Genetic and molecular background of pheochromocytoma and paraganglioma

Pheochromocytomas (PCC) and abdominal paragangliomas (PGL), collectively denoted PPGL, are neuroendocrine tumors (NET) with a highly diverse genetic and molecular etiology, arisen in the adrenal medulla and abdominal paraganglia respectively. The tumors often cause cardiovascular symptoms due to the high production of catecholamines, and malignancy occurs in 10% of the PCCs and 30% of the PGLs. The genetic background of the PPGL disease constitutes of hereditary mutations in a growing list of susceptibility genes, although a large subset of the sporadic tumors still has an unknown etiology. This thesis work aimed to further characterize the genetic and molecular background of PPGL, in order to contribute to better diagnosis, prognosis and treatment for the patients. In the first study we investigated the role of susceptibility gene promoter methylation in PPGL. By studying the gene expression and assessing the promoter methylation levels, it was found that the VHL gene is epigenetically inactivated in PPGL. Subsequently, in order to investigate the established susceptibility genes in a large cohort, we used a targeted sequencing approach in the second study and found that next-generation sequencing is fast and cost-effective method for mutational screening of PPGL. Additionally, the NF1 gene was found to be the most frequently mutated gene, and in the third study we used the NF1 mutational status obtained in the second study to investigate if immunohistochemistry could be used as a screening tool for NF1 mutations. We found a strong sensitivity but poor specificity for the method and therefore recommend genetic screening as the most efficient tool to identify NF1 patients. The list of PPGL susceptibility genes is constantly growing, and one of the latest genes verified is the HRAS gene. In the fourth study we screened a large cohort of PPGL for mutations in the HRAS gene and compared with the overall gene expression obtained using a mRNA microarray approach. Taken together with HRAS mutations in the literature, the overall HRAS mutation frequency was calculated to 5.2% in PPGL. The gene expression profiling showed that the HRAS mutated tumors clustered together with the NF1- and RET-mutated tumors that are associated with activation of kinase pathways. With the mutational information obtained in the second study, we were able to screen PCCs without known genetic drivers. In the fifth study, these tumors underwent whole-exome sequencing, detecting recurrent mutations in the KMT2D gene. After screening of a verification cohort, a total KMT2D mutation frequency of 14% was established. In the sixth study we screened PGLs for mutations in the KMT2D gene. All PGLs exhibited wild-type however KMT2D gene over-expression was observed in PGLs compared to normal adrenal samples. These results would imply dysregulation of methyltransferase as a novel disease mechanism in PPGL. In summary, the studies included in the thesis have increased the knowledge of the genetic and molecular background of PPGL. The results may therefore in the long run contribute to better diagnosis, prognosis and development of future treatment options for the patients

Планування ЗЕД на підприємствах малого та середнього бізнесу

Pheochromocytomas (PCC) and abdominal paragangliomas (PGL) display a highly diverse genetic background and recent gene expression profiling studies have shown that PCC and PGL (together PPGL) alter either kinase signaling pathways or the pseudo-hypoxia response pathway dependent of the genetic composition. Recurrent mutations in the Harvey rat sarcoma viral oncogene homolog (HRAS) have recently been verified in sporadic PPGLs. In order to further establish the HRAS mutation frequency and to characterize the associated expression profiles of HRAS mutated tumors, 156 PPGLs for exon 2 and 3 hotspot mutations in the HRAS gene was screened, and compared with microarray-based gene expression profiles for 93 of the cases. The activating HRAS mutations G13R, Q61R, and Q61K were found in 10/142 PCC (7.0%) and a Q61L mutation was revealed in 1/14 PGL (7.1%). All HRAS mutated cases included in the mRNA expression profiling grouped in Cluster 2, and 21 transcripts were identified as altered when comparing the mutated tumors with 91 HRAS wild-type PPGL. Somatic HRAS mutations were not revealed in cases with known PPGL susceptibility gene mutations and all HRAS mutated cases were benign. The HRAS mutation prevalence of all PPGL published up to date is 5.2% (49/950), and 8.8% (48/548) among cases without a known PPGL susceptibility gene mutation. The findings support a role of HRAS mutations as a somatic driver event in benign PPGL without other known susceptibility gene mutations. HRAS mutated PPGL cluster together with NF1- and RET-mutated tumors associated with activation of kinase-signaling pathways.Funding Agencies|Swedish Cancer Foundation; StratCan; Swedish Research Council; Cancer Research Foundations of Radiumhemmet; Karolinska Institutet; Stockholm County Council</p

Демографический потенциал Республики Беларусь

Материалы III Междунар. науч. конф. студентов, аспирантов и молодых ученых, Гомель, 20 мая 2010 г

Thought for Food: Understanding Educational Disparities in Food Consumption

__Abstract__ \n \nHigher educated individuals are healthier and live longer than their lower educated peers. One reason is that lower educated individuals engage more in unhealthy behaviours including consumption of a poor diet, but it is not clear why they do so. In this paper we develop an economic theory of unhealthy food choice, and use a Discrete Choice Experiment to discriminate between the theoretical parameters. Differences in health knowledge appear to be responsible for the greatest part of the education disparity in diet. However, when faced with the most explicit health information regarding diet, lower educated individuals still state choices that imply a lower concern for negative health consequences. This is consistent with a theoretical prediction that part of the education differences across health behaviours is driven by the "marginal value of health" rising with education

Equity and justice in global warming policy

Many countries are implementing or at least considering policies to counter increasingly certain negative impacts from climate change. An increasing amount of research has been devoted to the analysis of the costs of climate change and its mitigation, as well as to the design of policies, such as the international Kyoto Protocol, post-Kyoto negotiations, regional initiatives, and unilateral actions. Although most studies on climate change policies in economics have considered efficiency aspects, there is a growing literature on equity and justice. Climate change policy has important dimensions of distributive justice, both within and across generations, but in this paper we survey only studies on the intragenerational aspect, i.e.., within a generation. We cover several domains including the international, regional, national, sectoral and inter-personal, and examine aspects such as the distribution of burdens from climate change, climate change policy negotiations in general, implementation of climate agreements using tradable emission permits, and the uncertainty of alternatives to emission reductions

Assumption without representation: the unacknowledged abstraction from communities and social goods

We have not clearly acknowledged the abstraction from unpriceable “social goods” (derived from communities) which, different from private and public goods, simply disappear if it is attempted to market them. Separability from markets and economics has not been argued, much less established. Acknowledging communities would reinforce rather than undermine them, and thus facilitate the production of social goods. But it would also help economics by facilitating our understanding of – and response to – financial crises as well as environmental destruction and many social problems, and by reducing the alienation from economics often felt by students and the public

Fysioterapeutstudenters förhållningssätt till samband mellan funktionsnedsättning och långvarig ryggsmärta

Bakgrund: Patienter med långvarig ländryggssmärta upplever ofta funktionsnedsättning, utan att där finns en tydlig koppling till vävnadsskada. Funktionsnedsättning kan delvis vara skapad av vården, av att patienter har fått kontraproduktiva råd av vårdgivare. Syfte: Att undersöka attityder och attitydskillnader mellan studenter i termin 1 och 6 på fysioterapeutprogrammet vid Uppsala Universitet gällande kopplingen mellan långvarig ländryggssmärta och funktionsnedsättning, samt om den egna upplevelsen av smärta påverkar resultatet. Metod: Studenter i termin 1 respektive 6 på fysioterapeutprogrammet vid Uppsala Universitet svarade på Health Care Providers Pain and Impairment Relationship Scale (HC-PAIRS). HC-PAIRS mäter i hur stor utsträckning vårdpersonal associerar funktionsnedsättning med långvarig icke-specifik ländryggssmärta. Resultat: Termin 6 svarade signifikant lägre än termin 1, vilket betyder att studenterna i termin 1 har mer negativa förväntningar på funktionsförmågan hos patienter med ländryggssmärta (55 mot 46). Signifikanta skillnader fanns inom områdena “förväntningar på funktion”, “förväntningar på social förmåga” och “behov av bot”, men inte inom “projicerad kognition”. Egen upplevelse av smärta påverkade inte resultatet. Slutsats: Studenter i termin 6 har ett mer positivt synsätt på funktionsförmågan hos patienter med långvarig ländryggssmärta än studenter i termin 1. Spridningen är dock stor i båda terminerna.Background: Patients with persistent spinal pain often experience a loss of function, without a clear association with tissue damage. Loss of function may partly be healthcare caused, after patients being provided counterproductive advice by their caregiver. Purpose: To investigate the differences in attitudes among first term and last term physical therapy students at Uppsala University, in regards to persistent spinal pain and loss of function and to investigate if student’s own experience of persistent pain influences these attitudes. Method: The students answered the Health Care Providers Pain and Impairment Relations Scale (HC-PAIRS) Questionnaire. HC-PAIRS measures to what extent health care providers link loss of function to persistent spinal pain. Results: There was a significant difference between the semesters. The students in semester one having a higher overall score compared to the students in semester six (55,5 compared to 46). There were significant differences regarding “functional expectations”, “social expectations” and “need for cure”, but not in “projected cognition”. The students’ own experiences of persistent pain did not affect their scoring. Conclusion: Students in semester six had a more positive outlook on the functional ability among patients with persistent spinal pain than students in semester one. However, there was a vast spread of results within both semesters

Fysioterapeutstudenters förhållningssätt till samband mellan funktionsnedsättning och långvarig ryggsmärta

Bakgrund: Patienter med långvarig ländryggssmärta upplever ofta funktionsnedsättning, utan att där finns en tydlig koppling till vävnadsskada. Funktionsnedsättning kan delvis vara skapad av vården, av att patienter har fått kontraproduktiva råd av vårdgivare. Syfte: Att undersöka attityder och attitydskillnader mellan studenter i termin 1 och 6 på fysioterapeutprogrammet vid Uppsala Universitet gällande kopplingen mellan långvarig ländryggssmärta och funktionsnedsättning, samt om den egna upplevelsen av smärta påverkar resultatet. Metod: Studenter i termin 1 respektive 6 på fysioterapeutprogrammet vid Uppsala Universitet svarade på Health Care Providers Pain and Impairment Relationship Scale (HC-PAIRS). HC-PAIRS mäter i hur stor utsträckning vårdpersonal associerar funktionsnedsättning med långvarig icke-specifik ländryggssmärta. Resultat: Termin 6 svarade signifikant lägre än termin 1, vilket betyder att studenterna i termin 1 har mer negativa förväntningar på funktionsförmågan hos patienter med ländryggssmärta (55 mot 46). Signifikanta skillnader fanns inom områdena “förväntningar på funktion”, “förväntningar på social förmåga” och “behov av bot”, men inte inom “projicerad kognition”. Egen upplevelse av smärta påverkade inte resultatet. Slutsats: Studenter i termin 6 har ett mer positivt synsätt på funktionsförmågan hos patienter med långvarig ländryggssmärta än studenter i termin 1. Spridningen är dock stor i båda terminerna.Background: Patients with persistent spinal pain often experience a loss of function, without a clear association with tissue damage. Loss of function may partly be healthcare caused, after patients being provided counterproductive advice by their caregiver. Purpose: To investigate the differences in attitudes among first term and last term physical therapy students at Uppsala University, in regards to persistent spinal pain and loss of function and to investigate if student’s own experience of persistent pain influences these attitudes. Method: The students answered the Health Care Providers Pain and Impairment Relations Scale (HC-PAIRS) Questionnaire. HC-PAIRS measures to what extent health care providers link loss of function to persistent spinal pain. Results: There was a significant difference between the semesters. The students in semester one having a higher overall score compared to the students in semester six (55,5 compared to 46). There were significant differences regarding “functional expectations”, “social expectations” and “need for cure”, but not in “projected cognition”. The students’ own experiences of persistent pain did not affect their scoring. Conclusion: Students in semester six had a more positive outlook on the functional ability among patients with persistent spinal pain than students in semester one. However, there was a vast spread of results within both semesters