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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>
  • Cutas, Daniela, 1978-, et al. (författare)
  • Legal imperialism in the regulation of stem cell research and therapy: the problem of extraterritorial jurisdiction
  • 2010
  • Ingår i: Capps BJ & Campbell AV (eds.). CONTESTED CELLS: Global Perspectives on the Stem Cell Debate. - London : Imperial College Press. - 978-1-84816-437-6 ; s. 95-119
  • Bokkapitel (övrigt vetenskapligt)abstract
    • Countries worldwide have very different national regulations on human embryonic stem (ES) cell research, informed by a range of ethical values. Some countries find reason to extend the applicability of their regulations on such research to its citizens when they visit other countries. Extraterritorial jurisdiction has recently been identified as a potential challenge towards global regulation of ES cell research. This chapter explores the implications and impact of extraterritorial jurisdiction and global regulation of ES cell research on researchers, clinicians and national health systems, and how this may affect patients. The authors argue that it would make ethical sense for ES cell restrictive countries to extend its regulations on ES cell research beyond its borders, because, if these countries really consider embryo destruction to be objectionable on the basis on the status of the embryo, then they ought to count it morally on par with murder (and thus have a moral imperative to protect embryos from the actions of its own citizens). However, doing so could lead to a legal situation that would result in substantial harm to central values in areas besides research, such as health care, the job market, basic freedom of movement, and strategic international finance and politics. Thus, it seems that restrictive extraterritorial jurisdiction in respect to ES cell research would be deeply problematic, given that the ethical permissibility of ES cell research is characterised by deep and wide disagreement.
  • Stattin, Pär, et al. (författare)
  • Surveillance and deferred treatment for localized prostate cancer : Population based study in the National Prostate Cancer Register of Sweden
  • 2008
  • Ingår i: Journal of Urology. - Baltimore : Williams and Wilkins. - 0022-5347 .- 1527-3792. ; 180:6, s. 2423-2430
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>PURPOSE: To what extent active surveillance and deferred treatment for localized risk prostate cancer are used is unclear. We assessed the use of surveillance and of deferred treatment in a population based, nationwide cohort in Sweden.</p> <p>MATERIALS AND METHODS: In the National Prostate Cancer Register of Sweden, with a 98% coverage vs the compulsory Swedish Cancer Registry, we identified 8,304 incident cases of prostate cancer in 1997 to 2002 with age younger than 70 years, clinical local stage T1 or 2, N0 or Nx, M0 or Mx and serum prostate specific antigen less than 20 ng/ml. Data were extracted from medical charts for 7,782 of these men (94%) at a median of 4 years after diagnosis.</p> <p>RESULTS: Primary treatment was surveillance for 2,065 men (26%), radical prostatectomy for 3,722 (48%), radiotherapy for 1,632 (21%) and hormonal treatment for 363 (5%). Men on surveillance had lower local tumor stage, grade and prostate specific antigen, and were older than those who received active primary treatment (p &lt;0.001). After a median surveillance of 4 years 711 men (34%) on surveillance had received deferred treatment, which was radical prostatectomy for 279 (39%), radiotherapy for 212 (30%) and hormonal treatment for 220 (30%).</p> <p>CONCLUSIONS: Surveillance was a common treatment for patients younger than 70 years with localized prostate cancer in Sweden in 1997 to 2002, 26% of men with localized prostate cancer started surveillance and after a median followup of 4 years, 66% of these men remained on surveillance.</p>
  • Aulin, Cecilia, 1979- (författare)
  • Extracellular Matrix Based Materials for Tissue Engineering
  • 2010
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>The extracellular matrix is (ECM) is a network of large, structural proteins and polysaccharides, important for cellular behavior, tissue development and maintenance. Present thesis describes work exploring ECM as scaffolds for tissue engineering by manipulating cells cultured <em>in vitro</em> or by influencing ECM expression <em>in vivo</em>. By culturing cells on polymer meshes under dynamic culture conditions, deposition of a complex ECM could be achieved, but with low yields. Since the major part of synthesized ECM diffused into the medium the rate limiting step of deposition was investigated. This quantitative analysis showed that the real rate limiting factor is the low proportion of new proteins which are deposited as functional ECM. It is suggested that cells are pre-embedded in for example collagen gels to increase the steric retention and hence functional deposition.</p> <p>The possibility to induce endogenous ECM formation and tissue regeneration by implantation of growth factors in a carrier material was investigated. Bone morphogenetic protein-2 (BMP-2) is a growth factor known to be involved in growth and differentiation of bone and cartilage tissue. The BMP-2 processing and secretion was examined in two cell systems representing endochondral (chondrocytes) and intramembranous (mesenchymal stem cells) bone formation. It was discovered that chondrocytes are more efficient in producing BMP-2 compared to MSC. The role of the antagonist noggin was also investigated and was found to affect the stability of BMP-2 and modulate its effect. Finally, an injectable gel of the ECM component hyaluronan has been evaluated as delivery vehicle in cartilage regeneration. The hyaluronan hydrogel system showed promising results as a versatile biomaterial for cartilage regeneration, could easily be placed intraarticulary and can be used for both cell based and cell free therapies.</p>
  • Hörer, Tal M., 1971-, et al. (författare)
  • Complications but not obesity or diabetes mellitus have impact on the intraperitoneal lactate/pyruvate ratio measured by microdialysis
  • 2010
  • Ingår i: Scandinavian Journal of Gastroenterology. - 1502-7708. ; 45:1, s. 115-121
  • Tidskriftsartikel (refereegranskat)abstract
    • <p><strong>Objective</strong>: Studies have shown a higher risk of postoperative complications in diabetic and obese patients. An increased intraperitoneal lactate/pyruvate ratio as measured by microdialysis has been reported before postoperative complications have been discovered. It is not known whether diabetes or obesity have any influence on the intraperitoneal metabolism (lactate/pyruvate ratio, glucose, glycerol) in relation to major abdominal surgery. The aim of this study was to investigate the postoperative intraperitoneal and subcutaneous carbohydrate and fat metabolism as measured by microdialysis in obese and diabetic patients after major abdominal surgery without postoperative complications.</p><p><strong>Material and methods:</strong> Seven obese patients (body mass index &gt; 30 kg/m(2)) and six diabetic but non-obese patients were studied up to 48 h after major abdominal surgery and were compared with 31 non-diabetic, non-obese patients, all without complications. Microdialysis was performed to measure glucose, lactate, pyruvate and glycerol intraperitoneally and subcutaneously. The lactate/pyruvate ratio was calculated.</p><p><strong>Results:</strong> The lactate/pyruvate ratio did not differ between the groups. In the diabetic patients, glucose levels were higher intraperitoneally at both Days 1 and 2 compared to controls. Higher glycerol levels were found subcutaneously in obese patients at Day 2. CONCLUSIONS: The lactate/pyruvate ratio does not increase intraperitoneally after non-complicated major abdominal surgery in diabetic and obese patients. Obese patients have increased release of free fatty acids and glycerol subcutaneously, while diabetic patients show higher glucose levels intraperitoneally than controls.</p>
  • Löfgren, Magnus, 1979- (författare)
  • Behavioral effects of female sex steroid hormones <em></em> models of PMS and PMDD in Wistar rats<em></em>
  • 2009
  • Ingår i: Stress- och könshormoners verkningar på centrala nervsystemet. - Umaå : Department of Clinical Sciences, Division of Obstetrics and Gynecology. - 978-91-7264-796-1
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p><strong>Background </strong>Animal models can be used to mimic human conditions of psychopathology, and also as pre-clinical models to evaluate candidate drugs. With hormonal treatment it is possible to produce behavior in the rat which corresponds to the mental symptoms of pre-menstrual syndrome (PMS), and pre-menstrual dysphoric disorder (PMDD). PMS affects 25-30 % of all women in fertile age and 3-8% are diagnosed with the more severe condition PMDD. The cardinal mental symptoms are; irritability, mood-swings, depression, anxiety, fatigue, insomnia, difficulties with concentration and memory and learning difficulties. The symptoms of PMS/PMDD occur in the luteal phase in conjunction with increasing concentrations of progesterone (P4) and P4-metabolites. In anovulatory cycles the symptoms are absent. The hormones which produce the monthly reoccurring negative symptoms on mood are foremost the neuroactive metabolites; allopregnanolone (ALLO) and tetrahydro-deoxycorticosterone (THDOC). ALLO is produced by the corpus luteum, but can also be synthesized in the brain, both ALLO and THDOC can also be released from the adrenal cortex during stress. These steroids are active on the inhibitory GABA neurotransmitter system through the GABA<sub>A</sub> receptor, and the effects are similar to that of alcohol and benzodiazepines. These steroids have strong sedative and hypnotic effects. A paradox is that some individuals seem to react with negative mood on sex steroids while all fertile women have the cyclical steroid changes during the menstrual cycle. Some individuals are more sensitive to neuroactive steroids with influences of personality, heritability and stress factors.</p> <p><strong>Aims </strong>The thesis aims were to develop pre-clinical animal models of PMS/PMDD and to investigate induction of ALLO tolerance, individual sensitivity to neurosteroids and the interactions between chronic social stress and neurosteroids.</p> <p><strong>Methods </strong>In these studies male and female Wistar rats were used to test steroid hormone effects on learning and memory and behaviors analogous to negative mood symptoms. This was accomplished through hormonal treatment and a subsequent withdrawal period from P4 (P4) + estradiol (E2) (PEWD), or ALLO. To assess tolerance, memory and learning in the Morris water maze (MWM) was studied. Anxiety-like behaviors were tested with the elevated plus maze (EPM), open field test (OFT), and the intruder test (IT). The EPM or OFT was used to classify the rats as high or low responders on risk-taking and explorative behavior (HR/LR). For social ranking order assessment the tube test (TT) and food competition test (FCT) were used. Chronic social stress was accomplished through co-habituation with two older rats (chronic subordination stress). In female rats the estrous cycle followed using staining of vaginal smears. Concentration of corticosterone (CORT) was measured by radio-immuno-assay (RIA).</p> <p><strong>Results </strong>In the MWM ALLO pre-treatment produced tolerance to the acute negative ALLO effects. Both male and female rats showed behavioral correlations between the EPM and OFT tests, and correlations were also seen in CORT levels. Individuals with the stable trait of high risk-taking and explorative behavior (HR) were more sensitive to PEWD induction of anxiety-like behavior. These animals also showed decreased CORT levels during withdrawal. Chronic subordination stress enhanced the response to PEWD on measures of locomotor activity and social anxiety-like behavior.</p> <p><strong>Conclusions </strong>It is possible to induce tolerance to the negative ALLO effects on learning and memory. The animal models of anxiety-like behavior show an individual PEWD response profile where HR rats are more sensitive. Exposure to chronic social stress enhanced the PEWD response. Hence there are both inherent and environmental factors behind the behavioral response to steroid hormones in rats.</p>
  • Krakau, Karolina, 1968- (författare)
  • Energy Balance out of Balance after Severe Traumatic Brain Injury
  • 2010
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>The overall aim of the research presented here was to expand the knowledge on metabolic course and nutritional outcome in patients with severe traumatic brain injury and to analyze the use and accuracy of different methods of assessment.</p> <p>Study I, a systematic review of 30 articles demonstrated consistent data on increased metabolic rate, of catabolism and of upper gastrointestinal intolerance in the majority of the patients during early post injury period. Data also indicated a tendency of less morbidity and mortality in early fed patients.</p> <p>Study II, a retrospective survey, based on medical records of 64 patients from three regions in Sweden, showed that the majority of patients regained their independence in eating within six months post injury. However, energy intake was set at a low level and 68 % of the patients developed malnutrition with 10 to 29 % loss of initial body mass during the first and second month post injury.</p> <p>Study III, a questionnaire based study addressed to 74 care units caring for patients with severe traumatic brain injury showed that resources in terms of qualified staff members were reportedly good, but nutritional guidelines were adopted in less than half of the units, screening for malnutrition at admission was rarely performed and surveillance of energy intake declined when oral intake began. Moreover, assessment of energy requirements relied on calculations and the profession in charge to estimate energy requirement varied depending on nutritional route and unit speciality. At transferral between units nutritional information was lost.</p> <p>Study IV and V, a prospective descriptive study on metabolic course, energy balance and methods of assessment in six patients showed that patients were in negative energy balance from 3<sup>rd</sup> week post injury and lost 8-19 % of their initial body weight. Concurrent nutritional problems were difficulties in retaining enteral and/or parenteral nutrition delivery routes until oral feeding was considered satisfactory. The majority of methods for predicting energy expenditure agreed poorly with measured energy expenditure.  The Penn-State equation from 1998 was the only valid predictive method during mechanical ventilation.</p> <p>This thesis concludes that patients with moderate or severe traumatic brain injury exhibit a wide range of increased metabolic rate, catabolism and upper gastrointestinal intolerance during the early post-injury period. Most patients regain independence in eating, but develop malnutrition. Suggested explanations, other than the systemic disturbances early post injury, could be the use of inaccurate predictions of energy expenditure, deficient nutritional routines and difficulties in securing alternative nutritional routes until oral feeding is satisfactory. The impact of timing, content and ways of administration of nutritional support on neurological outcome after a severe traumatic brain injury remains to be demonstrated.</p>
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