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- Juth, Niklas, 1973, et al.
(author)
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The Ethics of Screening in Health Care and Medicine: Serving Society or Serving the Patient?
- 2012
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Book (other academic/artistic)abstract
- Medical or health-oriented screening programs are amongst the most debated aspects of health care and public health practices in health care and public health ethics, as well as health policy discussions. In spite of this, most treatments of screening in the research literature restrict themselves to isolated scientific aspects, sometimes complemented by economic analyses or loose speculations regarding policy aspects. At the same time, recent advances in medical genetics and technology, as well as a rapidly growing societal focus on public health concerns, inspires an increase in suggested or recently started screening programs. This book involves an in-depth analysis of the ethical, political and philosophical issues related to health-oriented screening programs. It explores the considerations that arise when heath care interacts with other societal institutions on a large scale, as is the case with screening: What values may be promoted or compromised by screening programs? What conflicts of values do typically arise – both internally and in relation to the goals of health care, on the one hand, and the goals of public health and the general society, on the other? What aspects of screening are relevant for determining whether it should be undertaken or not and how it should be organised in order to remain defensible? What implications does the ethics of screening have for health care ethics as a whole? These questions are addressed by applying philosophical methods of conceptual analysis, as well as models and theories from moral and political philosophy, medical ethics, and public health ethics, to a large number of ongoing and proposed screening programs which makes this book the first comprehensive work on the ethics of screening. Analyses and suggestions are made that are of potential interest to health care staff, medical researchers, policy makers and the general public.
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| 2. |
- Bin Kaderi, Mohamed Arifin, 1978-
(author)
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Assessment of Novel Molecular Prognostic Markers in Chronic Lymphocytic Leukemia
- 2010
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Doctoral thesis (other academic/artistic)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.
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| 3. |
- Norberg, Maria, 1976-
(author)
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In Vitro Drug Sensitivity and Apoptosis in Chronic Lymphocytic Leukemia
- 2010
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Doctoral thesis (other academic/artistic)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.
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| 6. |
- Munthe, Christian, 1962
(author)
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The Price of Precaution and the Ethics of Risk
- 2011
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Book (other academic/artistic)abstract
- Since a couple of decades, the notion of a precautionary principle plays a central and increasingly influential role in international as well as national policy and regulation regarding the environment and the use of technology. Urging society to take action in the face of potential risks of human activities in these areas, the recent focus on climate change has further sharpened the importance of this idea. However, the idea of a precautionary principle has also been problematised and criticised by scientists, scholars and policy activists, and been accused of almost every intellectual sin imaginable: unclarity, impracticality, arbitrariness and moral as well as political unsoundness. In that light, the very idea of precaution as an ideal for policy making rather comes out as a dead end. On the basis of these contrasting starting points, Christian Munthe undertakes an innovative, in-depth philosophical analysis of what the idea of a precautionary principle is and should be about. A novel theory of the ethics of imposing risks is developed and used as a foundation for defending the idea of precaution in environmental and technological policy making against its critics, while at the same time avoiding a number of identified flaws. The theory is shown to have far-reaching consequences for areas such as bio-, information- and nuclear technology, and global environmental policy in areas such as climate change. The author argues that, while the price we pay for precaution must not be too high, we have to be prepared to pay it in order to act ethically defensible. A number of practical suggestions for precautionary regulation and policy making are made on the basis of this, and some challenges to basic ethical theory as well as consumerist societies, the global political order and liberal democracy are identified
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| 7. |
- Nord, Helena, 1980-
(author)
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Application of Genomic and Expression Arrays for Identification of new Cancer Genes
- 2010
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Doctoral thesis (other academic/artistic)abstract
- Copy number variation (CNV) comprises a recently discovered kind of variation involving deletion and duplication of DNA segments of variable size, ranging from a few hundred basepairs to several million. By altering gene dosage levels or disrupting proximal or distant regulatory elements CNVs create human diversity. They represent also an important factor in human evolution and play a role in many disorders including cancer. Array-based comparative genomic hybridization as well as expression arrays are powerful and suitable methods for determination of copy number variations or gene expression changes in the human genome. In paper I we established a 32K clone-based genomic array, covering 99% of the current assembly of the human genome with high resolution and applied it in the profiling of 71 healthy individuals from three ethnic groups. Novel and previously reported CNVs, involving ~3.5% of the genome, were identified. Interestingly, 87% of the detected CNV regions overlapped with known genes indicating that they probably have phenotypic consequences. In papers II through IV we applied this platform to different tumor types, namely two collections of brain tumors, glioblastoma (paper II) and medulloblastoma (paper III), and a set of bladder carcinoma (paper IV) to identify chromosomal alterations at the level of DNA copy number that could be related to tumor initiation/progression. Tumors of the central nervous system represent a heterogeneous group of both benign and malignant neoplasms that affect both children and adults. Glioblastoma and medulloblastoma are two malignant forms. Glioblastoma often affects adults while the embryonal tumor medulloblastoma is the most common malignant brain tumor among children. The detailed profiling of 78 glioblastomas, allowed us to identify a complex pattern of aberrations including frequent and high copy number amplicons (detected in 79% of samples) as well as a number of homozygously deleted loci. These regions encompassed not only previously reported oncogenes and tumor suppressor genes but also numerous novel genes. In paper III, a subset of 26 medulloblastomas was analyzed using the same genomic array. We observed that alterations involving chromosome 17, especially isochromosome 17q, were the most common genomic aberrations in this tumor type, but copy number alterations involving other chromosomes: 1, 7 and 8 were also frequent. Focal amplifications, on chromosome 1 and 3, not previously described, were also detected. These loci may encompass novel genes involved in medulloblastoma development. In paper IV we examined for the presence of DNA copy number alterations and their effect on gene expression in a subset of 21 well-characterized Ta bladder carcinomas, selected for the presence or absence of recurrences. We identified a number of novel genes as well as a significant association between amplifications and high-grade and recurrent tumors which might be clinically useful. The results derived from these studies increase our understanding of the genetic alterations leading to the development of these tumor forms and point out candidate genes that may be used in future as targets for new diagnostic and therapeutic strategies.
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| 8. |
- Munthe, Christian, 1962
(author)
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Will IVF ever be the norm?
- 2014
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In: Future of IVF - A Brave New World? ESHRE symposium, September 26-27, Stockholm.
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Conference paper (other academic/artistic)
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