| 1. |
- Andersson, Ulrika, et al.
(författare)
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Germline rearrangements in families with strong family history of glioma and malignant melanoma, colon, and breast cancer
- 2014
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Ingår i: Neuro-Oncology. - : Oxford University Press. - 1522-8517 .- 1523-5866. ; 16:10, s. 1333-1340
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Tidskriftsartikel (refereegranskat)abstract
- Background: Although familial susceptibility to glioma is known, the genetic basis for this susceptibility remains unidentified in the majority of glioma-specific families. An alternative approach to identifying such genes is to examine cancer pedigrees, which include glioma as one of several cancer phenotypes, to determine whether common chromosomal modifications might account for the familial aggregation of glioma and other cancers. Methods: Germline rearrangements in 146 glioma families (from the Gliogene Consortium; http://www.gliogene.org/) were examined using multiplex ligation-dependent probe amplification. These families all had at least 2 verified glioma cases and a third reported or verified glioma case in the same family or 2 glioma cases in the family with at least one family member affected with melanoma, colon, or breast cancer. The genomic areas covering TP53, CDKN2A, MLH1, and MSH2 were selected because these genes have been previously reported to be associated with cancer pedigrees known to include glioma. Results: We detected a single structural rearrangement, a deletion of exons 1-6 in MSH2, in the proband of one family with 3 cases with glioma and one relative with colon cancer. Conclusions: Large deletions and duplications are rare events in familial glioma cases, even in families with a strong family history of cancers that may be involved in known cancer syndromes.
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| 2. |
- Aradottir, Steina
(författare)
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Phosphatidylethanol - formation and degradation in blood and organs.
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Phosphatidylethanol (PEth) is an abnormal phospholipid formed exclusively by the action of phospholipase D (PLD) in the presence of ethanol. The degradation of PEth is slow and due to its accumulation in some cells the possibility to use PEth as marker of ethanol intake has been proposed. It has also been suggested that PEth mediates some of the damaging effects of ethanol on cells. This study was made to investigate the formation and degradation of PEth, after ethanol exposure, in organs, blood, and cell-lines from animals and humans both in vivo and in vitro. After different in vivo alcohol exposures, the level of PEth accumulated in organs of rats was measured. Blood from humans, rats, a pig and a ferret was also incubated in vitro with ethanol for investigation of the PEth formation. The degradation of PEth was studied in human blood and in two cell-lines in vitro. PEth content in organs and blood from cadavers of alcoholics was measured. The effect of storage conditions on PEth content in blood and organs was studied. PEth was measured in blood from two groups of alcoholic patients and related to the ethanol intake and to three clinically available markers of chronic ethanol intake. PEth was analysed by high performance liquid chromatography (HPLC) and evaporative light scattering detection. The analytical method for PEth was improved by using internal standard, and by modifying the extraction method the limit of quantification could be lowered. Rats exposed to ethanol acutely or chronically formed PEth in most of their organs. The amount of PEth formed in the organs varied, and it was shown that both the differences in type of exposition, and ethanol concentrations, are of importance. Also the rate of PEth degradation varied among the organs. No in vivo PEth formation occurred in the rat blood. PEth was formed in human blood incubated in vitro with ethanol. However, in blood from rat, pig, and ferret, no PEth formation occurred in vitro. PEth formation in human blood in vitro was linear with time and ethanol concentration dependant; individual variation in formation rate was demonstrated. No degradation of PEth could be observed in human blood during 48 hours in vitro. Very high PEth concentrations were found in organs and blood from the autopsied alcoholics, probably due to formation of PEth during freezing at –20°C. Storage of rat organs and human blood at –20°C with ethanol present highly elevates PEth levels. Rat organs and human blood without ethanol present can be frozen at –20°C without affecting PEth levels. In blood from alcoholics PEth had a diagnostic sensitivity of 100% in inpatients and 98% in outpatients. The sensitivity of the other markers varied between 28% and 77%. PEth, CDT, and GGT correlated to ethanol intake with the strongest correlation found for PEth. Thus PEth is highly correlated to ethanol intake and the present results indicate that the diagnostic sensitivity is higher than in previously established alcohol markers.
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| 3. |
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| 4. |
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| 5. |
- Aradottir, Steina, et al.
(författare)
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Phosphatidylethanol in rat organs after ethanol exposure.
- 2002
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Ingår i: Alcoholism: Clinical and Experimental Research. - 0145-6008. ; 26:4, s. 514-518
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Phosphatidylethanol (PEth) is an abnormal phospholipid formed in mammalian cells that have been exposed to ethanol. It has been suggested that PEth mediates some of the damaging effects of ethanol on cells. This study was performed to investigate the level of PEth in organs of rats after in vivo alcohol exposure. METHODS: Three exposure models were studied: (1) acute, intraperitoneal injection of ethanol (n = 3 x 3); (2) chronic, forced ethanol drinking (n = 6); and (3) chronic, free choice of ethanol (n = 20). PEth was analyzed by high-performance liquid chromatography after lipid extraction of the organs. RESULTS: One acute injection gave detectable PEth levels in most organs analyzed, with maximal levels reached after 2 hr. The highest levels were reached in intestines, stomach, and lung. No PEth was detected in skeletal muscle, pancreas, or testis. The two exposure models for oral intake of ethanol also gave detectable PEth levels in most organs. The highest levels were reached in stomach, lung, and spleen. PEth was detected in muscle only in animals with heavy total alcohol intake. CONCLUSIONS: PEth is formed in most organs of rats exposed to ethanol acutely or chronically. Variations in PEth level and rates of PEth formation and PEth degradation are organ specific.
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| 6. |
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| 7. |
- Gustavsson, Lena, et al.
(författare)
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Regulation of phospholipase D activity in neuroblastoma cells
- 1996
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Ingår i: Journal of Lipid Mediators and Cell Signalling. - : Elsevier BV. - 0929-7855. ; 14:1-3, s. 229-235
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Tidskriftsartikel (refereegranskat)abstract
- The regulation of phospholipase D was studied in human neuroblastoma cells using phosphatidylethanol as a marker of the enzyme activity. Carbachol induced phospholipase D activity in SH-SY5Y cells. Muscarinic antagonists inhibited the response with potencies suggesting that muscarinic M1 receptors are responsible for the activation. In permeabilized SH-SY5Y cells, both the carbachol- and GTP gamma S-induced Peth formation was inhibited by GDP beta S, indicating that both responses are mediated via a G-protein. The protein kinase C inhibitors, bisindolylmaleimide and staurosporine significantly inhibited the carbachol-induced Peth formation whereas H7 had no effect. Thus, the cholinergic activation of phospholipase D in SH-SY5Y cells is probably mediated via a direct receptor-G-protein coupling but an involvement of protein kinase C cannot be excluded. Calmidazolium, a calmodulin antagonist, induced an increase in phosphatidylethanol formation in both SH-SY5Y and IMR-32 cells. This effect was inhibited by genistein and tyrphostin, indicating a tyrosine kinase dependent pathway for phospholipase D activation in neuroblastoma cells.
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| 8. |
- Hartmann, S., et al.
(författare)
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Phosphatidylethanol as a sensitive and specific biomarker-comparison with gamma-glutamyl transpeptidase, mean corpuscular volume and carbohydrate-deficient transferrin
- 2007
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Ingår i: Addiction Biology. - : Wiley. - 1369-1600 .- 1355-6215. ; 12:1, s. 81-84
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Tidskriftsartikel (refereegranskat)abstract
- Phosphatidylethanol (PEth), a direct ethanol metabolite, is detectable in blood for more than 2 weeks after sustained ethanol intake. Our aim was to assess the usefulness of PEth [comparing sensitivity, specificity and the area under the curve (AUC)] as compared with carbohydrate-deficient transferrin (CDT), gamma-glutamyl transpeptidase (GGT) and mean corpuscular volume (MCV), calculating the results from sober patients against those from alcohol-dependent patients during withdrawal. Fifty-six alcohol-dependent patients (ICD-10 F 10.25) in detoxification, age 43 years, GGT 81 U/l, MCV 96.4 fl, %CDT 4.2, 1400 g ethanol intake in the last 7 days (median), were included in the study. Over the time of 1 year, 52 samples from 35 sober forensic psychiatric addicted in-patients [age 34 years, GGT 16 U/l, MCV 91 fl, CDT 0.5 (median)] in a closed ward were drawn and used for comparison . PEth was measured in heparinized whole blood with a high-performance liquid chromatography method. GGT, MCV and %CDT were measured using routine methods. A receiver operating characteristic curve analysis was carried out, with 'current drinking status' (sober/drinking) as the state variable and PEth, MCV, GGT and CDT as test variables. The resulting AUC was 0.974 (P < 0.0001, confidence interval 0.932-1.016) for PEth. At a cut-off of 0.36 mu mol/l, the sensitivity was 94.5% and specificity 100%. The AUC for CDT, GGT and MCV were 0.931, 0.894 and 0.883, respectively. A significant Spearman's rank correlation was found between PEth and GGT (r = 0.739), CDT (r = 0.643), MVC (r = 0.639) and grams of ethanol consumed in the last 7 days (r = 0.802). Our data suggest that PEth has potential to be a sensitive and specific biomarker, having been found in previous studies to indicate longer lasting intake of higher amounts of alcohol.
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| 9. |
- Holm, Karolina, et al.
(författare)
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Global H3K27 trimethylation and EZH2 abundance in breast tumor subtypes
- 2012
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Ingår i: Molecular Oncology. - : Elsevier. - 1574-7891 .- 1878-0261. ; 6:5, s. 494-506
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Tidskriftsartikel (refereegranskat)abstract
- Polycomb repressive complex 2 (PRC2) and its core member enhancer of zeste homolog 2 (EZH2) mediate the epigenetic gene silencing mark: trimethylation of lysine 27 on histone 3 (H3K27me3). H3K27me3 is characteristic of the chromatin at genes involved in developmental regulation in undifferentiated cells. Overexpression of EZH2 has been found in several cancer types such as breast, prostate, melanoma and bladder cancer. Moreover, overexpression is associated with highly proliferative and aggressive types of breast and prostate tumors. We have analyzed the abundance of EZH2 and H3K27me3 using immunohistochemistry in two large and Well-characterized breast tumor data sets encompassing more than 400 tumors. The results have been analyzed in relation to the molecular subtypes of breast tumors (basal-like, luminal A, luminal B, HER2-enriched and normal-like), as well as in subtypes defined by clinical markers (triple negative, ER+/HER2-/Ki67low, ER+/HER2-/Ki67high and HER2+), and were validated in representative breast cancer cell lines by western blot. We found significantly different expression of both EZH2 and H3K27me3 across all subtypes with high abundance of EZH2 in basal-like, triple negative and HER2-enriched tumors, and high H3K27me3 in luminal A, HER2-enriched and normal-like tumors. Intriguingly, the two markers show an inverse correlation, particularly for the basal-like and triple negative tumors. Consequently, high expression of EZH2 was associated with poor distant disease-free survival whereas high expression of H3K27me3 was associated with better survival. Additionally, none of 182 breast tumors was found to carry a previously described EZH2 mutation affecting Tyr641. Our observation that increased expression of EZH2 does not necessarily correlate with increased abundance of H3K27me3 supports the idea that EZH2 can have effects beyond epigenetic silencing of target genes in breast cancer.
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| 10. |
- Kip, Miriam Julia, et al.
(författare)
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The usefulness of direct ethanol metabolites in assessing alcohol intake in nonintoxicated male patients in an emergency room setting
- 2008
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Ingår i: Alcoholism: Clinical and Experimental Research. - : Wiley. - 0145-6008 .- 1530-0277. ; 32:7, s. 1284-1291
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Tidskriftsartikel (refereegranskat)abstract
- Background: A major part of medical pathology in internal medicine is associated with chronic alcoholism. The aim of the current study was to investigate whether screening for Alcohol Use Disorders (AUD) can be improved through determination of direct ethanol metabolites compared to traditional biological state markers, the Alcohol Use Disorders Identification Test (AUDIT) and additional self-reports beyond the detection time period of a positive blood alcohol concentration (BAC). Methods: A total of 74 blood alcohol negative male patients who presented at the emergency room with either thoracic or gastrointestinal complaints were included. Phosphatidylethanol (PEth) was determined in whole blood, and ethyl glucuronide (EtG) in serum and urine samples. Traditional biological state markers [carbohydrate deficient transferrin (%CDT), gamma glutamyl transpeptidase (GGT), mean corpuscular volume (MCV)] were determined. The AUDIT was obtained and furthermore, all patients completed an additional self-report of alcohol consumption. Patients were divided into two (2) groups: AUDIT scores < 8 and AUDIT scores >= 8. Results: After assessment of the AUDIT, patients were allocated to one of the following groups: patients with AUDIT scores < 8 (n = 52) and with AUDIT scores >= 8 (n = 22). Twenty-five percent of the patients with AUDIT scores below the cut-off (n = 13/52) were tested positive for both PEth and UEtG. Of the patients who declared to be sober during the past 12 months, 38.5% were tested positive for PEth and UEtG. PEth discriminated similarly as %CDT for AUDIT scores >= 8 (AUC: 0.672; 95%CI 0.524 to 0.821). Self-reports of alcohol consumption were unreliable. Conclusion: Determination of direct ethanol metabolites such as PEth and UEtG provides additional evidence in screening for AUD in an ER setting. Determination of PEth might be considered complementary with or alternatively to %CDT.
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