126 results on '"Kärjä, V."'
Search Results
2. Programmed cell death 1 genetic variant and liver damage in nonalcoholic fatty liver disease
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Pipitone, R.M., primary, Malvestiti, F., additional, Pennisi, G., additional, Jamialahmadi, O., additional, Dongiovanni, P., additional, Bertolazzi, G., additional, Pihlajamäki, J., additional, Yki-Järvinen, H., additional, Vespasiani-Gentilucci, U., additional, Tavaglione, F., additional, Maurotti, S., additional, Bianco, C., additional, Di Maria, G., additional, Enea, M., additional, Fracanzani, A.L., additional, Kärjä, V., additional, Lupo, G., additional, Männistö, V., additional, Meroni, M., additional, Piciotti, R., additional, Qadri, S., additional, Zito, R., additional, Craxì, A., additional, Di Marco, V., additional, Cammà, C., additional, Tripodo, C., additional, Valenti, L., additional, Romeo, S., additional, Petta, S., additional, and Grimaudo, S., additional
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- 2023
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3. Efficacy and safety of myocardial gene transfer of adenovirus, adeno-associated virus and lentivirus vectors in the mouse heart
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Merentie, M, Lottonen-Raikaslehto, L, Parviainen, V, Huusko, J, Pikkarainen, S, Mendel, M, Laham-Karam, N, Kärjä, V, Rissanen, R, Hedman, M, and Ylä-Herttuala, S
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- 2016
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4. Strong claudin 5 expression is a poor prognostic sign in pancreatic adenocarcinoma
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Soini, Ylermi, Eskelinen, M., Juvonen, P., Kärjä, V., Haapasaari, K. M., Saarela, A., and Karihtala, P.
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- 2014
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5. Indications of hepatic and cardiac toxicity caused by subchronic Tricholoma flavovirens consumption
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Nieminen, P., Kärjä, V., and Mustonen, A.-M.
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- 2008
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6. Expression of claudins 7 and 18 in pancreatic ductal adenocarcinoma: association with features of differentiation
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Soini, Y, Takasawa, A, Eskelinen, M, Juvonen, P, Kärjä, V, Hasegawa, T, Murata, M, Tanaka, S, Kojima, T, and Sawada, N
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- 2012
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7. Total liver phosphatidylcholine content associates with non-alcoholic steatohepatitis and glycine N-methyltransferase expression
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Männistö, V. (Ville), Kaminska, D. (Dorota), Kärjä, V. (Vesa), Tiainen, M. (Mika), de Mello, V. D. (Vanessa D.), Hanhineva, K. (Kati), Soininen, P. (Pasi), Ala‐Korpela, M. (Mika), and Pihlajamäki, J. (Jussi)
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Proton magnetic resonance spectroscopy ,Phosphatidylcholine ,Phosphatidylethanolamine N-methyltransferase ,Glycine N-methyltransferase ,Nonalcoholic steatohepatitis ,Non-alcoholic fatty liver disease - Abstract
Background & Aims: Alterations in liver phosphatidylcholine (PC) metabolism have been implicated in the pathogenesis of non‐alcoholic fatty liver disease (NAFLD). Although genetic variation in the phosphatidylethanolamine N‐methyltransferase (PEMT) enzyme synthesizing PC has been associated with disease, the functional mechanism linking PC metabolism to the pathogenesis of non‐alcoholic steatohepatitis (NASH) remains unclear. Methods: Serum PC levels and liver PC contents were measured using proton nuclear magnetic resonance (NMR) spectroscopy in 169 obese individuals [age 46.6 ± 10 (mean ± SD) years, BMI 43.3 ± 6 kg/m2, 53 men and 116 women] with histological assessment of NAFLD; 106 of these had a distinct liver phenotype. All subjects were genotyped for PEMT rs7946 and liver mRNA expression of PEMT and glycine N‐methyltransferase (GNMT) was analysed. Results: Liver PC content was lower in those with NASH (P = 1.8 x 10−6) while serum PC levels did not differ between individuals with NASH and normal liver (P = 0.591). Interestingly, serum and liver PC did not correlate (rs = −0.047, P = 0.557). Serum PC and serum cholesterol levels correlated strongly (rs = 0.866, P = 7.1 x 10−49), while liver PC content did not correlate with serum cholesterol (rs = 0.065, P = 0.413). Neither PEMT V175M genotype nor PEMT expression explained the association between liver PC content and NASH. Instead, liver GNMT mRNA expression was decreased in those with NASH (P = 3.8 x 10−4) and correlated with liver PC content (rs = 0.265, P = 0.001). Conclusions: Decreased liver PC content in individuals with the NASH is independent of PEMT V175M genotype and could be partly linked to decreased GNMT expression.
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- 2019
8. Feasibility of mapping breast cancer with supine breast MRI in patients scheduled for oncoplastic surgery
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Joukainen, S., primary, Masarwah, A., additional, Könönen, M., additional, Husso, M., additional, Sutela, A., additional, Kärjä, V., additional, Vanninen, R., additional, and Sudah, M., additional
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- 2018
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9. Effects of Carboxylesterase 1 Genetic Variants on its Gene Expression, and Clopidogrel Pharmacokinetics and Antiplatelet Effects
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Neuvonen, M., primary, Tarkiainen, E.K., additional, Tornio, A., additional, Hirvensalo, P., additional, Tapaninen, T., additional, Paile-Hyvärinen, M., additional, Itkonen, M.K., additional, Holmberg, M.T., additional, Kärjä, V., additional, Männistö, V.T., additional, Neuvonen, P.J., additional, Pihlajamäki, J., additional, Backman, J.T., additional, and Niemi, M., additional
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- 2017
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10. TM6SF2gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease
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Dongiovanni, P., Petta, S., Maglio, C., Fracanzani, A., Pipitone, R., Mozzi, E., Motta, B., Kaminska, D., Rametta, R., Grimaudo, S., Pelusi, S., Montalcini, T., Alisi, A., Maggioni, M., Kärjä, V., Borén, J., Käkelä, P., Di Marco, V., Xing, C., Nobili, V., Dallapiccola, B., Craxi, A., Pihlajamäki, J., Fargion, S., Sjöström, L., Carlsson, L., Romeo, S., and Valenti, L.
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NASH, TM6SF2 - Published
- 2015
11. Efficacy and safety of myocardial gene transfer of adenovirus, adeno-associated virus and lentivirus vectors in the mouse heart
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Merentie, M, primary, Lottonen-Raikaslehto, L, additional, Parviainen, V, additional, Huusko, J, additional, Pikkarainen, S, additional, Mendel, M, additional, Laham-Karam, N, additional, Kärjä, V, additional, Rissanen, R, additional, Hedman, M, additional, and Ylä-Herttuala, S, additional
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- 2015
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12. 8-hydroxydeguanosine and nitrotyrosine are prognostic factors in urinary bladder carcinoma
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Soini, Ylermi, Haapasaari, Kirsi-Maria, Vaarala, Markku H, Turpeenniemi-Hujanen, Taina, Kärjä, V, and Karihtala, Peeter
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Cell Nucleus ,Cytoplasm ,Kelch-Like ECH-Associated Protein 1 ,NF-E2-Related Factor 2 ,Carcinoma ,Intracellular Signaling Peptides and Proteins ,Deoxyguanosine ,Enzyme-Linked Immunosorbent Assay ,Kaplan-Meier Estimate ,Peroxiredoxins ,Prognosis ,Immunohistochemistry ,Statistics, Nonparametric ,Oxidative Stress ,Thioredoxins ,Urinary Bladder Neoplasms ,8-Hydroxy-2'-Deoxyguanosine ,Biomarkers, Tumor ,Humans ,Tyrosine ,Original Article - Abstract
Oxidative stress markers and peroxiredoxins are connected to cancer. A large set of urinary bladder carcinomas were studied for the expression of nitrotyrosine and 8-hydroxydeguanosine (8OHdG) , two markers indicating oxidative damage. Serum and urine 8-OHdG were assessed in a subset of patients. We also analysed immunohisto-chemically the expression of nrf2, keap1, all six peroxiredoxins (prx) and thioredoxin (trx) in these tumors. 15 % of the cases showed 8OHdG and 36 % nitrotyrosine positivity. Expression of nitrotyrosine and 8OHdG associated with a poor prognosis (p=0.050, p=0.011, respectively). Peroxiredoxin positivity ranged from 39 % to 84 % lowest expression being for prx 4 and highest for prx 3. Prx 4 expression associated with a poor prognosis (p=0.025) with high grade (p=0.044) and larger tumors (p=0.023). Cytoplasmic trx positivity was seen in 91 % and nuclear in 59 % of tumors. Nuclear and cytoplasmic trx associated with each other (p
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- 2011
13. Nuclear Nrf2 expression is related to a poor survival in pancreatic adenocarcinoma
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Soini, Y., primary, Eskelinen, M., additional, Juvonen, P., additional, Kärjä, V., additional, Haapasaari, K.M., additional, Saarela, A., additional, and Karihtala, P., additional
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- 2014
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14. Secondary squamous cell prostate cancer after prostate brachytherapy treatment
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Aaltomaa, S., primary, Kärjä, V., additional, and Kainulainen, S., additional
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- 2011
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15. Vasopressor Agents After Experimental Brain Death: Effects of Dopamine and Vasopressin on Vitality of the Small Gut
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Martikainen, T.J., primary, Kurola, J., additional, Kärjä, V., additional, Parviainen, I., additional, and Ruokonen, E., additional
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- 2010
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16. Learning curve for add-on stereotactic core needle breast biopsy
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Koskela, A., primary, Berg, M., additional, Sudah, M., additional, Malinen, A., additional, Kärjä, V., additional, Mustonen, P., additional, Kataja, V., additional, Soimakallio, S., additional, and Vanninen, R., additional
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- 2006
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17. Epstein-Barr virus involvement in salivary gland lesions associated with Sjögren's syndrome.
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Syrjänen, S., Kärjä, V., Chang, Fuju, Johansson, B., Syrjänen, K., Syrjänen, S, Kärjä, V, Chang, F J, and Syrjänen, K
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- 1990
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18. Collagen IV and Tenascin Immunoreactivity as Prognostic Determinant in Benign and Malignant Salivary Gland Tumours
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Kärjä, V., primary, Syrjänen, K., additional, and Syrjänen, S., additional
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- 1995
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19. c-erbB-2 Oncogene Expression in Salivary Gland Tumours
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Kärjä, V., primary, Syrjänen, S., additional, Kataja, V., additional, and Syrjänen, K., additional
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- 1994
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20. Low-grade inflammation and the phenotypic expression of myocardial fibrosis in hypertrophic cardiomyopathy.
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Kuusisto J, Kärjä V, Sipola P, Kholová I, Peuhkurinen K, Jääskeläinen P, Naukkarinen A, Ylä-Herttuala S, Punnonen K, Laakso M, Kuusisto, Johanna, Kärjä, Vesa, Sipola, Petri, Kholová, Ivana, Peuhkurinen, Keijo, Jääskeläinen, Pertti, Naukkarinen, Anita, Ylä-Herttuala, Seppo, Punnonen, Kari, and Laakso, Markku
- Abstract
Objective: To investigate the role of inflammation in the phenotypic expression of myocardial fibrosis in hypertrophic cardiomyopathy (HCM).Design: Clinical study.Setting: Kuopio University Hospital and University of Eastern Finland, Kuopio, Finland.Subjects: Twenty-four patients with a single HCM-causing mutation D175N in the α-tropomyosin gene and 17 control subjects.Main Outcome Measures: Endomyocardial biopsy samples taken from the patients with HCM were compared with matched myocardial autopsy specimens. Levels of high-sensitivity C-reactive protein (hsCRP) and proinflammatory cytokines were measured in patients and controls. Myocardial late gadolinium enhancement (LGE) in cardiac MRI (CMRI) was detected.Results: Endomyocardial samples in patients with HCM showed variable myocyte hypertrophy and size heterogeneity, myofibre disarray, fibrosis, inflammatory cell infiltration and nuclear factor kappa B (NF-κB) activation. Levels of hsCRP and interleukins (IL-1β, IL-1RA, IL-6, IL-10) were significantly higher in patients with HCM than in control subjects. In patients with HCM, there was a significant association between the degree of myocardial inflammatory cell infiltration, fibrosis in histopathological samples and myocardial LGE in CMRI. Levels of hsCRP were significantly associated with histopathological myocardial fibrosis. hsCRP, tumour necrosis factor α and IL-1RA levels had significant correlations with LGE in CMRI.Conclusions: A variable myocardial and systemic inflammatory response was demonstrated in patients with HCM attributable to an identified sarcometric mutation. Inflammatory response was associated with myocardial fibrosis, suggesting that myocardial fibrosis in HCM is an active process modified by an inflammatory response. [ABSTRACT FROM AUTHOR]- Published
- 2012
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21. Protein p62 common in invaginations in benign meningiomas -- a possible predictor of malignancy.
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Kärjä, V. and Alafuzoff, I.
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PROTEINS ,UBIQUITIN ,CANCER ,P53 antioncogene ,GENES - Abstract
Objective: It is known that p62 is a cytosolic conserved protein that binds non-covalently to ubiquitin. Expression of p62 has been seen in inclusions in neoplasias like hepatocellular and breast carcinomas but also in neuronal inclusions of degenerative brain disorders. Dysfunction of ubiquitin system leads to presence of p53 in cells suggested to be a predictor of future recurrence of meningioma. Material: The study material included 45 benign meningiomas of postmenopausal women operated in Kuopio University Hospital between 1994 and 2002. Methods: Patterns of p62 immunopositivity in meningiomas was evaluated and the results were correlated to clinical and histological parameters. Results: Constant p62 labeling in at least each field measuring 1 mm in diameter was detected consisting of 5 different patterns. The most common labeling was seen in nuclear invaginations either as grains or homogenous labeling, followed by Marinesco like nuclear inclusions or rode like inclusions outside the invagination. In some cases cytoplasmic granular staining was seen. No correlation between different p62 patterns or extent of p62 expression, histological subtypes or proliferation marker Ki-67 was noted. Conclusion: Our results indicate that in the benign not recurrent meningiomas, signs of functioning proteosomal system, can be detected using the p62 labeling. The function of proteosomal system in malignant and specifically invasive meningiomas needs to be further elucidated. [ABSTRACT FROM AUTHOR]
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- 2006
22. Expression and mutations of p53 in salivary gland tumours.
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Kärjä, Vesa J., Syrjänen, Kari J., Kurvinen, Anna-Kaisa, Syrjänen, Stine M., Kärjä, V J, Syrjänen, K J, Kurvinen, A K, and Syrjänen, S M
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CANCER patients ,GENETIC polymorphisms ,IMMUNOHISTOCHEMISTRY ,ADENOMA ,ONCOLOGY ,TUMORS ,ADENOID cystic carcinoma ,CHI-squared test ,COMPARATIVE studies ,RESEARCH methodology ,MEDICAL cooperation ,MONOCLONAL antibodies ,ONCOGENES ,POLYMERASE chain reaction ,PROGNOSIS ,PROTEINS ,RESEARCH ,SALIVARY gland tumors ,SQUAMOUS cell carcinoma ,SURVIVAL analysis (Biometry) ,LOGISTIC regression analysis ,EVALUATION research ,SEQUENCE analysis - Abstract
A series of 219 salivary gland tumours (103 carcinomas and 116 benign tumours) were analysed for p53 protein expression using immunohistochemistry, and for mutations in p53 gene using non-radioactive single strand conformation polymorphism (SSCP). p53 expression was present in 36% (42/116) of the benign tumours and in 54% (56/103) of the carcinomas. The highest prevalence of p53 expression was found in adenoid cystic carcinomas (69%), followed by mucoepidermoid carcinomas (67%). Of the benign tumours, pleomorphic adenomas showed the highest prevalence of p53 positivity (41%). In malignant tumours, expression of p53 bore no correlation to local recurrence, metastatic disease or survival of the patients. Exons 5 through 9 were analysed and four mutations were found in 20 cases of p53-immunopositive tumours and two in 20 p53-negative tumours. Each of the exons 5, 6 and 8/9 had two mutations, whereas no mutations were detected in exon 7. [ABSTRACT FROM AUTHOR]
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- 1997
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23. Transmembrane 6 Superfamily Member 2 Gene Variant Disentangles Nonalcoholic Steatohepatitis From Cardiovascular Disease
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Enrico Mozzi, Jan Borén, Vesa Kärjä, Anna Ludovica Fracanzani, Lena M. S. Carlsson, Pirjo Käkelä, Tiziana Montalcini, Chao Xing, Bruno Dallapiccola, Salvatore Petta, Silvia Fargion, Raffaela Rametta, Lars Sjöström, Jussi Pihlajamäki, Luca Valenti, Antonio Craxì, Valerio Nobili, Anna Alisi, Marco Maggioni, Cristina Maglio, Vito Di Marco, Stefano Romeo, Dorota Kaminska, Rosaria Maria Pipitone, Stefania Grimaudo, Paola Dongiovanni, Benedetta Maria Motta, Serena Pelusi, Dongiovanni, P, Petta, S, Maglio, C, Fracanzani, A, Pipitone, R, Mozzi, E, Motta, B, Kaminska, D, Rametta, R, Grimaudo, S, Pelusi, S, Montalcini, T, Alisi, A, Maggioni, M, Kärjä, V, Borén, J, Käkelä, P, Di Marco, V, Xing, C, Nobili, V, Dallapiccola, B, Craxi, A, Pihlajamäki, J, Fargion, S, Sjöström, L, Carlsson, L, Romeo, S, and Valenti, L
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medicine.medical_specialty ,Hepatology ,medicine.diagnostic_test ,business.industry ,Fatty liver ,Odds ratio ,medicine.disease ,Lower risk ,Endocrinology ,Internal medicine ,Liver biopsy ,Cohort ,medicine ,Steatosis ,NASH, TM6SF2 ,business ,TM6SF2 - Abstract
Excess hepatic storage of triglycerides is considered a benign condition, but nonalcoholic steatohepatitis (NASH) may progress to fibrosis and promote atherosclerosis. Carriers of the TM6SF2 E167K variant have fatty liver as a result of reduced secretion of very-low-density lipoproteins (VLDLs). As a result, they have lower circulating lipids and reduced risk of myocardial infarction. In this study, we aimed to assess whether TM6SF2 E167K affects liver damage and cardiovascular outcomes in subjects at risk of NASH. Liver damage was evaluated in 1,201 patients who underwent liver biopsy for suspected NASH; 427 were evaluated for carotid atherosclerosis. Cardiovascular outcomes were assessed in 1,819 controls from the Swedish Obese Subjects (SOS) cohort. Presence of the inherited TM6SF2 E167K variant was determined by TaqMan assays. In the liver biopsy cohort, 188 subjects (13%) were carriers of the E167K variant. They had lower serum lipid levels than noncarriers (P
- Published
- 2015
24. Learning curve for add-on stereotactic breast biopsy
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Koskela, A., Berg, M., Sudah, M., Kärjä, V., Malinen, A., and Vanninen, R.
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- 2002
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25. Add-on stereotactic 14-G core needle breast biopsy: how many passes are enough to detect malignancy?
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Koskela, A., Sudah, M., Berg, M., Kärjä, V., Mustonen, P., and Vanninen, R.
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- 2002
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26. Different types of solid, non-palpable breast lesions: Stereotactic core needle biopsy using add-on stereotactic device
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Berg, M., Koskela, A., Sudah, M., Kärjä, V., and Vanninen, R.
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- 2002
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27. Correction: AAV2-VEGF-B gene therapy failed to induce angiogenesis in ischemic porcine myocardium due to inflammatory responses.
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Korpela H, Lampela J, Airaksinen J, Järveläinen N, Siimes S, Valli K, Nieminen T, Turunen M, Grönman M, Saraste A, Knuuti J, Hakulinen M, Poutiainen P, Kärjä V, Nurro J, and Ylä-Herttuala S
- Published
- 2024
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28. The amount of hyaluronic acid and airway remodelling increase with the severity of inflammation in neutrophilic equine asthma.
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Höglund N, Rossi H, Javela HM, Oikari S, Nieminen P, Mustonen AM, Airas N, Kärjä V, and Mykkänen A
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- Animals, Horses, Female, Male, Neutrophils, Inflammation veterinary, Inflammation pathology, Severity of Illness Index, Hyaluronic Acid blood, Asthma veterinary, Asthma pathology, Horse Diseases pathology, Airway Remodeling, Bronchoalveolar Lavage Fluid chemistry, Bronchoalveolar Lavage Fluid cytology
- Abstract
Background: Equine asthma (EA) is a chronic lower airway inflammation that leads to structural and functional changes. Hyaluronic acid (HA) has crucial functions in the extracellular matrix homeostasis and inflammatory mediator activity. HA concentration in the lungs increases in several human airway diseases. However, its associations with naturally occurring EA and airway remodelling have not been previously studied. Our aim was to investigate the association of equine neutrophilic airway inflammation (NAI) severity, airway remodelling, and HA concentration in horses with naturally occurring EA. We hypothesised that HA concentration and airway remodelling would increase with the severity of NAI. HA concentrations of bronchoalveolar lavage fluid supernatant (SUP) and plasma of 27 neutrophilic EA horses, and 28 control horses were measured. Additionally, remodelling and HA staining intensity were assessed from endobronchial biopsies from 10 moderate NAI horses, 5 severe NAI horses, and 15 control horses., Results: The HA concentration in SUP was higher in EA horses compared to controls (p = 0.007). Plasma HA concentrations were not different between the groups. In the endobronchial biopsies, moderate NAI horses showed epithelial hyperplasia and inflammatory cell infiltrate, while severe NAI horses also showed fibrosis and desquamation of the epithelium. The degree of remodelling was higher in severe NAI compared to moderate NAI (p = 0.048) and controls (p = 0.016). Intense HA staining was observed in bronchial cell membranes, basement membranes, and connective tissue without significant differences between the groups., Conclusion: The release of HA to the airway lumen increases in naturally occurring neutrophilic EA without clear changes in its tissue distribution, and significant airway remodelling only develops in severe NAI., (© 2024. The Author(s).)
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- 2024
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29. Metabolic signatures of metabolic dysfunction-associated steatotic liver disease in severely obese patients.
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Babu AF, Palomurto S, Kärjä V, Käkelä P, Lehtonen M, Hanhineva K, Pihlajamäki J, and Männistö V
- Abstract
Backround: Metabolic dysfunction-associated steatotic liver disease (MASLD) can lead to liver fibrosis, cirrhosis, and hepatocellular carcinoma. Still, most patients with MASLD die from cardiovascular diseases indicating metabolic alterations related to both liver and cardiovascular pathology., Aims and Methods: The aim of this study was to assess biologic pathways behind MASLD progression from steatosis to metabolic dysfunction-associated steatohepatitis (MASH) using non-targeted liquid chromatography-mass spectrometry analysis in 106 severely obese individuals (78 women, mean age 47.7 7 ± 9.2 years, body mass index 41.8 ± 4.3 kg/m²) undergoing laparoscopic Roux-en-Y gastric bypass., Results: We identified several metabolites that are associated with MASLD progression. Most importantly, we observed a decrease of lysophosphatidylcholines LPC(18:2), LPC(18:3), and LPC(20:3) and increase of xanthine when comparing those with steatosis to those with MASH. We found that indole propionic acid and threonine were negatively correlated to fibrosis, but not with the metabolic disturbances associated with cardiovascular risk. Xanthine, ketoleucine, and tryptophan were positively correlated to lobular inflammation and ballooning but also with insulin resistance, and dyslipidemia, respectively. The results did not change when taking into account the most important genetic risk factors of MASLD., Conclusions: Our findings suggest that there are several separate biological pathways, some of them independent of insulin resistance and dyslipidemia, associating with MASLD., Competing Interests: Conflict of interest The authors have no relevant conflict of interest to disclose. Ambrin Farizah Babu and Kati Hanhineva are employed by Afekta Technologies Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2024
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30. IL32 downregulation lowers triglycerides and type I collagen in di-lineage human primary liver organoids.
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Sasidharan K, Caddeo A, Jamialahmadi O, Noto FR, Tomasi M, Malvestiti F, Ciociola E, Tavaglione F, Mancina RM, Cherubini A, Bianco C, Mirarchi A, Männistö V, Pihlajamäki J, Kärjä V, Grimaudo S, Luukkonen PK, Qadri S, Yki-Järvinen H, Petta S, Manfrini S, Vespasiani-Gentilucci U, Bruni V, Valenti L, and Romeo S
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- Humans, Collagen Type I genetics, Collagen Type I metabolism, Triglycerides metabolism, Down-Regulation genetics, Interleukins genetics, Organoids, Fatty Liver, Liver Diseases
- Abstract
Steatotic liver disease (SLD) prevails as the most common chronic liver disease yet lack approved treatments due to incomplete understanding of pathogenesis. Recently, elevated hepatic and circulating interleukin 32 (IL-32) levels were found in individuals with severe SLD. However, the mechanistic link between IL-32 and intracellular triglyceride metabolism remains to be elucidated. We demonstrate in vitro that incubation with IL-32β protein leads to an increase in intracellular triglyceride synthesis, while downregulation of IL32 by small interfering RNA leads to lower triglyceride synthesis and secretion in organoids from human primary hepatocytes. This reduction requires the upregulation of Phospholipase A2 group IIA (PLA2G2A). Furthermore, downregulation of IL32 results in lower intracellular type I collagen levels in di-lineage human primary hepatic organoids. Finally, we identify a genetic variant of IL32 (rs76580947) associated with lower circulating IL-32 and protection against SLD measured by non-invasive tests. These data suggest that IL32 downregulation may be beneficial against SLD., Competing Interests: Declaration of interests S.R. has served as a consultant for AstraZeneca, Celgene, Sanofi, Amgen, Akcea Therapeutics, Camp4, Medacorp, and Pfizer in the last 5 years. S.R. has received research grants from AstraZeneca, Sanofi and Amgen. L.V. reports having received speaking fees from Gilead; having served as a consultant for Gilead, Pfizer, Astra Zeneca, Novo Nordisk, Intercept, and Ionis Pharmaceuticals; and having received research grants from Gilead. P.K.L. was supported by the Novo Nordisk, Sigrid Jusélius, and Instrumentarium Science Foundations., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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31. Programmed cell death 1 genetic variant and liver damage in nonalcoholic fatty liver disease.
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Pipitone RM, Malvestiti F, Pennisi G, Jamialahmadi O, Dongiovanni P, Bertolazzi G, Pihlajamäki J, Yki-Järvinen H, Vespasiani-Gentilucci U, Tavaglione F, Maurotti S, Bianco C, Di Maria G, Enea M, Fracanzani AL, Kärjä V, Lupo G, Männistö V, Meroni M, Piciotti R, Qadri S, Zito R, Craxì A, Di Marco V, Cammà C, Tripodo C, Valenti L, Romeo S, Petta S, and Grimaudo S
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- Humans, Liver pathology, Inflammation pathology, Apoptosis, Liver Cirrhosis complications, Non-alcoholic Fatty Liver Disease complications, Carcinoma, Hepatocellular pathology, Liver Neoplasms pathology
- Abstract
Background and Aims: Programmed cell death 1/programmed cell death-ligand 1 (PD-1/PDL-1) axis has been reported to modulate liver inflammation and progression to hepatocellular carcinoma (HCC) in patients with nonalcoholic fatty liver disease (NAFLD). Here, we examined whether the PDCD1 variation is associated with NAFLD severity in individuals with liver biopsy., Methods: We examined the impact of PDCD1 gene variants on HCC, as robust severe liver disease phenotype in UK Biobank participants. The strongest genetic association with the rs13023138 G>C variation was subsequently tested for association with liver damage in 2889 individuals who underwent liver biopsy for suspected nonalcoholic steatohepatitis (NASH). Hepatic transcriptome was examined by RNA-Seq in a subset of NAFLD individuals (n = 121). Transcriptomic and deconvolution analyses were performed to identify biological pathways modulated by the risk allele., Results: The rs13023138 C>G showed the most robust association with HCC in UK Biobank (p = 5.28E-4, OR = 1.32, 95% CI [1.1, 1.5]). In the liver biopsy cohort, rs13023138 G allele was independently associated with severe steatosis (OR 1.17, 95% CI 1.02-1.34; p = .01), NASH (OR 1.22, 95% CI 1.09-1.37; p < .001) and advanced fibrosis (OR 1.26, 95% CI 1.06-1.50; p = .007). At deconvolution analysis, rs13023138 G>C allele was linked to higher hepatic representation of M1 macrophages, paralleled by upregulation of pathways related to inflammation and higher expression of CXCR6., Conclusions: The PDCD1 rs13023138 G allele was associated with HCC development in the general population and with liver disease severity in patients at high risk of NASH., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2023
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32. AAV2-VEGF-B gene therapy failed to induce angiogenesis in ischemic porcine myocardium due to inflammatory responses.
- Author
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Korpela H, Lampela J, Airaksinen J, Järveläinen N, Siimes S, Valli K, Nieminen T, Turunen M, Grönman M, Saraste A, Knuuti J, Hakulinen M, Poutiainen P, Kärjä V, Nurro J, and Ylä-Herttuala S
- Subjects
- Animals, Swine, Vascular Endothelial Growth Factor A genetics, Vascular Endothelial Growth Factor A therapeutic use, Dependovirus genetics, Genetic Therapy methods, Myocardium, Vascular Endothelial Growth Factor B genetics, Genetic Vectors genetics
- Abstract
Therapeutic angiogenesis induced by gene therapy is a promising approach to treat patients suffering from severe coronary artery disease. In small experimental animals, adeno-associated viruses (AAVs) have shown good transduction efficacy and long-term transgene expression in heart muscle and other tissues. However, it has been difficult to achieve cardiac-specific angiogenic effects with AAV vectors. We tested the hypothesis whether AAV2 gene transfer (1 × 10
13 vg) of vascular endothelial growth factor B (VEGF-B186) together with immunosuppressive corticosteroid treatment can induce long-term cardiac-specific therapeutic effects in the porcine ischemic heart. Gene transfers were delivered percutaneously using direct intramyocardial injections, improving targeting and avoiding direct contact with blood, thus reducing the likelihood of immediate immune reactions. After 1- and 6-month time points, the capillary area was analyzed, myocardial perfusion reserve (MPR) was measured with radiowater positron emission tomography ([15 O]H2 O-PET), and fluorodeoxyglucose ([18 F]FDG) uptake was used to evaluate myocardial viability. Clinical chemistry and immune responses were analyzed using standard methods. After 1- and 6-month follow-up, AAV2-VEGF-B186 gene transfer failed to induce angiogenesis and improve myocardial perfusion and viability. Here, we show that inflammatory responses attenuated the therapeutic effect of AAV2 gene transfer by significantly reducing successful transduction and long-term gene expression despite the efforts to reduce the likelihood of immune reactions and the use of targeted local gene transfer methods., (© 2022. The Author(s).)- Published
- 2022
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33. Diagnostic performance of tomosynthesis, digital mammography and a dedicated digital specimen radiography system versus pathological assessment of excised breast lesions.
- Author
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Almasarweh S, Sudah M, Okuma H, Joukainen S, Kärjä V, Vanninen R, and Masarwah A
- Subjects
- Humans, Retrospective Studies, Mammography methods, Margins of Excision, Radiographic Image Enhancement methods, Calcinosis diagnostic imaging, Calcinosis surgery
- Abstract
Background: The aim of the study was to compare the performance of full-field digital mammography (FFDM), digital breast tomosynthesis and a dedicated digital specimen radiography system (SRS) in consecutive patients, and to compare the margin status of resected lesions versus pathological assessment., Patients and Methods: Resected tissue specimens from consecutive patients who underwent intraoperative breast specimen assessment following wide local excision or oncoplastic breast conservative surgery were examined by FFDM, tomosynthesis and SRS. Two independent observers retrospectively evaluated the visibility of lesions, size, margins, spiculations, calcifications and diagnostic certainty, and chose the best performing method in a blinded manner., Results: We evaluated 216 specimens from 204 patients. All target malignant lesions were removed with no tumouron-ink. One papilloma had positive microscopic margins and one patient underwent reoperation owing to extensive in situ components. There were no significant differences in measured lesion size among the three methods. However, tomosynthesis was the most accurate modality when compared with the final pathological report. Both observers reported that tomosynthesis had significantly better lesion visibility than SRS and FFDM, which translated into a significantly greater diagnostic certainty. Tomosynthesis was superior to the other two methods in identifying spiculations and calcifications. Both observers reported that tomosynthesis was the best performing method in 76.9% of cases. The interobserver reproducibilities of lesion visibility and diagnostic certainty were high for all three methods., Conclusions: Tomosynthesis was superior to SRS and FFDM for detecting and evaluating the target lesions, spiculations and calcifications, and was therefore more reliable for assessing complete excision of breast lesions., (© 2022 Sa’ed Almasarweh, Mazen Sudah, Hidemi Okuma, Sarianna Joukainen, Vesa Kärjä, Ritva Vanninen, Amro Masarwah, published by Sciendo.)
- Published
- 2022
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34. PSD3 downregulation confers protection against fatty liver disease.
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Mancina RM, Sasidharan K, Lindblom A, Wei Y, Ciociola E, Jamialahmadi O, Pingitore P, Andréasson AC, Pellegrini G, Baselli G, Männistö V, Pihlajamäki J, Kärjä V, Grimaudo S, Marini I, Maggioni M, Becattini B, Tavaglione F, Dix C, Castaldo M, Klein S, Perelis M, Pattou F, Thuillier D, Raverdy V, Dongiovanni P, Fracanzani AL, Stickel F, Hampe J, Buch S, Luukkonen PK, Prati D, Yki-Järvinen H, Petta S, Xing C, Schafmayer C, Aigner E, Datz C, Lee RG, Valenti L, Lindén D, and Romeo S
- Subjects
- Alleles, Animals, Biomarkers, Cell Line, Fatty Liver pathology, Gene Expression Profiling, Genetic Variation, Genotype, Guanine Nucleotide Exchange Factors metabolism, Hepatocytes metabolism, Humans, Liver metabolism, Liver pathology, Mice, Polymorphism, Single Nucleotide, RNA-Seq, Ribonucleases, Disease Susceptibility, Fatty Liver etiology, Fatty Liver metabolism, Gene Expression Regulation, Guanine Nucleotide Exchange Factors genetics
- Abstract
Fatty liver disease (FLD) is a growing health issue with burdening unmet clinical needs. FLD has a genetic component but, despite the common variants already identified, there is still a missing heritability component. Using a candidate gene approach, we identify a locus (rs71519934) at the Pleckstrin and Sec7 domain-containing 3 (PSD3) gene resulting in a leucine to threonine substitution at position 186 of the protein (L186T) that reduces susceptibility to the entire spectrum of FLD in individuals at risk. PSD3 downregulation by short interfering RNA reduces intracellular lipid content in primary human hepatocytes cultured in two and three dimensions, and in human and rodent hepatoma cells. Consistent with this, Psd3 downregulation by antisense oligonucleotides in vivo protects against FLD in mice fed a non-alcoholic steatohepatitis-inducing diet. Thus, translating these results to humans, PSD3 downregulation might be a future therapeutic option for treating FLD., (© 2022. The Author(s).)
- Published
- 2022
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35. Correction to: Small Intestinal Length Associates with Serum Triglycerides Before and After LRYGB.
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Käkelä P, Männistö V, Vaittinen M, Venesmaa S, Kärjä V, Virtanen K, Paajanen H, and Pihlajamäki J
- Published
- 2022
- Full Text
- View/download PDF
36. Can supine breast magnetic resonance imaging help hit the target in extreme oncoplastic surgery?
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Joukainen S, Okuma H, Kaarela O, Laaksonen E, Kärjä V, Vanninen R, Masarwah A, and Sudah M
- Subjects
- Adult, Aged, Female, Humans, Margins of Excision, Middle Aged, Postoperative Complications, Prospective Studies, Reoperation statistics & numerical data, Breast Neoplasms diagnostic imaging, Breast Neoplasms surgery, Magnetic Resonance Imaging methods, Mastectomy, Segmental methods, Supine Position
- Abstract
Objectives: To evaluate the clinical value of supine magnetic resonance imaging (MRI) for tumor localization in breast cancer patients with large or multifocal tumors detected by prone MRI, scheduled for oncoplastic breast conserving surgery (OBCS). Outcomes were compared with those of patients who underwent wide local excision (WLE) or OBCS without MRI guidance., Methods: Over a 2-year period, consecutive patients with large or multifocal disease scheduled for OBCS with MRI-only findings were invited to participate (Group-1). Supplementary supine MRI was performed, and tumor margins were marked in the surgical position. Consecutive patients with early, non-palpable breast cancer who underwent WLE (Group-2) or OBCS (Group-3) were included for comparisons. The primary outcome was reoperation due to an insufficient margin. Secondary outcomes included surgical complications and delayed adjuvant treatment., Results: Altogether, 102 breasts (98 patients) were analyzed. All preoperative demographic data were comparable among the three groups. Multifocality, tumor-to-breast volume ratio, and the volume of excised breast tissue were significantly greater in Group-1 than in Groups-2 and 3. Operation time was longer and the need for axillary clearance or surgery for both breasts was more common in Groups-1 and 3 than in Group-2. Adequate margins were achieved in all patients in Groups-1 and 2, and one patient underwent re-excision in Group-3., Conclusions: Supine MRI in the surgical position is a new, promising method to localize multifocal, large tumors visible on MRI. Its short-term outcomes were comparable with those of conventional WLE and OBCS., Competing Interests: Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2021
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37. Indole-3-Propionic Acid, a Gut-Derived Tryptophan Metabolite, Associates with Hepatic Fibrosis.
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Sehgal R, Ilha M, Vaittinen M, Kaminska D, Männistö V, Kärjä V, Tuomainen M, Hanhineva K, Romeo S, Pajukanta P, Pihlajamäki J, and de Mello VD
- Subjects
- Adult, Bariatric Surgery, Cell Adhesion drug effects, Cell Movement drug effects, Female, Gene Expression drug effects, Hepatic Stellate Cells metabolism, Humans, Liver cytology, Liver metabolism, Liver Cirrhosis etiology, Male, Middle Aged, Obesity complications, Obesity surgery, RNA, Messenger metabolism, Transforming Growth Factor beta1 metabolism, Indoles blood, Liver Cirrhosis blood, Obesity blood
- Abstract
Background and Aims: Gut microbiota-derived metabolites play a vital role in maintenance of human health and progression of disorders, including obesity and type 2 diabetes (T2D). Indole-3-propionic acid (IPA), a gut-derived tryptophan metabolite, has been recently shown to be lower in individuals with obesity and T2D. IPA's beneficial effect on liver health has been also explored in rodent and cell models. In this study, we investigated the association of IPA with human liver histology and transcriptomics, and the potential of IPA to reduce hepatic stellate cell activation in vitro., Methods: A total of 233 subjects (72% women; age 48.3 ± 9.3 years; BMI 43.1 ± 5.4 kg/m
2 ) undergoing bariatric surgery with detailed liver histology were included. Circulating IPA levels were measured using LC-MS and liver transcriptomics with total RNA-sequencing. LX-2 cells were used to study hepatoprotective effect of IPA in cells activated by TGF-β1., Results: Circulating IPA levels were found to be lower in individuals with liver fibrosis compared to those without fibrosis ( p = 0.039 for all participants; p = 0.013 for 153 individuals without T2D). Accordingly, levels of circulating IPA associated with expression of 278 liver transcripts ( p < 0.01) that were enriched for the genes regulating hepatic stellate cells (HSCs) activation and hepatic fibrosis signaling. Our results suggest that IPA may have hepatoprotective potential because it is able to reduce cell adhesion, cell migration and mRNA gene expression of classical markers of HSCs activation in LX-2 cells (all p < 0.05)., Conclusion: The association of circulating IPA with liver fibrosis and the ability of IPA to reduce activation of LX-2 cells suggests that IPA may have a therapeutic potential. Further molecular studies are needed to investigate the mechanisms how IPA can ameliorate hepatic fibrosis.- Published
- 2021
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38. Total liver phosphatidylcholine content associates with non-alcoholic steatohepatitis and glycine N-methyltransferase expression.
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Männistö V, Kaminska D, Kärjä V, Tiainen M, de Mello VD, Hanhineva K, Soininen P, Ala-Korpela M, and Pihlajamäki J
- Subjects
- Adult, Animals, Female, Humans, Liver pathology, Male, Middle Aged, Obesity pathology, Proton Magnetic Resonance Spectroscopy, RNA, Messenger, Glycine N-Methyltransferase genetics, Non-alcoholic Fatty Liver Disease genetics, Non-alcoholic Fatty Liver Disease pathology, Phosphatidylcholines analysis, Phosphatidylethanolamine N-Methyltransferase genetics
- Abstract
Background & Aims: Alterations in liver phosphatidylcholine (PC) metabolism have been implicated in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Although genetic variation in the phosphatidylethanolamine N-methyltransferase (PEMT) enzyme synthesizing PC has been associated with disease, the functional mechanism linking PC metabolism to the pathogenesis of non-alcoholic steatohepatitis (NASH) remains unclear., Methods: Serum PC levels and liver PC contents were measured using proton nuclear magnetic resonance (NMR) spectroscopy in 169 obese individuals [age 46.6 ± 10 (mean ± SD) years, BMI 43.3 ± 6 kg/m
2 , 53 men and 116 women] with histological assessment of NAFLD; 106 of these had a distinct liver phenotype. All subjects were genotyped for PEMT rs7946 and liver mRNA expression of PEMT and glycine N-methyltransferase (GNMT) was analysed., Results: Liver PC content was lower in those with NASH (P = 1.8 x 10-6 ) while serum PC levels did not differ between individuals with NASH and normal liver (P = 0.591). Interestingly, serum and liver PC did not correlate (rs = -0.047, P = 0.557). Serum PC and serum cholesterol levels correlated strongly (rs = 0.866, P = 7.1 x 10-49 ), while liver PC content did not correlate with serum cholesterol (rs = 0.065, P = 0.413). Neither PEMT V175M genotype nor PEMT expression explained the association between liver PC content and NASH. Instead, liver GNMT mRNA expression was decreased in those with NASH (P = 3.8 x 10-4 ) and correlated with liver PC content (rs = 0.265, P = 0.001)., Conclusions: Decreased liver PC content in individuals with the NASH is independent of PEMT V175M genotype and could be partly linked to decreased GNMT expression., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)- Published
- 2019
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39. Novel Lipid Long Intervening Noncoding RNA, Oligodendrocyte Maturation-Associated Long Intergenic Noncoding RNA, Regulates the Liver Steatosis Gene Stearoyl-Coenzyme A Desaturase As an Enhancer RNA.
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Benhammou JN, Ko A, Alvarez M, Kaikkonen MU, Rankin C, Garske KM, Padua D, Bhagat Y, Kaminska D, Kärjä V, Pihlajamäki J, Pisegna JR, and Pajukanta P
- Abstract
The global obesity epidemic is driving the concomitant rise in nonalcoholic fatty liver disease (NAFLD). To identify new genes involved in central liver functions, we examined liver RNA-sequence data from 259 patients who underwent morbidly obese bariatric surgery. Of these patients, 84 had normal liver histology, 40 simple steatosis, 43 nonalcoholic steatohepatitis, and the remaining 92 patients had varying degrees of NAFLD based on liver histology. We discovered oligodendrocyte maturation-associated long intergenic noncoding RNA ( OLMALINC ) , a long intervening noncoding RNA (lincRNA) in a human liver co-expression network (n = 75 genes) that was strongly associated with statin use and serum triglycerides (TGs). OLMALINC liver expression was highly correlated with the expression of known cholesterol biosynthesis genes and stearoyl-coenzyme A desaturase ( SCD ). SCD is the rate-limiting enzyme in monounsaturated fatty acids and a key TG gene that is known to be up-regulated in liver steatosis and NAFLD and resides adjacent to OLMALINC on the human chromosome 10q24.31. Next, we functionally demonstrated that OLMALINC regulates SCD as an enhancer-RNA (eRNA), thus describing the first lincRNA that functions as an eRNA to regulate lipid metabolism. Specifically, we show that OLMALINC promotes liver expression of SCD in cis through regional chromosomal DNA-DNA looping interactions. Conclusion: The primate-specific lincRNA OLMALINC is a novel epigenetic regulator of the key TG and NAFLD gene SCD ., (© 2019 The Authors. Hepatology Communications published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.)
- Published
- 2019
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40. Bile-duct proliferation as an unexpected side-effect after AAV2-LDLR gene transfer to rabbit liver.
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Hytönen E, Laurema A, Kankkonen H, Miyanohara A, Kärjä V, Hujo M, Laham-Karam N, and Ylä-Herttuala S
- Subjects
- Animals, Bile Ducts pathology, Biomarkers, Cholesterol metabolism, Dependovirus, Gene Expression, Immunohistochemistry, Lipid Metabolism, Liver pathology, Rabbits, Bile Ducts metabolism, Gene Transfer Techniques adverse effects, Genetic Vectors genetics, Liver metabolism, Parvovirinae genetics, Receptors, LDL genetics
- Abstract
Familial hypercholesterolemia (FH) is an inherited disease of lipoprotein metabolism caused by a defect in the LDL receptor (LDLR) leading to severe hypercholesterolemia, and associated with an increased risk of coronary heart disease and myocardial infarction. We have developed a gene therapy protocol for FH using AAV2, AAV9 and lentiviral vectors and tested safety and efficacy in LDL receptor deficient Watanabe Heritable Hyperlipidemic rabbits. We show that LV-LDLR produced a significant long-lasting decrease in total serum cholesterol whereas AAV9-LDLR resulted only in a transient decrease and AAV2-LDLR failed to reduce serum cholesterol levels. A significant pathological side effect, bile-duct proliferation, was seen in the liver of AAV2-LDLR rabbits associated with an increased expression of Cyr61 matricellular protein. Special attention should be given to liver changes in gene therapy applications when genes affecting cholesterol and lipoprotein metabolism are used for therapy.
- Published
- 2019
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41. Hyaluronan histochemistry-a potential new tool to assess the progress of liver disease from simple steatosis to hepatocellular carcinoma.
- Author
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Mustonen AM, Salvén A, Kärjä V, Rilla K, Matilainen J, and Nieminen P
- Subjects
- Humans, Hyaluronan Synthases metabolism, Liver Neoplasms metabolism, Carcinoma, Hepatocellular metabolism, Carcinoma, Hepatocellular pathology, Fatty Liver metabolism, Fatty Liver pathology, Hyaluronic Acid analysis, Hyaluronic Acid metabolism, Liver Neoplasms pathology
- Abstract
Nonalcoholic fatty liver disease is among the most common liver diseases worldwide and one cause of cirrhosis that can result in the development of hepatocellular carcinoma (HCC). Hyaluronan (HA) is a high-molecular-mass glycosaminoglycan with diverse functions in tissue injury and repair, for instance, in inflammation and fibrogenesis. The aim of the present study was to investigate the relationships between the HA synthesizing and degrading enzymes in a spectrum of liver pathologies. This was realized by histological staining of liver sections from controls and patients with simple steatosis, steatohepatitis, cirrhosis and HCC (n = 90). HA-positive staining intensified in connective tissue in all liver pathologies, and staining of CD44, the major HA receptor, similarly increased in steatohepatitis and cirrhosis. HA synthase 1 (HAS1)-positive staining was reduced in steatosis, steatohepatitis and HCC. Staining of HAS3, which produces HA of a lower molecular mass, promotes inflammation and is pathogenic in animal models, increased in all diagnoses. The responses in staining intensity of HAS2 and hyaluronidases 1-2 were specific for different cell types. These findings suggest that HAS1-2 are responsible for HA synthesis in healthy livers, while HAS3 increases in importance in liver diseases. It is noteworthy that the pathological changes in HA metabolism are already visible in simple steatosis and, thus, precede the histological changes of inflammation and fibrosis. It could be possible to intervene in disease progression at an early stage by influencing HA metabolism. The results could have potential clinical applications with HAS3 immunostaining supplementing the existing HCC diagnostics., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2019
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42. Small Intestinal Length Associates with Serum Triglycerides Before and After LRYGB.
- Author
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Käkelä P, Männistö V, Vaittinen M, Venesmaa S, Kärjä V, Virtanen K, Paajanen H, and Pihlajamäki J
- Subjects
- Adult, Aged, Female, Humans, Male, Middle Aged, Non-alcoholic Fatty Liver Disease blood, Non-alcoholic Fatty Liver Disease complications, Non-alcoholic Fatty Liver Disease diagnosis, Obesity, Morbid complications, Prospective Studies, Weight Loss physiology, Gastric Bypass methods, Intestine, Small, Laparoscopy methods, Obesity, Morbid blood, Obesity, Morbid surgery, Triglycerides blood
- Abstract
Background and Aims: Different bariatric procedures have been associated with variable weight loss and decrease in serum levels of lipids and lipoproteins. This variation could be partly related to the length of the small intestinal bypass. We evaluated the association of the small intestinal length with the non-alcoholic fatty liver disease (NAFLD) at baseline and with lipid metabolism before and after laparoscopic Roux-en-Y gastric bypass (LRYGB)., Methods: Seventy consecutive morbidly obese patients were recruited to this prospective study. A standard 60-cm biliopancreatic limb (BPL) and 120-cm alimentary limb (AL) was performed, and thereafter, the common channel (CC) length was measured during elective LRYGB. Histological analysis of liver biopsy to diagnose NAFLD was performed. The mRNA expression of genes participating in the cholesterol and fatty acid metabolism in the liver was analyzed., Results: Female sex (p = 0.006), serum triglycerides (TG, p = 0.016), serum alanine aminotransferase (ALT, p = 0.007), and liver steatosis (p = 0.001) associated with the small intestinal length (BPL + AL + CC) at baseline. Association remained significant between levels of serum TG and CC length (p = 0.048) at 1-year follow-up. Liver mRNA expression of genes regulating cholesterol synthesis and bile metabolism did not associate with the baseline small intestinal length., Conclusions: Our findings support the suggestions that small intestinal length regulates TG metabolism before and after LRYGB. Therefore, modification of the length of bypassed small intestine based on measured total small intestinal length could optimize the outcomes of the elective LRYGB.
- Published
- 2018
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43. Comprehensive Pharmacogenomic Study Reveals an Important Role of UGT1A3 in Montelukast Pharmacokinetics.
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Hirvensalo P, Tornio A, Neuvonen M, Tapaninen T, Paile-Hyvärinen M, Kärjä V, Männistö VT, Pihlajamäki J, Backman JT, and Niemi M
- Subjects
- Acetates metabolism, Adult, Area Under Curve, Cyclopropanes, Cytochrome P-450 CYP1A2 Inducers metabolism, Cytochrome P-450 CYP2C8 genetics, Cytochrome P-450 CYP2C8 metabolism, Female, Glucuronosyltransferase metabolism, Humans, In Vitro Techniques, Liver-Specific Organic Anion Transporter 1 genetics, Liver-Specific Organic Anion Transporter 1 metabolism, Male, Pharmacogenomic Testing, Polymorphism, Single Nucleotide, Quinolines metabolism, Sulfides, Sulfonylurea Receptors genetics, Sulfonylurea Receptors metabolism, Young Adult, Acetates pharmacokinetics, Cytochrome P-450 CYP1A2 Inducers pharmacokinetics, Glucuronosyltransferase genetics, Quinolines pharmacokinetics
- Abstract
To identify the genetic basis of interindividual variability in montelukast exposure, we determined its pharmacokinetics and sequenced 379 pharmacokinetic genes in 191 healthy volunteers. An intronic single nucleotide variation (SNV), strongly linked with UGT1A3*2, associated with reduced area under the plasma concentration-time curve (AUC
0-∞ ) of montelukast (by 18% per copy of the minor allele; P = 1.83 × 10-10 ). UGT1A3*2 was associated with increased AUC0-∞ of montelukast acyl-glucuronide M1 and decreased AUC0-∞ of hydroxymetabolites M5R, M5S, and M6 (P < 10-9 ). Furthermore, SNVs in SLCO1B1 and ABCC9 were associated with the AUC0-∞ of M1 and M5R, respectively. In addition, a candidate gene analysis suggested that CYP2C8 and ABCC9 SNVs also affect the AUC0-∞ of montelukast. The found UGT1A3 and ABCC9 variants associated with increased expression of the respective genes in human liver samples. Montelukast and its hydroxymetabolites were glucuronidated by UGT1A3 in vitro. These results indicate that UGT1A3 plays an important role in montelukast pharmacokinetics, especially in UGT1A3*2 carriers., (© 2017, The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)- Published
- 2018
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44. Serum, liver and bile sitosterol and sitostanol in obese patients with and without NAFLD.
- Author
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Tauriainen MM, Männistö V, Kaminska D, Vaittinen M, Kärjä V, Käkelä P, Venesmaa S, Gylling H, and Pihlajamäki J
- Subjects
- Adult, Female, Humans, Male, Middle Aged, Non-alcoholic Fatty Liver Disease complications, Obesity complications, Bile metabolism, Liver metabolism, Non-alcoholic Fatty Liver Disease blood, Obesity blood, Sitosterols blood
- Abstract
Background and aims : Non-alcoholic fatty liver disease (NAFLD) associates with low levels of serum plant sterols in cross-sectional studies. In addition, it has been suggested that the hepatic sterol transport mechanisms are altered in NAFLD. Therefore, we investigated the association between serum, liver and bile plant sterols and sitostanol with NAFLD. Methods : Out of the 138 individuals (age: 46.3 ± 8.9, body mass index: 43.3 ± 6.9 kg/m², 28% men and 72% women), 44 could be histologically categorized to have normal liver, and 94 to have NAFLD. Within the NAFLD group, 28 had simple steatosis and 27 had non-alcoholic steatohepatitis. Plant sterols and sitostanol were measured from serum ( n =138), liver ( n =38), and bile ( n =41). The mRNA expression of genes regulating liver sterol metabolism and inflammation was measured ( n =102). Results : Liver and bile sitostanol ratios to cholesterol were higher in those with NAFLD compared to those with histologically normal liver (all P <0.022). Furthermore, liver sitostanol to cholesterol ratio correlated positively with histological steatosis and lobular inflammation ( r
s > 0.407, P <0.01 for both). In contrast, liver sitosterol to cholesterol ratio correlated negatively with steatosis ( rs = -0.392, P =0.015) and lobular inflammation ( rs = -0.395, P =0.014). Transcriptomics analysis revealed suggestive correlations between serum plant sterol levels and mRNA expression. Conclusion : Our study showed that liver and bile sitostanol ratios to cholesterol associated positively and liver sitosterol ratio to cholesterol associated negatively with liver steatosis and inflammation in obese individuals with NAFLD.., (© 2018 The Author(s).)- Published
- 2018
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45. Myo- and cardiotoxic effects of the wild winter mushroom ( Flammulina velutipes) on mice.
- Author
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Mustonen AM, Määttänen M, Kärjä V, Puukka K, Aho J, Saarela S, and Nieminen P
- Subjects
- Animals, Cardiotoxicity etiology, Creatine Kinase blood, Male, Mice, Agaricales chemistry, Allergens adverse effects, Cardiotoxicity metabolism, Cardiotoxicity microbiology, Flammulina chemistry, Muscle, Skeletal metabolism, Myocardium metabolism
- Abstract
Rhabdomyolysis (destruction of striated muscle) is a novel form of mushroom poisoning in Europe and Asia indicated by increased circulating creatine kinase levels. Particular wild fungi have also been reported to induce elevated creatine kinase activities in mice. Flammulina velutipes (enokitake or winter mushroom) is one of the most actively cultivated mushroom species globally. As it is marketed as a medicinal mushroom and functional food, it is important to examine whether it could induce potentially harmful health effects similar to some previously studied edible fungi. The present study examined the effects of F. velutipes consumption on the plasma clinical chemistry, hematology, and organ histology of laboratory mice. Wild F. velutipes were dried, pulverized, mixed with a regular laboratory rodent diet, and fed to the animals at 0, 3, 6, or 9 g/kg body mass/day for five days ( n = 6/group). F. velutipes consumption caused increased activities of plasma creatine kinase and the MB-fraction of creatine kinase at 6-9 g/kg/d, indicating potentially deleterious effects on both skeletal and cardiac muscle. The plasma total and high-density lipoprotein cholesterol concentrations (at 9 g/kg/d) and white blood cell and lymphocyte counts (at 6-9 g/kg/d) decreased. Although the cholesterol-lowering properties of F. velutipes can be beneficial, the previously unexamined, potentially hazardous side effects of mushroom consumption (myo- and cardiotoxicity) should be thoroughly investigated before recommending this mushroom species as a health-promoting food item. Impact statement This work is important to the field of functional foods, as it provides novel information about the potential myo- and cardiotoxic properties of an edible mushroom, Flammulina velutipes. The results are useful and of importance because F. velutipes is an actively cultivated mushroom and marketed as a health-promoting food item. The findings contribute to the understanding of the complexity of the balance between the beneficial and potentially harmful effects of mushroom consumption.
- Published
- 2018
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46. Effects of Genetic Variants on Carboxylesterase 1 Gene Expression, and Clopidogrel Pharmacokinetics and Antiplatelet Effects.
- Author
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Neuvonen M, Tarkiainen EK, Tornio A, Hirvensalo P, Tapaninen T, Paile-Hyvärinen M, Itkonen MK, Holmberg MT, Kärjä V, Männistö VT, Neuvonen PJ, Pihlajamäki J, Backman JT, and Niemi M
- Subjects
- Biopsy, Carboxylic Ester Hydrolases blood, Carboxylic Ester Hydrolases chemistry, Carboxylic Ester Hydrolases metabolism, Clopidogrel, Cohort Studies, DNA Mutational Analysis, Dose-Response Relationship, Drug, Female, Finland, Gastric Bypass, Humans, Hydrolysis, Introns, Liver enzymology, Liver metabolism, Liver pathology, Male, Mutation, Missense, Platelet Aggregation Inhibitors administration & dosage, Platelet Aggregation Inhibitors blood, Platelet Aggregation Inhibitors pharmacology, RNA, Messenger metabolism, Reproducibility of Results, Ticlopidine administration & dosage, Ticlopidine blood, Ticlopidine pharmacokinetics, Ticlopidine pharmacology, Carboxylic Ester Hydrolases genetics, Gene Expression Regulation, Enzymologic, Pharmacogenomic Variants, Platelet Aggregation drug effects, Platelet Aggregation Inhibitors pharmacokinetics, Polymorphism, Single Nucleotide, Ticlopidine analogs & derivatives
- Abstract
Several single nucleotide variations (SNVs) affect carboxylesterase 1 (CES1) activity, but the effects of genetic variants on CES1 gene expression have not been systematically investigated. Therefore, our aim was to investigate effects of genetic variants on CES1 gene expression in two independent whole blood sample cohorts of 192 (discovery) and 88 (replication) healthy volunteers and in a liver sample cohort of 177 patients. Furthermore, we investigated possible effects of the found variants on clopidogrel pharmacokinetics (n = 106) and pharmacodynamics (n = 46) in healthy volunteers, who had ingested a single 300 mg or 600 mg dose of clopidogrel. Using massively parallel sequencing, we discovered two CES1 SNVs, rs12443580 and rs8192935, to be strongly and independently associated with a 39% (p = 4.0 × 10
-13 ) and 31% (p = 2.5 × 10-8 ) reduction in CES1 whole blood expression per copy of the minor allele. These findings were replicated in the replication cohort. However, these SNVs did not affect CES1 liver expression, or clopidogrel pharmacokinetics or pharmacodynamics. Conversely, the CES1 c.428G>A missense SNV (rs71647871) impaired the hydrolysis of clopidogrel, increased exposure to clopidogrel active metabolite and enhanced its antiplatelet effects. In conclusion, the rs12443580 and rs8192935 variants reduce CES1 expression in whole blood but not in the liver. These tissue-specific effects may result in substrate-dependent effects of the two SNVs on CES1-mediated drug metabolism., (© 2017 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)- Published
- 2018
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47. First in vivo detection and characterization of hyaluronan-coated extracellular vesicles in human synovial fluid.
- Author
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Mustonen AM, Nieminen P, Joukainen A, Jaroma A, Kääriäinen T, Kröger H, Lázaro-Ibáñez E, Siljander PR, Kärjä V, Härkönen K, Koistinen A, and Rilla K
- Subjects
- Adolescent, Adult, Aged, Female, Humans, Male, Middle Aged, Young Adult, Extracellular Vesicles chemistry, Hyaluronic Acid analysis, Synovial Fluid metabolism
- Abstract
Extracellular vesicles (EVs) function in intercellular signaling by transporting different membrane and cytosolic molecules, including hyaluronan (HA) and its synthesis machinery. As both EVs and HA are abundant in synovial fluid, we hypothesized that HA synthesized in synovial membrane would be carried on the surface of EVs. Synovial fluid (n = 15) and membrane samples (n = 5) were obtained from knee surgery patients. HA concentrations were analyzed in synovial fluid and HA and its synthesis machinery were examined with histochemical stainings in synovial membrane. To assess the size distribution of EVs in synovial fluid and to visualize HA on EVs, nanoparticle tracking analysis (NTA), confocal laser scanning microscopy (CLSM) and transmission electron microscopy (TEM) were utilized. The average HA concentration in synovial fluid was 2.0 ± 0.21 mg/ml without significant differences between the patients with trauma/diagnostic arthroscopy and primary or post-traumatic osteoarthritis. Positive stainings of HA synthases (HAS1-3), HA and its receptor CD44 in synovial cells indicated active HA secretion in synovial membrane. According to NTA, EVs were abundant in synovial fluid and their main populations were ≤300 nm in diameter after differential centrifugation. There were no significant differences in the EV counts between the patients with primary or post-traumatic osteoarthritis. TEM verified that HA-positive particles detected by CLSM were lipid membrane vesicles surrounded by a HA coat. Our results provide the first in vivo evidence that human synovial fluid contains HA-positive EVs, one source of which presumably is the long HAS-positive protrusions of synovial fibroblasts. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1960-1968, 2016., (© 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)
- Published
- 2016
- Full Text
- View/download PDF
48. The MBOAT7-TMC4 Variant rs641738 Increases Risk of Nonalcoholic Fatty Liver Disease in Individuals of European Descent.
- Author
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Mancina RM, Dongiovanni P, Petta S, Pingitore P, Meroni M, Rametta R, Borén J, Montalcini T, Pujia A, Wiklund O, Hindy G, Spagnuolo R, Motta BM, Pipitone RM, Craxì A, Fargion S, Nobili V, Käkelä P, Kärjä V, Männistö V, Pihlajamäki J, Reilly DF, Castro-Perez J, Kozlitina J, Valenti L, and Romeo S
- Subjects
- Acetyltransferases metabolism, Acyltransferases metabolism, Biopsy, Case-Control Studies, Cross-Sectional Studies, Europe epidemiology, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Liver metabolism, Liver pathology, Liver Cirrhosis diagnosis, Liver Cirrhosis ethnology, Liver Cirrhosis metabolism, Male, Membrane Proteins metabolism, Non-alcoholic Fatty Liver Disease diagnosis, Non-alcoholic Fatty Liver Disease ethnology, Non-alcoholic Fatty Liver Disease metabolism, Phenotype, Phosphatidylinositols metabolism, Proton Magnetic Resonance Spectroscopy, Risk Factors, Severity of Illness Index, Texas epidemiology, Triglycerides metabolism, Acetyltransferases genetics, Acyltransferases genetics, Liver Cirrhosis genetics, Membrane Proteins genetics, Non-alcoholic Fatty Liver Disease genetics, Polymorphism, Genetic, White People genetics
- Abstract
Background & Aims: Nonalcoholic fatty liver disease (NAFLD) is a leading cause of liver damage and is characterized by steatosis. Genetic factors increase risk for progressive NAFLD. A genome-wide association study showed that the rs641738 C>T variant in the locus that contains the membrane bound O-acyltransferase domain-containing 7 gene (MBOAT7, also called LPIAT1) and transmembrane channel-like 4 gene (TMC4) increased the risk for cirrhosis in alcohol abusers. We investigated whether the MBOAT7-TMC4 is a susceptibility locus for the development and progression of NAFLD., Methods: We genotyped rs641738 in DNA collected from 3854 participants from the Dallas Heart Study (a multi-ethnic population-based probability sample of Dallas County residents) and 1149 European individuals from the Liver Biopsy Cross-Sectional Cohort. Clinical and anthropometric data were collected, and biochemical and lipidomics were measured in plasma samples from participants. A total of 2736 participants from the Dallas Heart Study also underwent proton magnetic resonance spectroscopy to measure hepatic triglyceride content. In the Liver Biopsy Cross-Sectional Cohort, a total of 1149 individuals underwent liver biopsy to diagnose liver disease and disease severity., Results: The genotype rs641738 at the MBOAT7-TMC4 locus associated with increased hepatic fat content in the 2 cohorts, and with more severe liver damage and increased risk of fibrosis compared with subjects without the variant. MBOAT7, but not TMC4, was found to be highly expressed in the liver. The MBOAT7 rs641738 T allele was associated with lower protein expression in the liver and changes in plasma phosphatidylinositol species consistent with decreased MBOAT7 function., Conclusions: We provide evidence for an association between the MBOAT7 rs641738 variant and the development and severity of NAFLD in individuals of European descent. This association seems to be mediated by changes in the hepatic phosphatidylinositol acyl-chain remodeling., (Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
49. Fatty acid metabolism is altered in non-alcoholic steatohepatitis independent of obesity.
- Author
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Walle P, Takkunen M, Männistö V, Vaittinen M, Lankinen M, Kärjä V, Käkelä P, Ågren J, Tiainen M, Schwab U, Kuusisto J, Laakso M, and Pihlajamäki J
- Subjects
- Adult, Body Mass Index, Cholesterol Esters blood, Cholesterol Esters metabolism, Cohort Studies, Cross-Sectional Studies, Delta-5 Fatty Acid Desaturase, Fatty Acid Desaturases genetics, Fatty Acids blood, Fatty Liver complications, Fatty Liver epidemiology, Fatty Liver pathology, Female, Finland epidemiology, Gastric Bypass, Humans, Isoenzymes genetics, Isoenzymes metabolism, Liver metabolism, Liver pathology, Male, Metabolic Syndrome complications, Metabolic Syndrome epidemiology, Metabolic Syndrome metabolism, Metabolic Syndrome pathology, Middle Aged, Non-alcoholic Fatty Liver Disease complications, Non-alcoholic Fatty Liver Disease epidemiology, Non-alcoholic Fatty Liver Disease pathology, Obesity, Morbid surgery, Risk, Triglycerides blood, Triglycerides metabolism, Fatty Acid Desaturases metabolism, Fatty Acids metabolism, Fatty Liver metabolism, Gene Expression Regulation, Enzymologic, Liver enzymology, Non-alcoholic Fatty Liver Disease metabolism, Obesity, Morbid complications
- Abstract
Background: Non-alcoholic steatohepatitis (NASH) is associated with changes in fatty acid (FA) metabolism. However, specific changes in metabolism and hepatic mRNA expression related to NASH independent of simple steatosis, obesity and diet are unknown., Methods: Liver histology, serum and liver FA composition and estimated enzyme activities based on the FA ratios in cholesteryl esters and triglycerides were assessed in 92 obese participants of the Kuopio Obesity Surgery Study (KOBS) divided to those with normal liver, steatosis or NASH (30 men and 62 women, age 46.8±9.5years (mean±SD), BMI 44.2±6.2kg/m(2)). Plasma FA composition was also investigated in the Metabolic Syndrome in Men (METSIM) Study (n=769), in which serum alanine aminotransferase (ALT) was used as a marker of liver disease., Results: Obese individuals with NASH had higher activity of estimated activities of delta-6 desaturase (D6D, p<0.002) and stearoyl-CoA desaturase 1 (SCD1, p<0.002) and lower activity of delta-5 desaturase (D5D, p<0.002) when compared to individuals with normal liver. Estimated activities of D5D, D6D and SCD1 correlated positively between liver and serum indicating that serum estimates reflected liver metabolism. Accordingly, NASH was associated with higher hepatic mRNA expression of corresponding genes FADS1, FADS2 and SCD. Finally, differences in FA metabolism that associated with NASH in obese individuals were also associated with high ALT in the METSIM Study., Conclusions: We demonstrated alterations in FA metabolism and endogenous desaturase activities that associate with NASH, independent of obesity and diet. This suggests that changes in endogenous FA metabolism are related to NASH and that they may contribute to the progression of the disease., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
50. Increased Peroxiredoxin 6 Expression Predicts Biochemical Recurrence in Prostate Cancer Patients After Radical Prostatectomy.
- Author
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Raatikainen S, Aaaltomaa S, Kärjä V, and Soini Y
- Subjects
- Humans, Male, Middle Aged, Oxidative Stress, Prognosis, Prostatic Neoplasms surgery, Reactive Oxygen Species, Peroxiredoxin VI metabolism, Prostatectomy methods, Prostatic Neoplasms chemistry, Prostatic Neoplasms pathology
- Abstract
Background/aim: Elevated levels of oxidative stress biomarkers have been shown to associate with more aggressive behavior in malignancies. The aim of the present study was to determine the relationship between the expression of peroxiredoxins (Prx) and sulfiredoxin (Srx) in localized prostate cancer (PC) with clinicopathological parameters and outcome after radical prostatectomy (RP)., Materials and Methods: Samples of 240 RP patients were analyzed for Prx1, 2, 5 and 6 and Srx expression by immunohistochemistry and the results were correlated with clinicopathological data, biochemical recurrence-free survival (BFS), prostate cancer-specific survival (PCS) and overall survival (OS)., Results: Augmented Prx2 and Prx6 expression was associated with several conventional prognostic factors. Increased Prx2 and Prx6 expression predicted for shortened BFS (p=0.027 and p=0.020) and worse OS (p=0.045 and p=0.033). In the multivariate analysis, Prx6 expression was an independent predictor of BFS (p=0.030)., Conclusion: Elevated Prx6 expression associates with a worse prognosis after RP for clinically localized PC., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)
- Published
- 2015
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