64 research outputs found
Telomeres and telomerase and their functional applications in myeloproliferative neoplasms and acute myeloid leukemia
Myeloproliferative neoplasms (MPNs) are a group of diseases characterized by hyperproliferation in the myeloid lineages of the bone marrow, leading to increased levels of circulating mature blood cells from one or more lineages. MPNs consist of polycythemia vera, essential thrombocythemia and primary myelofibrosis. Several recurrent mutations are seen in MPNs, most of them resulting in an activation of the JAK/STAT signaling pathway. Telomeres are non-coding repetitive sequences of DNA located at the end of chromosomes. The telomeres are shortened with every cell division and when they become critically short, the cells enter a permanent growth arrest state called replicative senescence. When the telomeres are very short, the cells become genetically unstable and are more susceptible to genetic aberrations. There is accumulating evidence for a role for telomere dysregulation in the pathogenesis of MPNs and AML, and the overall aim of the studies included in this thesis was to better define this role.
To clarify a potential dysregulation of telomeres and telomere associated proteins in MPNs, we studied the telomere length (TL), TERT expression and expression of telomere associated proteins in 81 patients with MPNs and 43 healthy controls. We found that patients with MPNs have shorter telomeres in their granulocytes compared to that of healthy controls, but also compared to the patientsâ own lymphoid cells. There was no difference in TERT expression between patients and controls. The expression of two positive regulators of TL was lower, and the expression of two negative regulators of TL was higher in patients with MPNs. The dysregulation of telomere binding proteins may contribute to the telomere shortening seen in MPNs.
Genetic variants in the TERT locus are implicated in susceptibility to cancer and other diseases. Recent reports also revealed an association between the SNP TERT rs2736100_CC genotype and the risk of developing MPNs in Caucasian populations. We genotyped patients and healthy controls from Sweden and China and found that the TERT rs2736100_C allele is associated with an increased risk of MPN development in both populations. The association of the C-allele with an increased risk of MPNs was only seen in male MPN patients, who generally have a worse outcome than female MPN patients. Moreover, the Chinese healthy population had significantly lower frequency of the TERT rs2736100_C allele compared to their Swedish counterpart, which may contribute to the lower MPN incidence seen in China compared to that in Europe. Patients with the TERT rs2736100_CC had the highest TERT expression, which may make them more susceptible to develop MPNs.
The evolution of an acute promyelocytic leukemia (APL)-clone in a patient with a very late relapse was studied to distinguish between a relapse of the first APL, a secondary APL or a second de novo APL, and thereby guide future treatment decisions. Based on identical breakpoints of the PML-RARα gene, but differences in genetic aberrations and mutations in the FLT3-gene, we conclude that the patient most likely suffered a true relapse of her initial APL. We hypothesize that the PML-RARα- bearing pre-leukemic clone survived the initial chemotherapy and did not develop into an APL until seventeen years later, when the clone acquired another FLT3 mutation and other genetic aberrations.
JAK2 inhibitors have proven effective in reducing symptoms and splenomegaly in patients with myelofibrosis, but they do not eliminate the disease initiating clones. A telomerase inhibitor is in clinical trials for MF with promising results, but with severe myelosuppression as a side-effect. We studied the effect of the JAK2 inhibitor LY2784544 in combination with the telomerase inhibitor GRN163L in a JAK2V617F âbearing erythroleukemia cell line. The combination had a larger effect on viability and number of cells than either of the drugs alone. Treatment with LY2784544 alone increased the fraction of HEL cells expressing the stem cell marker CD34, an effect that was partially mediated by an up-regulation of the transcription factor KLF4. Importantly, accumulation of CD34 positive cells was not seen after combined LY2784544/GRN163 treatment. This suggests that combining JAK2- and telomerase inhibition may have a therapeutic benefit, and that KLF4 may be a potential therapeutic target in MPNs. Furthermore, JAK2 inhibition reduced the telomerase activity, indicating a direct effect of JAK/STAT signaling on telomere regulation in MPNs
The ICF core sets for hearing loss project : functioning and disability from the patient perspective
OBJECTIVE : To explore areas of functioning, disability, and environmental factors of adults with hearing loss (HL) by using the ICF classification as a tool to determine and document each element.
DESIGN : A qualitative study applying mainly focus-group methodology was applied.
STUDY SAMPLE : Thirty-six Dutch and South African adults (â„ 18 years of age) with HL (20-95 dB HL) who used oral communication as first communication. Summative content analysis was performed on the transcripts by linkage to appropriate ICF categories.
RESULTS : 143 ICF categories were identified, most of which belonged to the Activities & Participation (d) component, closely followed by the Environmental factors component. Participants specifically mentioned categories related to oral communication and interaction. Assistive technology (such as hearing aids), noise, and support by and attitudes of others in the environment of the participants were considered highly influential for functioning and disability.
CONCLUSIONS : The present study illustrates the complex and encompassing nature of aspects involved in functioning and disability of adults with HL. Findings highlight the necessity of using a multidimensional tool, such as the ICF, to map functioning and disability with hearing loss, allowing consideration and evaluation of aspects that are both internal and external.The Oticon Foundationhttp://www.tandfonline.com/loi/iija20hb2017Speech-Language Pathology and Audiolog
Soluble receptor for AGE in diabetic nephropathy and its progression in Finnish individuals with type 1 diabetes
Aims/hypothesisActivation of the receptor for AGE (RAGE) has been shown to be associated with diabetic nephropathy. The soluble isoform of RAGE (sRAGE) is considered to function as a decoy receptor for RAGE ligands and thereby protects against diabetic complications. A possible association between sRAGE and diabetic nephropathy is still, however, controversial and a more comprehensive analysis of sRAGE with respect to diabetic nephropathy in type 1 diabetes is therefore warranted.MethodssRAGE was measured in baseline serum samples from 3647 participants with type 1 diabetes from the nationwide multicentre Finnish Diabetic Nephropathy (FinnDiane) Study. Associations between sRAGE and diabetic nephropathy, as well as sRAGE and diabetic nephropathy progression, were evaluated by regression, competing risks and receiver operating characteristic curve analyses. The non-synonymous SNP rs2070600 (G82S) was used to test causality in the Mendelian randomisation analysis.ResultsBaseline sRAGE concentrations were highest in participants with diabetic nephropathy, compared with participants with a normal AER or those with microalbuminuria. Baseline sRAGE was associated with progression from macroalbuminuria to end-stage renal disease (ESRD) in the competing risks analyses, but this association disappeared when eGFR was entered into the model. The SNP rs2070600 was strongly associated with sRAGE concentrations and with progression from macroalbuminuria to ESRD. However, Mendelian randomisation analysis did not support a causal role for sRAGE in progression to ESRD.Conclusions/interpretationsRAGE is associated with progression from macroalbuminuria to ESRD, but does not add predictive value on top of conventional risk factors. Although sRAGE is a biomarker of diabetic nephropathy, in light of the Mendelian randomisation analysis it does not seem to be causally related to progression from macroalbuminuria to ESRD.</p
Soluble receptor for AGE in diabetic nephropathy and its progression in Finnish individuals with type 1 diabetes
Aims/hypothesis Activation of the receptor for AGE (RAGE) has been shown to be associated with diabetic nephropathy. The soluble isoform of RAGE (sRAGE) is considered to function as a decoy receptor for RAGE ligands and thereby protects against diabetic complications. A possible association between sRAGE and diabetic nephropathy is still, however, controversial and a more comprehensive analysis of sRAGE with respect to diabetic nephropathy in type 1 diabetes is therefore warranted. Methods sRAGE was measured in baseline serum samples from 3647 participants with type 1 diabetes from the nationwide multicentre Finnish Diabetic Nephropathy (FinnDiane) Study. Associations between sRAGE and diabetic nephropathy, as well as sRAGE and diabetic nephropathy progression, were evaluated by regression, competing risks and receiver operating characteristic curve analyses. The non-synonymous SNP rs2070600 (G82S) was used to test causality in the Mendelian randomisation analysis. Results Baseline sRAGE concentrations were highest in participants with diabetic nephropathy, compared with participants with a normal AER or those with microalbuminuria. Baseline sRAGE was associated with progression from macroalbuminuria to end-stage renal disease (ESRD) in the competing risks analyses, but this association disappeared when eGFR was entered into the model. The SNP rs2070600 was strongly associated with sRAGE concentrations and with progression from macroalbuminuria to ESRD. However, Mendelian randomisation analysis did not support a causal role for sRAGE in progression to ESRD. Conclusions/interpretations RAGE is associated with progression from macroalbuminuria to ESRD, but does not add predictive value on top of conventional risk factors. Although sRAGE is a biomarker of diabetic nephropathy, in light of the Mendelian randomisation analysis it does not seem to be causally related to progression from macroalbuminuria to ESRD.Peer reviewe
New susceptibility loci associated with kidney disease in type 1 diabetes
WOS:000309817900008Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genome-wide association studies (GWAS) of T1D DN comprising âŒ2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (Pâ=â1.2Ă10(-8)) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (Pâ=â2.0Ă10(-9)). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-ÎČ1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, Pâ=â2.1Ă10(-7)), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN.Peer reviewe
PAPPA PĂ ANSTALTâ En kvalitativ studie med Ă„tta fĂ€der pĂ„ anstalt, om deras tankar och upplevelser kring sina barn
Uppsatsens syfte Àr att undersöka hur fÀder som sitter frihetsberövade upplever sitt faderskap. För att förstÄ detta har vi anvÀnt oss av fyra frÄgestÀllningar.
1. Hur beskriver mÀnnen faderskap och hur upplever de sitt eget faderskap?
2. Vilka kÀnslor, kring faderskapet och kontakten med barnen under anstaltsvistelsen, beskrivs?
3. Vilka strategier anvÀnder fÀderna för att hantera kÀnslor som Àr relaterade till barnet?
4. Vilka möjligheter anser fÀderna att sig ha att utöva förÀldraskap under tid pÄ anstalt?
Denna uppsats Àr skriven ur fÀdernas perspektiv och inte barnens.
Efter att genomfört Ätta halvstrukturerade intervjuer pÄ en anstalt, analyserade vi vÄrt resultat med hjÀlp av teorierna; coping, KASAM, socialkonstruktivistiskt perspektiv pÄ faderskap och teorier som förklarar reaktioner i samband med skam.
NÀr vi sammanstÀllde vÄrt resultat kunde vi se en tydlig bild av moderna fÀder som önskade att fÄ nÀrvara mer i sina barns vardag. De berÀttade alla vilka svÄrigheter som fanns att under anstaltstid kunna utöva ett önskvÀrt faderskap. Orsakerna var flera; bÄde dÄliga besöks rum, som gjorde att man undvek att ta emot barnen pÄ besök eller att man kunde vara placerad lÄngt ifrÄn sin familj. MÀnnen hanterade sina kÀnslor och situationer pÄ olika sÀtt, men de flesta anvÀnde undvikande copingstrategier. Vi tyckte oss Àven kunna utlÀsa ett uttryck för skamkÀnslor hos ett par av respondenterna. KriminalvÄrden insatser för fÀder under anstalts tid skulle kunna utvecklas betydligt. Utbildning om barns behov borde vara obligatoriskt för all personal som arbetar inom kriminalvÄrden. Besöksrum och besökslÀgenheter borde anpassas efter barns behov. KriminalvÄrden borde uttalat arbeta mer nÀtverksinriktat Àn vad de gör idag. VÄr tolkning Àr att mycket av arbetet med familje- och barnperspektivet fÄtt stÄ tillbaka och inte utvecklats i större utstrÀckning sedan kriminalvÄrden 2006 infört ett utökat sÀkerhetsarbete. FÀderna i studien upplever att det förhöjda sÀkerhetsarbetet skapat svÄrigheter för dem att utöva sitt faderskap
PAPPA PĂ ANSTALTâ En kvalitativ studie med Ă„tta fĂ€der pĂ„ anstalt, om deras tankar och upplevelser kring sina barn
Uppsatsens syfte Àr att undersöka hur fÀder som sitter frihetsberövade upplever sitt faderskap. För att förstÄ detta har vi anvÀnt oss av fyra frÄgestÀllningar.
1. Hur beskriver mÀnnen faderskap och hur upplever de sitt eget faderskap?
2. Vilka kÀnslor, kring faderskapet och kontakten med barnen under anstaltsvistelsen, beskrivs?
3. Vilka strategier anvÀnder fÀderna för att hantera kÀnslor som Àr relaterade till barnet?
4. Vilka möjligheter anser fÀderna att sig ha att utöva förÀldraskap under tid pÄ anstalt?
Denna uppsats Àr skriven ur fÀdernas perspektiv och inte barnens.
Efter att genomfört Ätta halvstrukturerade intervjuer pÄ en anstalt, analyserade vi vÄrt resultat med hjÀlp av teorierna; coping, KASAM, socialkonstruktivistiskt perspektiv pÄ faderskap och teorier som förklarar reaktioner i samband med skam.
NÀr vi sammanstÀllde vÄrt resultat kunde vi se en tydlig bild av moderna fÀder som önskade att fÄ nÀrvara mer i sina barns vardag. De berÀttade alla vilka svÄrigheter som fanns att under anstaltstid kunna utöva ett önskvÀrt faderskap. Orsakerna var flera; bÄde dÄliga besöks rum, som gjorde att man undvek att ta emot barnen pÄ besök eller att man kunde vara placerad lÄngt ifrÄn sin familj. MÀnnen hanterade sina kÀnslor och situationer pÄ olika sÀtt, men de flesta anvÀnde undvikande copingstrategier. Vi tyckte oss Àven kunna utlÀsa ett uttryck för skamkÀnslor hos ett par av respondenterna. KriminalvÄrden insatser för fÀder under anstalts tid skulle kunna utvecklas betydligt. Utbildning om barns behov borde vara obligatoriskt för all personal som arbetar inom kriminalvÄrden. Besöksrum och besökslÀgenheter borde anpassas efter barns behov. KriminalvÄrden borde uttalat arbeta mer nÀtverksinriktat Àn vad de gör idag. VÄr tolkning Àr att mycket av arbetet med familje- och barnperspektivet fÄtt stÄ tillbaka och inte utvecklats i större utstrÀckning sedan kriminalvÄrden 2006 infört ett utökat sÀkerhetsarbete. FÀderna i studien upplever att det förhöjda sÀkerhetsarbetet skapat svÄrigheter för dem att utöva sitt faderskap
Henkilövetoisen tarinan kehittelyprosessi yhteistyössÀ nÀyttelijÀn kanssa - Mike Leigh`n työmetodiin pohjautuva harjoitus
InternetsprÄk i anvÀndarkommentarer : Lingvistisk analys av material frÄn fyra lÀsargrupper
The present study examines typical features of internet language found in user-generated comments collected from commenting groups from four online magazines aimed at different readerships: (1) adult women (Working Mother and Mothering), (2) adult men (Esquire), (3) young women (Seventeen) and (4) young men (Gameinformer). Approximately 5,000 words from each commenting group were collected, creating a 21,087 word corpus which was analyzed with regard to typographic (emoticons, nonstandard typography of and, personal pronouns you and I) and orthographic features (abbreviations, acronyms) as well as syntactic and stylistic features resembling spoken language (contracted forms, ellipsis of subject and/or verb and commenting tone). The results show that adult men wrote the longest comments, followed by adult women, young men and young women in descending order. Furthermore, as for the typical features regarding typography and orthography, it was found that among the four commenting groups, adult men and adult women used them very sparsely, young men used them occasionally and young women used the features most frequently. The analysis of tone showed that adult men mostly used an aggressive or neutral tone, while adult women, young women and young men mostly used a friendly or neutral tone. Young women used an aggressive tone more often than adult women and young men. Moreover, regarding the syntactic and stylistic features, results revealed that the young men were the most frequent users of ellipsis of subject and/or verb, followed by adult women, young women and adult men. Contracted forms were used extensively in the potential places of contractions, regardless of commenting group. Since young men used the ellipsis of subject and/or verb most frequently of all commenting groups and also used the contracted forms in all potential places of contractions, the conclusion is that the young men used a style that is closer to spoken English than the three other commenting groups.Den hÀr studien undersöker sprÄkdrag som Àr typiska för sprÄk pÄ internet. Det material som har undersöks har hÀmtats frÄn anvÀndarkommentarer i nÀttidningar som Àr riktade till fyra olika lÀsargrupper: (1) kvinnor (Working Mother, Mothering), (2) mÀn (Esquire), (3) unga kvinnor (Seventeen) och (4) unga mÀn (Gameinformer). Cirka 5 000 ord hÀmtades frÄn kommentarsfÀlten för varje tidning, vilket resulterade i en korpus som omfattade 21 087 ord totalt. Korpusen analyserades med hÀnsyn till typografiska sprÄkdrag (smileys, ickestandardiserad stavning av personliga pronomen I och you samt and) och ortografiska sprÄkdrag (förkortningar, akronymer) samt syntaktiska och stilistiska sprÄkdrag som pÄminner om talsprÄk (sammandragningar, ellips av subjekt och/eller predikatsverb, tonlÀge). Resultaten visade att mÀn skrev de lÀngsta kommentarerna, följda av kvinnor, unga mÀn och unga kvinnor i fallande ordning. Vad gÀller typiska typografiska och ortografiska sprÄkdrag visar resultatet att de Äterfanns mycket sparsamt i kvinnornas och mÀnnens data, att de Äterfanns dÄ och dÄ i de unga mÀnnens data och att de unga kvinnorna var de som anvÀnde dessa sprÄkdrag mest frekvent. Analys av tonlÀge i anvÀndarkommentarerna visade att mÀn oftast anvÀnde en aggressiv eller neutral ton, medan kvinnor, unga kvinnor och unga mÀn oftast anvÀnde en vÀnskaplig eller neutral ton. Unga kvinnor anvÀnde en aggressiv ton oftare Àn kvinnor och unga mÀn. Utöver detta visade resultatet att ellips av subjekt och/eller predikatsverb var mest frekvent i de unga mÀnnens anvÀndarkommentarer, följt av kvinnornas, de unga kvinnornas och mÀnnens. Sammandragna former anvÀndes nÀst intill undantagslöst i hela korpusen. Eftersom pojkarna uppvisade mest frekvent anvÀndning av ellips av subjekt och/eller predikatsverb samt anvÀnde sammandragna former i full utstrÀckning, kan slutsatsen dras att de unga mÀnnens syntax Àr mer pÄverkad av engelskt talsprÄk Àn syntaxen hos de tre andra kommenterande grupperna
Hur skapar man engagemang i religionsundervisningen? : En kvalitativ undersökning av tre elevers och en lÀrares syn pÄ religionsÀmnet
Syftet med denna uppsats Àr att ta reda pÄ hur man kan skapa engagemang i dagens religionsundervisning. Jag vill med denna studie undersöka hur lÀrare arbetar för att intressera elever och hur man engagera dem. Sedan vill jag Àven fÄ en inblick i hur elever uppfattar religionsundervisningen och hur de tycker att en intressevÀckande lektion eller upplÀgg för religionsundervisningen ser ut. Fyra kvalitativa intervjuer har gjorts med en högstadielÀrare och tvÄ högstadieelever samt en gymnasieelev. Resultatet visar att religionsÀmnet till viss del fortfarande i hög grad förknippas med tro utifrÄn informanterna, vilket försvÄrar arbetet för lÀrare, eftersom elever inte ser nÄgot syfte eller mening med religionskunskap. Det Àr av stor vikt att skapa ett syfte med undervisningen dÀr lÀraren regelbundet funderar och reflekterar över de didaktiska grundfrÄgorna: Vad, Hur och Varför i frÄgan om hur man skapar engagemang i religionsundervisningen. Det Àr dÀrför centralt att variera undervisningen för att stimulera eleverna genom att de fÄr anvÀnda alla sina sinnen
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