) and non-head injuredcontrols (n = 38) for 7 BDNF single-nucleotide polymorphisms. Subjects were administrated the Armed Forces QualificationTest (AFQT) at three different time periods: pre-injury on induction into the military, Phase II (10–15 years post-injury, andPhase III (30–35 years post-injury). Two single-nucleotide polymorphisms, rs7124442 and rs1519480, were significantlyassociated with post-injury recovery of general cognitive intelligence with the most pronounced effect at the Phase II timepoint, indicating lesion-induced plasticity. The genotypes accounted for 5% of the variance of the AFQT scores,independently of other significant predictors such as pre-injury intelligence and percentage of brain volume loss. Thesedata indicate that genetic variations in BDNF play a significant role in lesion-induced recovery following pTBI. Identifying theunderlying mechanism of this brain-derived neurotrophic factor effect could provide insight into an important aspect ofpost-traumatic cognitive recovery.
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| 12. |
- Zainuddin, Norafiza, 1978-
(författare)
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Molecular Genetic Analysis in B-cell Lymphomas : A Focus on the p53 Pathway and p16INK4a
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The presence of TP53 mutations has been associated with inferior outcome in diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL). In DLBCL, the impact of the TP53 codon 72 polymorphism and MDM2 SNP309 has not been clearly elucidated, whereas MDM2 SNP309 was suggested as a poor-prognostic marker in CLL. In addition, p16INK4a promoter hypermethylation has been implicated as a negative prognostic factor in DLBCL. The aim of this thesis was to further evaluate these molecular markers in well-characterised materials of DLBCL and CLL. In paper I, we investigated the prognostic role of TP53 mutation, codon 72 polymorphism and MDM2 SNP309 in DLBCL (n=102). The presence of TP53 mutations (12.7%) correlated with a poor lymphoma-specific and progression-free survival, and a particularly pronounced effect was observed in the germinal center subtype. Neither the MDM2 SNP309 nor the TP53 codon 72 polymorphism had an impact on age of onset or survival. In paper II, we applied pyrosequencing to measure the level of p16INK4a methylation in DLBCL (n=113). Thirty-seven percent of cases displayed p16INK4a methylation; however, no clear association could be observed between degree of methylation and clinical characteristics or lymphoma-specific survival. In papers III–IV, we investigated the prognostic role of MDM2 SNP309 (n=418) and TP53 mutation (n=268) in CLL. No correlation was observed between any particular MDM2 SNP309 genotype and time to treatment and overall survival. Furthermore, no association was found between the different MDM2 SNP309 genotypes and established CLL prognostic markers. TP53 mutations were detected in 3.7% of CLL patients; where the majority showed a concomitant 17p-deletion and only three carried TP53 mutations without 17p-deletion. We confirmed a significantly shorter overall survival and time to treatment in patients with both TP53 mutation and 17p-deletion. Altogether, our studies could confirm the negative prognostic impact of TP53 mutations in DLBCL, whereas MDM2 SNP309 and TP53 codon 72 polymorphisms appear to lack clinical relevance. We also question the role of p16INKa methylation as a poor-prognostic factor in DLBCL. Finally, the presence of TP53 mutation in CLL appears to be rare at disease onset and instead arise during disease progression.
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| 13. |
- Badhai, Jitendra, et al.
(författare)
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Differential expression of RPS19 5’UTR variants implicated in Diamond-Blackfan anemia
- 2012
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Heterozygous mutations in the ribosomal protein (RP) S19 gene RPS19 are found in about 25% of patients with the congenital erythroblastopenia Diamond-Blackfan anemia (DBA). The RPS19 gene encodes a single RPS19 isoform from three known transcriptional start sites (TSS) with different 5’ untranslated region (UTR). The regulation of RPS19 expression is poorly understood as well as the significance of different 5’UTRs. A few rare sequence variants within the 5’UTR have also been reported in patients with DBA. We determined the transcriptional start sites (TSS) and the tissue distribution of variant 5’UTRs of RPS19. Twenty-nine novel TSS in K562 cells and testis were identified. We then analyzed the relative proportion of three selected 5’UTRs of different length on a panel of primary tissues. The shorter 5’UTR were most abundant in all tissues but with large variations in relative levels of shorter versus longer transcripts. To clarify the effect of different RPS19 5’UTRs on translation we designed and expressed constructs using three 5’UTRs of different length. The short 5’UTR(+35nt.) translate 4-6 folds more efficiently than the two longer variants with 5’UTRs of 382nt. and 467nt., respectively We also introduced DBA associated insertion (c.-149_-148insGCCA, c.-149_-148insAGCC ) and deletion (c.-144_-141delTTTC) variants in the 5’UTR. . Interestingly, the DBA associated 5’UTR sequence variants showed a 20-30% reduction in RPS19 levels when compared to the corresponding w.t. constructs. Our results indicate that the RPS19 gene has a broad range of TSS with tissue specific variations. We also show that sequence variants in the 5’UTR in some DBA patients reduce RPS19 expression with implications for the pathophysiology of the disease.
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| 14. |
- Bonaïti, Bernard, et al.
(författare)
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TTR familial amyloid polyneuropathy : does a mitochondrial polymorphism entirely explain the parent-of-origin difference in penetrance?
- 2010
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438.
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Tidskriftsartikel (refereegranskat)abstract
- The Val30Met transthyretin familial amyloid polyneuropathy (TTR-V30M-FAP) is the most frequent familial amyloidosis, with autosomal dominant transmission. This severe disease shows important differences in age of onset and penetrance. Recently, a difference in penetrance according to the gender of the transmitting parent was elicited in different geographic areas with a higher penetrance in case of maternal transmission of the trait. In addition, differences in mitochondrial haplogroup distribution in early and late onset Swedish and French cases of TTR-V30M-FAP suggested that a polymorphism of mitochondrial DNA could be one underlying mechanism of the phenotypic variation. We further investigated this hypothesis by modeling the penetrance function with a parent-of-origin and/or a mitochondrial polymorphism effect in samples of Portuguese (n=33) and Swedish families (n=86) with TTR-V30M-FAP in which several individuals had been tested for mitochondrial haplogroups. Our analysis showed that a mitochondrial polymorphism effect was sufficient to explain the observed difference in penetrance according to gender of the transmitting parent in the Portuguese sample, whereas, in the Swedish sample, a clear residual parent-of-origin effect remained. This study further supported the role of a mitochondrial polymorphism effect that might induce a higher penetrance in case of maternal inheritance of the disease. In clinical practice, these results might help to better delineate the individual disease risk and have a significant impact on the management of both patients and carriers.
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| 15. |
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| 16. |
- Fröjmark, Anne-Sophie, et al.
(författare)
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Cooperative effect of ribosomal protein s19 and Pim-1 kinase on murine c-Myc expression and myeloid/erythroid cellularity
- 2010
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Ingår i: Journal of Molecular Medicine. - : Springer. - 0946-2716 .- 1432-1440. ; 88:1, s. 39-46
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Tidskriftsartikel (refereegranskat)abstract
- Diamond Blackfan anemia (DBA) is a bone marrow failure syndrome associated with heterozygous mutations in the ribosomal protein S19 (RPS19) gene in a subgroup of patients. One of the interacting partners with RPS19 is the oncoprotein PIM-1 kinase. We intercrossed Rps19+/- and Pim-1-/- mice strains to study the effect from the disruption of both genes. The double mutant (Rps19+/-Pim-1-/-) mice display normal growth with increased peripheral white- and red blood cell counts when compared to the w.t. mice (Rps19+/+Pim-1+/+). Molecular analysis of bone marrow cells in Rps19+/-Pim-1-/- mice revealed up-regulated levels of c-Myc and the anti-apoptotic factors Bcl2, BclXL and Mcl-1. This is associated with a reduction of the apoptotic factors Bak and Caspase 3 as well as the cell cycle regulator p21. Our findings suggest that combined Rps19 insufficiency and Pim-1 deficiency promote murine myeloid cell growth through a deregulation of c-Myc and a simultaneous up-regulation of anti-apoptotic Bcl proteins.
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| 17. |
- Halldórsdóttir, Anna Margrét, 1973-
(författare)
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Genetic and Epigenetic Profiling of Mantle Cell Lymphoma and Chronic Lymphocytic Leukemia
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) both belong to the group of mature B-cell malignancies. However, MCL is typically clinically aggressive while the clinical course of CLL varies. CLL can be divided into prognostic subgroups based on IGHV mutational status and into multiple subsets based on closely homologous (stereotyped) B-cell receptors. In paper I we investigated 31 MCL cases using high-density 250K single-nucleotide polymorphism arrays and gene expression arrays. Although most copy-number aberrations (CNAs) were previously reported in MCL, a novel deletion was identified at 20q (16%) containing the candidate tumor suppressor gene ZFP64. A high proliferation gene expression signature was associated with poor prognosis, large CNAs, 7p gains and 9q losses. Losses at 1p/8p/13q/17p were associated with increased genomic complexity. In paper II we sequenced exons 4 to 8 of the TP53 gene in 119 MCL cases. 17p copy-number status was known from previous studies or determined by real-time quantitative polymerase chain reaction. TP53 mutations were detected in 14% of cases and were strongly associated with poor survival while 17p deletions were more common (32%) but did not predict survival. In papers III and IV we applied high-resolution genomic 27K methylation arrays to 20 MCL and 39 CLL samples. In paper III MCL displayed a homogenous methylation profile without correlation with the proliferation signature whereas MCL was clearly separated from CLL. Gene ontology analysis revealed enrichment of developmental genes, in particular homeobox transcription factor genes, among targets methylated in MCL. In paper IV we compared three different stereotyped CLL subsets: #1 (IGHV unmutated), #2 (IGHV3-21) and #4 (IGHV mutated). Many genes were differentially methylated between each two subsets and immune response genes (e.g. CD80 and CD86) were enriched among genes methylated in subset #1 but not in subsets #2/#4.In summary, CNAs were frequent and not random in MCL. Specific CNAs correlated with a high proliferation gene expression signature or genomic complexity. TP53 mutations predicted short survival whereas 17p deletions did not. A high proliferation signature was not associated with differential DNA methylation in MCL, which demonstrated a homogeneous methylation pattern. In contrast, genomic methylation patterns differed between MCL and CLL and between stereotyped CLL subsets.
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| 18. |
- Hayat Roshanai, Afsaneh
(författare)
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Psychological and Behavioral Aspects of Receiving Genetic Counseling for Hereditary Cancer
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The overall aims of this thesis were to investigate psychological and behavioral effects of receiving cancer genetic counseling for breast, ovarian and colorectal cancer and/or with a family history of these cancer types and to determine whether counselees’ informational needs were met. Study I was performed 3-7 years post-counseling. Participants (n=214) reported a relatively high level of anxiety but a low level of depression compared to cancer patients in general. However, there was no indication that the distress experienced was due to the counseling. Moderate changes in life and family relations, high level of adherence to recommended controls and satisfaction was reported. Study II was a randomized control trial (RCT) intervention study which involved 147 counselees. An increase in the level of knowledge and correct estimation of personal risk was reported in both the intervention and control groups, although this increase declined at later follow-up. Enhanced information led to significantly greater satisfaction with the given information, and the way of informing relatives. Most counselees had shared information with their at-risk relatives. Study III focused on sharing information with at-risk relatives among participants in study II and their relatives (n=81). Counselees were interviewed and answered a questionnaire, whilst their relatives only answered the questionnaire. Counselees reported positive/neutral feelings about communicating genetic information and mostly interpreted their relatives’ reactions as positive/ neutral. Also, approximately 50% of relatives reported positive/neutral reactions and were generally satisfied with the received information. Study IV was conducted in Sweden and Norway based on 235 counselees. Counselees expected counselors to be skillful and thoughtful, take them seriously and provide risk estimations and medical information. Most important issues to counselees were satisfactorily addressed by the counselors. Analyzing importance rankings resulted in five categories of needs: a need for facts, caring communication and medical information, need for understanding and support in sharing genetic information, practical care and medical/practical information. In conclusion, no adverse psychological or behavioral effect on counselees was observed. Apparently, genetic counseling is managed properly and counselors successfully address counselees’ needs. Providing extended information does not seem necessary, however, tailoring information to individual counselees needs may create a more effective counseling.
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| 19. |
- Kaderi, Mohd Arifin, et al.
(författare)
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Lack of association between the MDM2 promoter polymorphism SNP309 and clinical outcome in chronic lymphocytic leukemia
- 2010
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Ingår i: Leukemia Research. - : Elsevier BV. - 0145-2126 .- 1873-5835. ; 34:3, s. 335-339
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Tidskriftsartikel (refereegranskat)abstract
- The 309T>G polymorphism in the promoter region of the MDM2gene, known as SNP309, has recently been suggested as an unfavorable prognostic marker in chronic lymphocytic leukemia (CLL) although this has been questioned. To investigate this further, we analyzed the MDM2 SNP309 genotypes in 418 CLL patients and correlated the results with established CLL prognostic factors, time to treatment and overall survival. In this Swedish cohort, no association existed between any particular MDM2 SNP309 genotype, overall survival and time to treatment. Furthermore, no correlation was shown between the MDM2 SNP309 genotypes and Binet stage, IGHV mutational status and recurrent genomic aberrations. In summary, this study argues against the use of the MDM2 SNP309 as a prognostic marker in CLL.
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| 20. |
- Kaderi, Mohd Arifin, et al.
(författare)
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LPL is the strongest prognostic factor in a comparative analysis of RNA-based markers in early chronic lymphocytic leukemia
- 2011
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Ingår i: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 0390-6078 .- 1592-8721. ; 96:8, s. 1153-1160
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:The expression levels of LPL, ZAP70, TCL1A, CLLU1 and MCL1 have recently been proposed as prognostic factors in chronic lymphocytic leukemia. However, few studies have systematically compared these different RNA-based markers.DESIGN AND METHODS:Using real-time quantitative PCR, we measured the mRNA expression levels of these genes in unsorted samples from 252 newly diagnosed chronic lymphocytic leukemia patients and correlated our data with established prognostic markers (for example Binet stage, CD38, IGHV gene mutational status and genomic aberrations) and clinical outcome.RESULTS:High expression levels of all RNA-based markers, except MCL1, predicted shorter overall survival and time to treatment, with LPL being the most significant. In multivariate analysis including the RNA-based markers, LPL expression was the only independent prognostic marker for overall survival and time to treatment. When studying LPL expression and the established markers, LPL expression retained its independent prognostic strength for overall survival. All of the RNA-based markers, albeit with varying ability, added prognostic information to established markers, with LPL expression giving the most significant results. Notably, high LPL expression predicted a worse outcome in good-prognosis subgroups, such as patients with mutated IGHV genes, Binet stage A, CD38 negativity or favorable cytogenetics. In particular, the combination of LPL expression and CD38 could further stratify Binet stage A patients.CONCLUSIONS:LPL expression is the strongest RNA-based prognostic marker in chronic lymphocytic leukemia that could potentially be applied to predict outcome in the clinical setting, particularly in the large group of patients with favorable prognosis.
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