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1.
  • Bin Kaderi, Mohamed Arifin, 1978- (författare)
  • Assessment of Novel Molecular Prognostic Markers in Chronic Lymphocytic Leukemia
  • 2010
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • The clinical course of chronic lymphocytic leukemia (CLL) is highly heterogeneous, which has prompted 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 GNAS1, BCL2 and MDM2 genes and the RNA expression levels of the LPL, ZAP70, TCL1, CLLU1 and MCL1 genes were suggested as novel prognostic markers in CLL. In papers I-III, we performed genotyping analyses of the GNAS1 T393C, BCL2 -938C>A and MDM2 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. In paper IV, we measured the RNA expression levels of LPL, ZAP70, TCL1, CLLU1 and MCL1 in 252 CLL cases and correlated these levels with clinical outcome. Here, we verified that high expression of all these RNA-based markers, except MCL1, were associated with an unfavourable prognosis. We also confirmed a close relationship between IGHV mutation status and the RNA-based markers, especially for LPL and CLLU1 expression. Among the RNA-based markers, multivariate analysis revealed LPL 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 LPL expression status giving the most significant results. In summary, data from papers I-III could not verify the GNAS1 T393C, BCL2 -938C>A and MDM2 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 LPL expression appears to be the strongest among the RNA-based markers for CLL prognostication. Further efforts to standardize LPL quantification are required before it can be applied in the clinical laboratory to predict clinical outcome in this disease.
2.
  • Norberg, Maria, 1976- (författare)
  • In Vitro Drug Sensitivity and Apoptosis in Chronic Lymphocytic Leukemia
  • 2010
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • 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. In paper I-II, the in vitro 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. 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. In paper III, the anti-apoptotic BCL2 family member BFL1 was evaluated in 37 CLL cases. Levels of BFL1 were higher in fludarabine-resistant patients compared to fludarabine-sensitive patients. In addition, the high expression of BFL1 inversely correlated to fludarabine-induced apoptosis in CLL cells. A single nucleotide polymorphism in the anti-apoptotic BCL2 gene (-938C>A) has been suggested as a novel poor-prognostic marker in CLL. In paper IV, we investigated this BCL2 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. 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>A polymorphism does not appear to have any prognostic significance.
3.
  • 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.
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4.
  • Rostami, Elham, 1979- (författare)
  • Traumatic brain injury in humans and animal models
  • 2012
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • Traumatic brain injuries (TBI) are receiving increasing attention due to a combination of injuries related to war and sports, as well as to an increasing number of traffic accident survivors. Today the leading cause of death in young adults in industrialized nations is traumatic brain injury and in the population under 35 years, the death rate is 3.5 times that of cancer and heart disease combined. Despite a major improvement in the outcome of TBI in the acute setting, the assessment, therapeutic interventions and prevention of long-term complications remain a challenge. The challenges today are primarily related to a rapid diagnosis, identification of patient’s pathophysiological heterogeneity and to limit the secondary injuries. TBI is a complex condition that can be caused by focal or diffuse primary impacts that may initiate complex secondary neurochemical processes that proceeds over hours and days. The major secondary events include neuronal death, ischemia, excitotoxicity, mitochondrial failure, oxidative stress, oedema and inflammation. In addition, the brain’s restorative capacity involving neurotrophins, in particular brain derived neurotrophic factor (BDNF), is triggered. Animal models are necessary to gain a deeper insight into the events that follow a TBI, and to ultimately apply the findings to the clinical setting. The aim of this thesis was to identify distinct pathological processes in different types of TBI by using animal models that mimic distinct types of TBI found in patients. We investigated alterations in gene expression, serum biomarkers and secondary processes such as inflammatory response involving the complement cascade. In addition we aimed to assess the effects of heterogeneity of TBI patients, based on their genetic background, on the outcome of TBI, with specific focus on BDNF. We used animal models to mimic three major types of TBI; blast wave, penetrating and rotational acceleration TBI. We found distinct profiles of alteration in gene expression in these models. The histological findings in blast and rotational TBI indicated these injuries to be mild. The hallmark of the rotational TBI was axonal injuries found in anatomical locations comparable with clinical findings in diffuse axonal injuries (DAI) in humans. Despite the mild type of injury displayed in the histology and behavioural outcome, significant increases in the serum biomarkers Tau, S100B, NF-H and MBP were observed up to 2 weeks following the injury. The complement cascade was initiated in both penetrating and rotational TBI, detected by C1q and C3. However, the terminal pathway that generates cell death, detected by C5b9, was only activated in the penetrating TBI. This suggests that axonal injuries and secondary axotomy found in the rotational TBI are not complement mediated. In order to investigate whether genetic heterogeneity can be used to predict injury outcome and brain plasticity following TBI, we targeted the ApoE ε4 allele and the BDNF gene. We investigated whether there was an association between the presence of the ApoE ε4 allele and BDNF polymorphisms and cognitive outcome in veterans who had suffered penetrating head injury. We found that the genetic polymorphisms of BDNF predict general intelligence following penetrating TBI. Subsequently we investigated the expression of BDNF and its receptors TrkB-full length, TrkB-truncated and p75NTR, in animals exposed to penetrating TBI. The expression of TrkB truncated and p75NTR was altered in the chronic phase. In summary, these results show the importance of categorizing the different types of TBI, not only through the use of animal models but also in the clinical setting. Each type of TBI shows distinct patterns of gene expression, behavioural outcome, and morphological changes that may be reflected in the release of serum biomarkers. In the clinical setting, the situation is further complicated by the coexistence of different types of injuries. In addition to this, the genetic background of each patient contributes to the heterogeneity of TBI pathology as well as their ability to recover. The use of distinct types of TBI models will provide essential information about the underlying pathology, which can then be applied to the clinical setting. This will contribute to the establishment of better diagnostic tools as well as more individualized treatment approaches.
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5.
  • 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.
6.
  • Zainuddin, Norafiza, 1978- (författare)
  • Molecular Genetic Analysis in B-cell Lymphomas A Focus on the p53 Pathway and p16INK4a
  • 2010
  • Doktorsavhandling (övrigt vetenskapligt)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.
7.
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8.
  • Kaderi, Mohd Arifin, et al. (författare)
  • LPL is the strongest prognostic factor in a comparative analysis of RNA-based markers in early chronic lymphocytic leukemia
  • 2011
  • Ingår i: Haematologica (online). - 0390-6078 .- 1592-8721. ; 96:8, s. 1153-1160
  • 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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9.
  • 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)
10.
  • Halldórsdóttir, Anna Margrét, 1973- (författare)
  • Genetic and Epigenetic Profiling of Mantle Cell Lymphoma and Chronic Lymphocytic Leukemia
  • 2011
  • Doktorsavhandling (övrigt vetenskapligt)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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