| 1. |
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| 2. |
- Ahlén Bergman, Emma, et al.
(author)
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Increased CD4+ T cell lineage commitment determined by CpG methylation correlates with better prognosis in urinary bladder cancer patients
- 2018
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In: Clinical Epigenetics. - : BMC. - 1868-7083 .- 1868-7075. ; 10
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Journal article (peer-reviewed)abstract
- BACKGROUND: Urinary bladder cancer is a common malignancy worldwide. Environmental factors and chronic inflammation are correlated with the disease risk. Diagnosis is performed by transurethral resection of the bladder, and patients with muscle invasive disease preferably proceed to radical cystectomy, with or without neoadjuvant chemotherapy. The anti-tumour immune responses, known to be initiated in the tumour and draining lymph nodes, may play a major role in future treatment strategies. Thus, increasing the knowledge of tumour-associated immunological processes is important. Activated CD4+ T cells differentiate into four main separate lineages: Th1, Th2, Th17 and Treg, and they are recognized by their effector molecules IFN-γ, IL-13, IL-17A, and the transcription factor Foxp3, respectively. We have previously demonstrated signature CpG sites predictive for lineage commitment of these four major CD4+ T cell lineages. Here, we investigate the lineage commitment specifically in tumour, lymph nodes and blood and relate them to the disease stage and response to neoadjuvant chemotherapy.RESULTS: Blood, tumour and regional lymph nodes were obtained from patients at time of transurethral resection of the bladder and at radical cystectomy. Tumour-infiltrating CD4+ lymphocytes were significantly hypomethylated in all four investigated lineage loci compared to CD4+ lymphocytes in lymph nodes and blood (lymph nodes vs tumour-infiltrating lymphocytes: IFNG -4229 bp p < 0.0001, IL13 -11 bp p < 0.05, IL17A -122 bp p < 0.01 and FOXP3 -77 bp p > 0.05). Examination of individual lymph nodes displayed different methylation signatures, suggesting possible correlation with future survival. More advanced post-cystectomy tumour stages correlated significantly with increased methylation at the IFNG -4229 bp locus. Patients with complete response to neoadjuvant chemotherapy displayed significant hypomethylation in CD4+ T cells for all four investigated loci, most prominently in IFNG p < 0.0001. Neoadjuvant chemotherapy seemed to result in a relocation of Th1-committed CD4+ T cells from blood, presumably to the tumour, indicated by shifts in the methylation patterns, whereas no such shifts were seen for lineages corresponding to IL13, IL17A and FOXP3.CONCLUSION: Increased lineage commitment in CD4+ T cells, as determined by demethylation in predictive CpG sites, is associated with lower post-cystectomy tumour stage, complete response to neoadjuvant chemotherapy and overall better outcome, suggesting epigenetic profiling of CD4+ T cell lineages as a useful readout for clinical staging.
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| 3. |
- Lavebratt, Catharina, et al.
(author)
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CRY2 is associated with depression
- 2010
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In: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 5:2
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Journal article (peer-reviewed)abstract
- Background: Abnormalities in the circadian clockwork often characterize patients with major depressive and bipolar disorders. Circadian clock genes are targets of interest in these patients. CRY2 is a circadian gene that participates in regulation of the evening oscillator. This is of interest in mood disorders where a lack of switch from evening to morning oscillators has been postulated.Principal Findings: We observed a marked diurnal variation in human CRY2 mRNA levels from peripheral blood mononuclear cells and a significant up-regulation (P = 0.020) following one-night total sleep deprivation, a known antidepressant. In depressed bipolar patients, levels of CRY2 mRNA were decreased (P = 0.029) and a complete lack of increase was observed following sleep deprivation. To investigate a possible genetic contribution, we undertook SNP genotyping of the CRY2 gene in two independent population-based samples from Sweden (118 cases and 1011 controls) and Finland (86 cases and 1096 controls). The CRY2 gene was significantly associated with winter depression in both samples (haplotype analysis in Swedish and Finnish samples: OR = 1.8, P = 0.0059 and OR = 1.8, P = 0.00044, respectively).Conclusions: We propose that a CRY2 locus is associated with vulnerability for depression, and that mechanisms of action involve dysregulation of CRY2 expression.
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| 4. |
- Olofsson, Louise, 1977, et al.
(author)
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CCAAT/enhancer binding protein alpha (C/EBPalpha) in adipose tissue regulates genes in lipid and glucose metabolism and a genetic variation in C/EBPalpha is associated with serum levels of triglycerides.
- 2008
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In: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 93:12, s. 4880-6
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Journal article (peer-reviewed)abstract
- CONTEXT: CCAAT/enhancer binding protein alpha (C/EBPalpha) is a transcription factor involved in adipogenesis and hepatic glucose and lipid metabolism. OBJECTIVE: The aim of the study was to test the hypothesis that adipose tissue C/EBPalpha regulates genes in lipid and glucose metabolism and to test for an association between a polymorphism in C/EBPalpha and metabolic parameters. DESIGN AND METHODS: Adipose tissue C/EBPalpha mRNA expression was analyzed at four time points in obese subjects with (n = 12) and without (n = 12) the metabolic syndrome during caloric restriction (450 kcal/d for 16 wk) using DNA microarray and real-time PCR. Adenoviral overexpression of C/EBPalpha was used to identify genes regulated by C/EBPalpha in 3T3-L1 cells. Association between a genetic variation in C/EBPalpha (rs12691) and metabolic parameters was tested in the Swedish Obese Subjects (SOS) study (n = 528) and replicated in Finnish individuals from the Botnia type 2 diabetes study (n = 4,866). RESULTS: During caloric restriction, adipose tissue C/EBPalpha mRNA levels were reduced in subjects with the metabolic syndrome (P = 0.024) and correlated to metabolic parameters. In 3T3-L1 cells, C/EBPalpha regulated the expression of adiponectin; hexokinase 2; lipoprotein lipase; diacylglycerol O-acyltransferase 1 and 2; ATP-binding cassette, sub-family D, member 2; acyl-coenzyme A synthetase long-chain family member 1; CD36; and hydroxysteroid 11-beta dehydrogenase 1. Furthermore, the expression of the human homologs, except adiponectin, correlated to C/EBPalpha mRNA levels in human adipose tissue. The AA genotype of rs12691 was associated with higher serum triglyceride levels in the SOS study (P = 0.022), and this association was replicated in the Botnia study (P = 0.041). CONCLUSIONS: Adipose tissue C/EBPalpha regulates several genes in glucose and lipid metabolism, and a genetic variation in C/EBPalpha is associated with triglycerides in two independent populations.
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| 5. |
- Olofsson, Louise, 1977, et al.
(author)
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Preliminary report: Zn-alpha2-glycoprotein genotype and serum levels are associated with serum lipids.
- 2010
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In: Metabolism. - : Elsevier BV. - 1532-8600 .- 0026-0495. ; 59:9, s. 1316-1318
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Journal article (peer-reviewed)abstract
- Zn-alpha2-glycoprotein (ZAG) is a serum protein implicated in cancer cachexia and lipolysis. Our aim was to investigate serum levels of ZAG and polymorphisms in the ZAG gene in relation to serum lipids in man. Serum levels of ZAG correlated with serum levels of cholesterol (P = .00088) in healthy subjects and during weight loss (P = .059). The ZAG genotype was associated with total cholesterol (P = .014) and low-density lipoprotein cholesterol (P = .026) in healthy subjects, and the associations were replicated in an additional cohort (P = .0017 and P = .060, respectively). Our data indicate that ZAG plays a role in lipid metabolism.
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| 6. |
- Sjöholm, Johanna, 1994, et al.
(author)
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Eko Marina III - inventering, kartläggning och miljömärkning av Sveriges fritidsbåtshamnar
- 2021
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Reports (other academic/artistic)abstract
- Eko Marina ett projekt i tre delar som påbörjades i oktober 2019. “Eko Marina I” startades som ett pilotprojekt med syfte att undersöka om ett miljömärkningssystem skulle kunna vara ett användbart verktyg för att få fritidsbåtshamnar att minska sin negativa miljöpåverkan. Som en del av Eko Marina I presenterades även ett första förslag på ett miljöindex (index 1.0) att basera en eventuell miljömärkning på. “Eko Marina II” fortsatte bygga på grunden till en miljömärkning genom att vidareutveckla indexet (index 2.0), presentera de förväntade positiva effekterna av användningen av en indexbaserad miljömärkning samt formulera ett första förslag till affärsmodell och format för miljömärkningen. Denna rapport redovisar arbetet i Eko Marina III, vilket syftat till att vidareutveckla prototypen samt affärsmodellen för en digital stödplattform och miljömärkning i ett app-format. Eko Marina III omfattar även en nationell inventering av Sveriges fritidsbåtshamnar, en kartläggning av fritidsbåtshamnars organisation, infrastruktur, närliggande aktörer, inställningen till en miljömärkning samt en utvärdering av vilka incitament som finns för fritidsbåtshamnar i omställningen till ett hållbart båtliv. Projektgruppen har bestått av personer med bred kompetens inom bland annat tillsynsarbete, juridik, drift av hamnverksamhet, marin ekologi, marin geologi samt utvecklande av miljöcertifiering inom sjöfartsområdet.
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| 7. |
- Sjöholm, Johanna, et al.
(author)
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Eko Marina III - Inventering, kartläggning och miljömärkning av Sveriges fritidsbåtshamnar : Inventering av Sveriges fritidsbåtshamnar, kartläggning av fritidsbåtshamnars uppbyggnad samt utvecklig av prototyp för Eko Marinas miljömärkningssystem
- 2021
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Reports (other academic/artistic)abstract
- Eko Marina III är den tredje delen av ett projekt som påbörjades i oktober 2019, med övergripande syfte att undersöka förutsättningarna för att utveckla en miljömärkning för fritidsbåtshamnar för att minska deras negativa miljöpåverkan. Denna del av projektet har fokuserat på tre primära områden: 1. en inventering av Sveriges fritidsbåtshamnar, 2. en kartläggning över hur fritidbåtshamnarna ser ut samt 3. utvecklingen av ett digitalt verktyg som kan bära miljömärkningsindexet, men också utgöra en stödplattform för fritidsbåtshamnarna i deras miljöarbete. Inventeringen resulterade i att 2 654 fritidsbåtshamnar listades. Det tidigare antagandet om att omkring 1 500 fritidsbåtshamnar finns i Sverige har därmed visat sig vara en kraftig underskattning.För att undersöka hur intresset bland fritidsbåthamnarna såg ut för ett digitalt verktyg för stöd i sitt miljöarbete tillfrågades även hamnrepresentanterna i enkätundersökning om vilka olika digitala funktioner de hade ett intresse av. Projektgruppen valde att arbeta vidare med att utveckla ett stödsystem för egenkontroll, vilket 73 procent av respondenterna svarade att de hade ett medel- till stort intresse av. Detta beslut grundade sig dels på respondenternas svar, men även på de intervjuer med fritidsbåtshamnar som har gjorts under projektet, där det blivit tydligt att många hamnar saknar kunskap och förståelse för sitt miljöansvar och behöver stöd för att upprätta en systematisk egenkontroll för att undvika att utsläpp sker. För att illustrera hur den digitala stödplattformen (verktyget) som utvecklats i detta projekt kan användas i olika typer av verksamheter och vilka funktioner som kan ingå, valdes exemplet båtbottentvätt, där en stegvis genomgång av egenkontrollen presenteras i bilaga 5.Det digitala verktygets övergripande syfte är att hjälpa fritidsbåtshamnar att upprätta ett systematiskt egenkontrollarbete där risker identifieras, rutiner och åtgärder tas fram, arbetet dokumenteras och följs upp för att säkerställa att hamnens miljöpåverkan på havsmiljön minimeras. En prototyp av det digitala verktyget har under projektet visats upp för en arbetsgrupp och referensgrupp bestående av branschorganisationer, hamnar, myndigheter och forskare. Överlag var mottagandet positivt – deltagarna såg många möjligheter för effektivisering av den egna verksamheten, driva miljöengagemang hos klubbmedlemmar samt stöd för att prioritera utvecklingen av miljöarbetet hamnarna. Däremot uppfattades komplexiteten och detaljnivån som ett potentiellt hinder för hamnar som inte har kommit långt i miljöarbetet. En utmaning i det framtida utvecklingsarbetet blir att hitta ett sätt att möta och kunna hantera fritidsbåtshamnarnas heterogenitet, där variation av hamnarnas finansiella förutsättningar, kunskap i miljöbalken samt kommunernas fokus på tillsyn är så olika.
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| 8. |
- Sjöholm, Kajsa, 1971, et al.
(author)
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A microarray search for genes predominantly expressed in human omental adipocytes: adipose tissue as a major production site of serum amyloid A.
- 2005
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In: Journal of Clinical Endocrinology & Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 90:4, s. 2233-9
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Journal article (peer-reviewed)abstract
- To identify genes predominantly expressed in omental adipocytes, microarray expression profiles from 33 human tissues or cell types were analyzed, using an algorithm developed for identification of transcripts predominantly expressed in a certain tissue. Both known adipocyte-specific and more unexpected genes were among the 28 genes identified. To validate the approach, adipocyte expression of three of these genes, acute-phase serum amyloid A (A-SAA), aquaporin 7, and transport secretion protein-2.2, was compared with 17 other human tissues by real-time PCR. The unexpectedly high expression of A-SAA in adipocytes was further verified by Northern blot and immunohistochemistry. The liver, reported to be the main production site for A-SAA, displayed the second highest expression using microarray and real-time PCR. In obese subjects, adipose tissue mRNA and serum A-SAA levels were down-regulated during an 18-wk diet regime (P < 0.05 and P < 0.0001, respectively). A-SAA serum levels were highly correlated to adipose tissue mRNA levels (P < 0.001) and to the total (P < 0.0001) and sc (P < 0.0001) adipose tissue areas, as analyzed by computed tomography. We show that adipose tissue is a major expression site of A-SAA during the nonacute-phase reaction condition. This provides a direct link between adipose tissue mass and a marker for low-grade inflammation and cardiovascular risk.
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| 9. |
- Sjöholm, Louise
(author)
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Gene-environment factors in depressive disorders with a focus on circadian genes
- 2010
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Doctoral thesis (other academic/artistic)abstract
- Depressive disorders have a multifactorial etiology, where both environmental and genetic risk factors contribute. Depression is characterized by a depressed mood and accompanied by e.g. loss of interest and pleasure, disturbed sleep and appetite and difficulties in concentrating. A disturbed sleep-wake pattern as well as disruptions of other biological (circadian) rhythms is a hallmark of depression. This fact has led researchers to believe that disruptions of biological rhythms generated by the suprachiasmatic nucleus in the hypothalamus is one possible mechanism behind depressive disorders. A guiding hypothesis in this thesis is that there are protective and vulnerability variations in circadian clock genes regarding development of depressive disorders and that their identification will facilitate improvement of diagnosis and treatment. The main goal of this thesis was to identify circadian clock gene variants associated with depressive disorders in relation with environmental factors. In paper I, two proposed etiological models for major depression, one model for females and one for males, were applied on the Swedish population-based material (PART) to test the ability of the models to predict major depression and other depressive disorders. Path- and correlation analyses were performed using 16 risk factors. The model was successfully replicated in both genders and predicted two-third of the liability to develop major depression as well as other subtypes of unipolar depression. These results support a similar etiology in major depression and other depressive disorders (Bipolar Disorder, Dysthymia, Mixed Anxiety Depression and Minor Depression). In paper II, the Leu7Pro polymorphism in preproNPY was investigated in PART. The Pro7 allele was shown to be protective against major depression and dysthymia in a dominant model, and this was true also in an environment-induced vulnerable state in the depressed individuals. In paper III, genetic variants in 18 circadian genes were investigated for association to major depression and dysthymia in PART. Genetic variations in PER2 were found to be associated with depression vulnerability in two of three sample sets used. This genetic risk did not seem to require exposure to the potential sleep disturbance factors stressful life events and financial strain. In paper IV, we investigated the involvement of circadian clock genes in comorbidity between major depression and alcohol abuse or dependence in the Finnish population-based cohort Health2000. This comorbid condition was found to be associated with variants in the CLOCK gene. Together with previous reports, our results indicate that CLOCK may be a vulnerability factor for depression in individuals with alcohol use disorders. In paper V the circadian gene CRY2 was investigated with regard to mRNA levels in healthy controls and patients with depression, before, during and after one night of sleep deprivation. We also aimed at identifying variations in the CRY2 gene associated with depression in Swedish and Finnish samples with seasonal affective disorder. CRY2 mRNA levels were reduced in blood from bipolar disorder patients in depressive state and mRNA levels were non-responsive to total sleep-deprivation. Furthermore, CRY2 SNPs were found to associate with seasonal affective disorder in both sample sets. To further investigate CRY2´s role in affective disorders, Swedish bipolar patients with the severe phenotype rapid cycling were investigated in paper VI. Risk and protective CRY2 haplotypes were identified that were similar to, and had similar effect sizes as, those in paper V. In conclusion, results in this thesis support the involvement of circadian genes in depression, seasonal affective disorder and bipolar disorder. The associations found with NPY and PER2 didnot seem to be affected by exposure to the depression risk factors that were identified in paper I. The associations found here need to be replicated and investigated further.
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| 10. |
- Sjöholm, Louise K, et al.
(author)
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Evaluation of Post-Mortem Effects on Global Brain DNA Methylation and Hydroxymethylation.
- 2018
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In: Basic & Clinical Pharmacology & Toxicology. - : Wiley. - 1742-7835 .- 1742-7843. ; 122:2, s. 208-213
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Journal article (peer-reviewed)abstract
- The number of epigenetic studies on brain functions and diseases are dramatically increasing, but little is known about the impact of post-mortem intervals and post-sampling effects on DNA modifications such as 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC). Here, we examined post-mortem-induced changes in global brain 5mC and 5hmC levels at post-mortem intervals up to 540 min., and studied effects of tissue heat stabilization, using LUMA and ELISA. The global 5mC and 5hmC levels were generally higher in the cerebellum of adult rats than neonates. When measured by ELISA, the global 5mC content in adults, but not neonates, decreased with the post-mortem interval reaching a significantly lower level in cerebellum tissue at the post-mortem interval 540 min. (2.9 ± 0.7%; mean ± S.E.M.) compared to control (3.7 ± 0.6%). The global 5hmC levels increased with post-mortem interval reaching a significantly higher level at 540 min. (0.29 ± 0.06%) compared to control (0.19 ± 0.03%). This suggests that the post-mortem interval may confound 5mC and 5hmC analysis in human brain tissues as the post-mortem handling could vary substantially. The reactive oxygen species (ROS) level in cerebellum also increased over time, in particular in adults, and may be part of the mechanism that causes the observed post-mortem changes in 5mC and 5hmC. The global 5mC and 5hmC states were unaffected by heat stabilization, allowing analysis of tissues that are stabilized to preserve more labile analytes. Further studies in human samples are needed to confirm post-mortem effects on DNA methylation/hydroxymethylation and elucidate details of the underlying mechanisms.
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