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  • Bin Kaderi, Mohamed Arifin, 1978- (författare)
  • Assessment of Novel Molecular Prognostic Markers in Chronic Lymphocytic Leukemia
  • 2010
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>The clinical course of chronic lymphocytic leukemia (CLL) is highly heterogeneous, which has prompted<sup> </sup>the search for biomarkers that can predict prognosis in this disease. The IGHV gene mutation status and certain genomic aberrations have been identified as reliable prognostic markers of clinical outcome for this disorder. However, the search for more feasible prognostic markers in CLL is still being pursued. Recently, certain single nucleotide polymorphisms (SNPs) in the <em>GNAS1</em>, <em>BCL2</em> and <em>MDM2</em> genes and the RNA expression levels of the <em>LPL</em>, <em>ZAP70</em>, <em>TCL1, CLLU1 </em>and <em>MCL1</em> genes were suggested as novel prognostic markers in CLL.</p> <p>In papers I-III, we performed genotyping analyses of the <em>GNAS1</em> T393C, <em>BCL2</em> -938C&gt;A and <em>MDM2</em> SNP309 polymorphisms in 268-418 CLL patients and related the genotypes with clinical data. Association studies between the polymorphisms and established prognostic markers (i.e. IGHV mutation status, genomic aberrations, CD38 expression) were also performed. Our studies did not find any significant relationship between these SNPs with either clinical outcome or other known prognostic markers in CLL.</p> <p>In paper IV, we measured the RNA expression levels of <em>LPL</em>, <em>ZAP70</em>, <em>TCL1,</em> <em>CLLU1</em> and <em>MCL1</em> in 252 CLL cases and correlated these levels with clinical outcome. Here, we verified that high expression of all these RNA-based markers, except <em>MCL1</em>, were associated with an unfavourable prognosis. We also confirmed a close relationship between IGHV mutation status and the RNA-based markers, especially for <em>LPL</em> and <em>CLLU1</em> expression. Among the RNA-based markers, multivariate analysis revealed <em>LPL</em> expression as the strongest independent prognostic marker for overall survival and time to treatment. Furthermore, the RNA-based markers could add further prognostic information to established markers in subgroups of patients, with <em>LPL</em> expression status giving the most significant results.</p> <p>In summary, data from papers I-III could not verify the <em>GNAS1</em> T393C, <em>BCL2</em> -938C&gt;A and <em>MDM2 </em>SNP309 polymorphisms as prognostic markers in CLL. Future SNP markers must hence be confirmed in large, independent cohorts before being proposed as prognostic marker in CLL. In paper IV, we conclude that <em>LPL</em> expression appears to be the strongest among the RNA-based markers for CLL prognostication. Further efforts to standardize <em>LPL</em> quantification are required before it can be applied in the clinical laboratory to predict clinical outcome in this disease.<em></em></p>
  • Norberg, Maria, 1976- (författare)
  • <em>In Vitro</em> Drug Sensitivity and Apoptosis in Chronic Lymphocytic Leukemia
  • 2010
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Chronic lymphocytic leukemia (CLL) is a heterogeneous malignancy displaying varying clinical outcome, where molecular markers today can divide patients into prognostic subgroups. Despite the introduction of new agents for treatment, remissions are usually not sustained in CLL and resistance towards treatment can partly be explained by aberrant apoptosis. The aim of this thesis was to find new drugs for CLL patients resistant to conventional therapy and to analyze genes involved in apoptosis within different prognostic subgroups.</p> <p>In paper I-II, the <em>in vitro</em> activity of substances was investigated using the fluorometric microculture cytotoxicity assay (FMCA). When evaluating rapamycin (paper I), an inhibitor of mTOR, in 97 tumor samples from different entities, CLL was found to be one of the most sensitive tumor types. Combination experiments on patient CLL cells indicated that rapamycin acted synergistically with the CLL drugs vincristine and chlorambucil.</p> <p>An investigation of 20 anti-cancer agents in cells from 40 CLL patients (paper II) revealed that prednisolone and rolipram displayed high activity in poor-prognostic patients, in particular IGHV unmutated CLL. Furthermore, when used in combination these agents were found to produce a synergistic effect.</p> <p>In paper III, the anti-apoptotic BCL2 family member <em>BFL1</em> was evaluated in 37 CLL cases. Levels of <em>BFL1</em> were higher in fludarabine-resistant patients compared to fludarabine-sensitive patients. In addition, the high expression of <em>BFL1</em> inversely correlated to fludarabine-induced apoptosis in CLL cells.</p> <p>A single nucleotide polymorphism in the anti-apoptotic <em>BCL2</em> gene (-938C&gt;A) has been suggested as a novel poor-prognostic marker in CLL. In paper IV, we investigated this<em> BCL2</em> polymorphism in 268 CLL patients and correlated genotypes to clinical data. However, no association could be confirmed between this polymorphism and clinical outcome or established prognostic markers.</p> <p>In conclusion, this thesis has shown that rapamycin is a potential drug for treatment in CLL. Furthermore, prednisolone and rolipram were identified as interesting candidates for treatment of poor-prognostic patients. Finally, the anti-apoptotic protein BFL1 may contribute to chemoresistance and hence represents a potential therapeutic target in CLL, whereas from our data, the BCL2 -938C&gt;A polymorphism does not appear to have any prognostic significance.</p>
  • Munthe, Christian, 1962- (författare)
  • Etiska aspekter på regenerativ medicin Ethical aspects on regenerative medicine
  • 2003
  • Ingår i: SNIB-konferensen 2003, Chalmers tekniska högskola, Göteborg, 16-18 maj 2003.
  • Konferensbidrag (övrigt vetenskapligt)abstract
    • Inom den regenerativa medicinen strävar man efter att ersätta skadat eller sjukligt biologiskt mänskligt material (celler, organ, kroppsdelar) med nya biologiska komponenter. Området aktualiserar en rad etiska frågeställningar vad gäller (1) produktionen av ersättningsmaterialet (t.ex. embryonala stamceller eller införskaffande av transplantationsvävnad från donatorer), (2) risker i samband med försök på människa (genmodifierat material, material från djur), samt (3) gränserna för hur långt man bör gå i denna slags försök att förlänga människans livsspann. Föredraget ger en kort översikt över dessa frågeställningar, ståndpunkter och argument i debatten kring dem.
  • Munthe, Christian, 1962-, et al. (författare)
  • The Return of Lombroso? Ethical Aspects of (Visions of) Preventive Forensic Screening
  • 2015
  • Ingår i: Public Health Ethics. - 1754-9973 .- 1754-9981. ; 8:3, s. 270-283
  • Tidskriftsartikel (refereegranskat)abstract
    • The vision of legendary criminologist Cesare Lombroso to use scientific theories of individual causes of crime as a basis for screening and prevention programmes targeting individuals at risk for future criminal behaviour has resurfaced, following advances in genetics, neuroscience and psychiatric epidemiology. This article analyses this idea and maps its ethical implications from a public health ethical standpoint. Twenty-seven variants of the new Lombrosian vision of forensic screening and prevention are distinguished, and some scientific and technical limitations are noted. Some lures, biases and structural factors, making the application of the Lombrosian idea likely in spite of weak evidence are pointed out and noted as a specific type of ethical aspect. Many classic and complex ethical challenges for health screening programmes are shown to apply to the identified variants and the choice between them, albeit with peculiar and often provoking variations. These variations are shown to actualize an underlying theoretical conundrum in need of further study, pertaining to the relationship between public health ethics and the ethics and values of criminal law policy.
  • Zainuddin, Norafiza, 1978- (författare)
  • Molecular Genetic Analysis in B-cell Lymphomas<em></em> A Focus on the p53 Pathway and <em>p16<sup>INK4a</sup></em>
  • 2010
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>The presence of <em>TP53</em> mutations has been associated with inferior outcome in diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL).<em> </em>In DLBCL, the impact of the <em>TP53</em> codon 72 polymorphism and <em>MDM2</em> SNP309 has not been clearly elucidated, whereas <em>MDM2</em> SNP309 was suggested as a poor-prognostic marker in CLL. In addition, <em>p16<sup>INK4a</sup> </em>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.</p> <p>In paper I, we investigated the prognostic role of <em>TP53</em> mutation, codon 72 polymorphism and <em>MDM2</em> SNP309 in DLBCL (n=102). The presence of <em>TP53</em> 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 <em>MDM2</em> SNP309 nor the <em>TP53</em> codon 72 polymorphism had an impact on age of onset or survival. In paper II, we applied pyrosequencing to measure the level of <em>p16<sup>INK4a</sup></em> methylation in DLBCL (n=113). Thirty-seven percent of cases displayed <em>p16<sup>INK4a</sup></em> methylation; however, no clear association could be observed between degree of methylation and clinical characteristics or lymphoma-specific survival.</p> <p>In papers III–IV, we investigated the prognostic role of <em>MDM2</em> SNP309 (n=418) and <em>TP53</em> mutation (n=268) in CLL. No correlation was observed between any particular <em>MDM2</em> SNP309 genotype and time to treatment and overall survival.<strong> </strong>Furthermore, no association was found between the different <em>MDM2</em> SNP309 genotypes and established CLL prognostic markers. <em>TP53</em> mutations were detected in 3.7% of CLL patients; where the majority showed a concomitant 17p-deletion and only three carried <em>TP53</em> mutations without 17p-deletion. We confirmed a significantly shorter overall survival and time to treatment in patients with both <em>TP53</em> mutation and 17p-deletion.</p> <p>Altogether, our studies could confirm the negative prognostic impact of <em>TP53</em> mutations in DLBCL, whereas <em>MDM2</em> SNP309 and <em>TP53</em> codon 72 polymorphisms appear to lack clinical relevance. We also question the role of <em>p16<sup>INKa</sup></em> methylation as a poor-prognostic factor in DLBCL. Finally, the presence of <em>TP53</em> mutation in CLL appears to be rare at disease onset and instead arise during disease progression.</p>
  • Munthe, Christian, 1962- (författare)
  • Will IVF ever be the norm?
  • 2014
  • Ingår i: Future of IVF - A Brave New World? ESHRE symposium, September 26-27, Stockholm.
  • Konferensbidrag (övrigt vetenskapligt)
  • Halldórsdóttir, Anna Margrét, 1973- (författare)
  • Genetic and Epigenetic Profiling of Mantle Cell Lymphoma and Chronic Lymphocytic Leukemia
  • 2011
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>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 <em>IGHV</em> mutational status and into multiple subsets based on closely homologous (stereotyped) B-cell receptors. In <strong>paper I</strong> 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 <em>ZFP64</em>. 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 <strong>paper II</strong> we sequenced exons 4 to 8 of the <em>TP53</em> gene in 119 MCL cases. 17p copy-number status was known from previous studies or determined by real-time quantitative polymerase chain reaction. <em>TP53</em> 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 <strong>papers III</strong> and <strong>IV</strong> we applied high-resolution genomic 27K methylation arrays to 20 MCL and 39 CLL samples. In <strong>paper III</strong> 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 <strong>paper IV</strong> we compared three different stereotyped CLL subsets: #1 (<em>IGHV</em> unmutated), #2 (<em>IGHV3-21</em>) and #4 (<em>IGHV</em> mutated). Many genes were differentially methylated between each two subsets and immune response genes (e.g. <em>CD80</em> and <em>CD86</em>) were enriched among genes methylated in subset #1 but not in subsets #2/#4.</p> <p>In summary, CNAs were frequent and not random in MCL. Specific CNAs correlated with a high proliferation gene expression signature or genomic complexity. <em>TP53</em> 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.</p>
  • Karypidis, A.-H., et al. (författare)
  • Deletion polymorphism of the UGT2B17 gene is associated with increased risk for prostate cancer and correlated to gene expression in the prostate
  • 2008
  • Ingår i: The Pharmacogenomics Journal. - Avenet, NJ : Nature Pub. Group. - 1470-269X .- 1473-1150. ; 8:2, s. 147-151
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Metabolism of androgens includes glucuronidation, the major pathway of steroid elimination in several steroid target tissues. Glucuronidation is catalysed by UDP-glucuronosyltransferases (UGTs). UGT2B17 has been shown to be particularly active against androgens and is highly abundant in the prostate. Recently, we discovered that deletion of the UGT2B17 gene is associated with low or undetectable urinary testosterone levels. Here, we determined the phenotypic outcome of the deletion by quantifying the UGT2B17 mRNA expression in normal prostate tissues in individuals with different genotypes. Additionally, the frequency of UGT2B17 deletion polymorphism was studied in a Swedish population-based case–control study including 176 patients diagnosed with prostate cancer and 161 controls. We found that the individuals homozygous for the insertion allele expressed 30 times more UGT2B17 mRNA in prostate tissue than the heterozygotes. Carriers of the deletion allele had a significantly increased risk of prostate cancer (OR=2.07; 95% CI=1.32–3.25). In conclusion, these results show the UGT2B17 deletion polymorphism is associated with prostate cancer risk. </p>
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