umu.sePublications
Change search
Link to record
Permanent link

Direct link
BETA
Nilsson, Torbjörn K.
Alternative names
Publications (10 of 75) Show all publications
Johansson, K., Jansson, J.-H., Johansson, L., Wiklund, P.-G., Nilsson, T. K. & Lind, M. (2018). D-Dimer is associated with first-ever intracerebral hemorrhage: a nested case-control study. Stroke, 49(9), 2034-2039
Open this publication in new window or tab >>D-Dimer is associated with first-ever intracerebral hemorrhage: a nested case-control study
Show others...
2018 (English)In: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 49, no 9, p. 2034-2039Article in journal (Refereed) Published
Abstract [en]

Background and Purpose - Hypertension is the most important risk factor for intracerebral hemorrhage (ICH), but further characterization is needed for groups at high risk of ICH. One way to predict the risk of developing a disease is with plasma biomarkers. This study aimed to investigate the association between the biomarker, D-dimer, and ICH risk.

Methods - This population-based, nested case-control study was conducted using data from 2 population-based surveys; the Vasterbotten Intervention Programme and MONICA Northern Sweden (Monitoring Trends and Determinants in Cardiovascular Disease). All participants underwent a health examination and blood sampling at baseline before the event. Cases (n=141) were diagnosed with a first-ever ICH between 1985 and March 2007. One or 2 controls (n=255) were matched to each case.

Results - The median age was 60 years; 39% of participants were women; and the median time from blood sampling to ICH was 5.2 years. When D-dimer was evaluated as a continuous variable, it was significantly associated with ICH. After multivariable adjustment (for hypertension, body mass index, cholesterol levels, diabetes mellitus, and smoking), the odds ratio was 1.36 per SD of D-dimcr (95% CI, 1.05-1.77). When participants were stratified in 3 groups according to time from blood sampling at health examination to ICH, we found that the association between D-dimer levels and ICH was most pronounced in individuals with the shortest time from blood sampling to ICH event (<3.5 years; odds ratio, 1.78; 95% CI, 1.05-3.05).

Conclusions - High plasma concentrations of D-dimer were associated with increased risk of a future ICH, after adjusting for cardiovascular risk factors. This association was predominantly driven by the cases with the shortest time from blood sampling to ICH event.

Place, publisher, year, edition, pages
Lippincott Williams & Wilkins, 2018
Keywords
biomarkers, case-control studies, cerebral hemorrhage, fibrin fragment, fibrinolysis
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-153829 (URN)10.1161/STROKEAHA.118.021751 (DOI)000442858100014 ()30354971 (PubMedID)
Funder
Västerbotten County CouncilNorrbotten County Council
Available from: 2018-12-11 Created: 2018-12-11 Last updated: 2019-01-07Bibliographically approved
Kim, J., Lei, Y., Guo, J., Kim, S.-E., Wlodarczyk, B. J., Cabrera, R. M., . . . Finnell, R. H. (2018). Formate rescues neural tube defects caused by mutations in Slc25a32. Proceedings of the National Academy of Sciences of the United States of America, 115(18), 4690-4695
Open this publication in new window or tab >>Formate rescues neural tube defects caused by mutations in Slc25a32
Show others...
2018 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 18, p. 4690-4695Article in journal (Refereed) Published
Abstract [en]

Periconceptional folic acid (FA) supplementation significantly reduces the prevalence of neural tube defects (NTDs). Unfortunately, some NTDs are FA resistant, and as such, NTDs remain a global public health concern. Previous studies have identified SLC25A32 as a mitochondrial folate transporter (MFT), which is capable of transferring tetrahydrofolate (THF) from cellular cytoplasm to the mitochondria in vitro. Herein, we show that gene trap inactivation of Slc25a32 (Mft) in mice induces NTDs that are folate (5-methyltetrahydrofolate, 5-mTHF) resistant yet are preventable by formate supplementation. Slc25a32gt/gt embryos die in utero with 100% penetrant cranial NTDs. 5-mTHF supplementation failed to promote normal neural tube closure (NTC) in mutant embryos, while formate supplementation enabled the majority (78%) of knockout embryos to complete NTC. A parallel genetic study in human subjects with NTDs identified biallelic loss of function SLC25A32 variants in a cranial NTD case. These data demonstrate that the loss of functional Slc25a32 results in cranial NTDs in mice and has also been observed in a human NTD patient.

Keywords
neural tube defects, Slc25a32, folate, formate
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-147816 (URN)10.1073/pnas.1800138115 (DOI)000431119600057 ()29666258 (PubMedID)
Available from: 2018-05-22 Created: 2018-05-22 Last updated: 2018-06-09Bibliographically approved
Isaksson, H. S., Farkas, S. A., Mueller, P., Gustafsson, D. & Nilsson, T. K. (2018). Whole genome microarray expression analysis in blood identifies pathways linked to signs and symptoms of a patient with hypercalprotectinaemia and hyperzincaemia. Clinical and Experimental Immunology, 191(2), 240-251
Open this publication in new window or tab >>Whole genome microarray expression analysis in blood identifies pathways linked to signs and symptoms of a patient with hypercalprotectinaemia and hyperzincaemia
Show others...
2018 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 191, no 2, p. 240-251Article in journal (Refereed) Published
Abstract [en]

A child, 2 years with the hypercalprotectinaemia with hyperzincaemia' clinical syndrome, presented with atypical symptoms and signs, notably persistent fever of approximately 38 degrees C, thrombocythaemia of >700x10(9)/l and a predominance of persistent intestinal symptoms. In an effort to find a cure by identifying the dysregulated pathways we analysed whole-genome mRNA expression by the Affymetrix HG U133 Plus 20 array in blood on three occasions 3-5 months apart. Major up-regulation was demonstrated for the Janus kinase/signal transducer and activators of transcription (JAK/STAT) pathway including, in particular, CD177, S100A8, S100A9 and S100A12, accounting for the thrombocytosis; a large number of interleukins, their receptors and activators, accounting for the febrile apathic state; and the high mobility group box 1 (HMBG1) gene, possibly accounting for part of the intestinal symptoms. These results show that gene expression array technology may assist the clinician in the diagnostic work-up of individual patients with suspected syndromal states of unknown origin, and the expression data can guide the selection of optimal treatment directed at the identified target pathways.

Keywords
expression array, fever, hypercalprotectinaemia, hyperzincaemia, thrombocytaemia
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-144081 (URN)10.1111/cei.13064 (DOI)000419624200012 ()28984903 (PubMedID)
Available from: 2018-01-31 Created: 2018-01-31 Last updated: 2018-06-09Bibliographically approved
Geoghegan, F., Buckland, R. J., Rogers, E. T., Khalifa, K., O'Connor, E. B., Rooney, M. F., . . . Porter, R. K. (2017). Bioenergetics of acquired cisplatin resistant H1299 non-small cell lung cancer and P31 mesothelioma cells. OncoTarget, 8(55), 94711-94725
Open this publication in new window or tab >>Bioenergetics of acquired cisplatin resistant H1299 non-small cell lung cancer and P31 mesothelioma cells
Show others...
2017 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 55, p. 94711-94725Article in journal (Refereed) Published
Abstract [en]

Acquired cisplatin resistance is a common feature of tumours following cancer treatment with cisplatin and also of non-small cell lung cancer (H1299) and mesothelioma (P31) cell lines exposed to cisplatin. To elucidate the cellular basis of acquired cisplatin resistance, a comprehensive bioenergetic analysis was undertaken. We demonstrate that cellular oxygen consumption was significantly decreased in cisplatin resistant cells and that the reduction was primarily due to reduced mitochondrial activity as a result of reduced mitochondrial abundance. The differential mitochondrial abundance was supported by data showing reduced sirtuin 1 (SIRT1), peroxisome-proliferator activator receptor-gamma co-activator 1-alpha (PGC1 alpha), sirtuin 3 (SIRT3) and mitochondrial transcription factor A (TFAM) protein expression in resistant cells. Consistent with these data we observed increased reactive oxygen species (ROS) production and increased hypoxia inducible factor 1-alpha (HIF1 alpha) stabilization in cisplatin resistant cells when compared to cisplatin sensitive controls. We also observed an increase in AMP kinase subunit alpha 2 (AMPK alpha 2) transcripts and protein expression in resistant H1299 cells. mRNA expression was also reduced for cisplatin resistant H1299 cells in these genes, however the pattern was not consistent in resistant P31 cells. There was very little change in DNA methylation of these genes, suggesting that the cells are not stably reprogrammed epigenetically. Taken together, our data demonstrate reduced oxidative metabolism, reduced mitochondrial abundance, potential for increased glycolytic flux and increased ROS production in acquired cisplatin resistant cells. This suggests that the metabolic changes are a result of reduced SIRT3 expression and increased HIF-1 alpha stabilization.

Place, publisher, year, edition, pages
IMPACT JOURNALS LLC, 2017
Keywords
cisplatin resistance, bioenergetics, SIRT3, non-small cell lung cancer, mesothelioma
National Category
Cell Biology Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-142242 (URN)10.18632/oncotarget.21885 (DOI)000414608400121 ()
Available from: 2017-12-11 Created: 2017-12-11 Last updated: 2018-06-09Bibliographically approved
Keskin, I., Birve, A., Berdynski, M., Hjertkvist, K., Rofougaran, R., Nilsson, T. K., . . . Andersen, P. M. (2017). Comprehensive analysis to explain reduced or increased SOD1 enzymatic activity in ALS patients and their relatives. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 18(5-6), 457-463
Open this publication in new window or tab >>Comprehensive analysis to explain reduced or increased SOD1 enzymatic activity in ALS patients and their relatives
Show others...
2017 (English)In: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, ISSN 2167-8421, E-ISSN 2167-9223, Vol. 18, no 5-6, p. 457-463Article in journal (Refereed) Published
Abstract [en]

Objective: To characterise stabilities in erythrocytes of mutant SOD1 proteins, compare SOD1 enzymatic activities between patients with different genetic causes of ALS and search for underlying causes of deviant SOD1 activities in individuals lacking SOD1 mutations.Methods: Blood samples from 4072 individuals, ALS patients with or without a SOD1 mutation, family members and controls were studied. Erythrocyte SOD1 enzymatic activities normalised to haemoglobin content were determined, and effects of haemoglobin disorders on dismutation assessed. Coding SOD1 sequences were analysed by Sanger sequencing, exon copy number variations by fragment length analysis and by TaqMan Assay.Results: Of the 44 SOD1 mutations found, 75% caused severe destabilisation of the mutant protein but in 25% it was physically stable. Mutations producing structural changes caused halved erythrocyte SOD1 activities. There were no differences in SOD1 activities between patients without a SOD1 mutation and control individuals or carriers of TBK1 mutations and C9orf72(HRE). In the low and high SOD1 activity groups no deviations were found in exon copy numbers and intron gross structures. Thalassemias and iron deficiency were associated with increased SOD1 activity/haemoglobin ratios.Conclusion: Adjunct erythrocyte SOD1 activity analysis reliably signals destabilising SOD1 mutations including intronic mutations that are missed by exon sequencing.

Place, publisher, year, edition, pages
TAYLOR & FRANCIS LTD, 2017
Keywords
Amyotrophic lateral sclerosis, superoxide dismutase, mutation, enzymatic activity
National Category
Clinical Medicine
Identifiers
urn:nbn:se:umu:diva-138241 (URN)10.1080/21678421.2017.1301481 (DOI)000405584600019 ()
Available from: 2017-08-16 Created: 2017-08-16 Last updated: 2018-06-09Bibliographically approved
Farkas, S. A., Sorbe, B. G. & Nilsson, T. K. (2017). Epigenetic changes as prognostic predictors in endometrial carcinomas. Epigenetics, 12(1), 19-26
Open this publication in new window or tab >>Epigenetic changes as prognostic predictors in endometrial carcinomas
2017 (English)In: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 12, no 1, p. 19-26Article in journal (Refereed) Published
Abstract [en]

Endometrial carcinoma is one of the most frequent gynecological malignancies of the female. The diagnostic and prognostic markers for the high-risk subgroups with unfavorable prognosis are under intense debate worldwide, and, therefore, the aim of this study was to identify new potential DNA methylation markers for the high-risk groups. We used the Illumina Infinium HumanMethylation450 BeadChip to analyze the DNA methylation pattern and investigated its association with clinicopathological features important for defining the high-risk (FIGO-grade 3) and low-risk (FIGO-grade 1) groups of patients with endometrial cancer (n = 31 and n = 39, respectively). We identified specific DNA methylation signature in high-risk endometrial tumors, and potential molecular biomarker genes (TBX2, CHST11, and NID2) associated with unfavorable clinical predictive and prognostic factors.

Keywords
DNA methylation, endometrial cancer, FIGO grade, prognosis
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-133259 (URN)10.1080/15592294.2016.1252891 (DOI)000394449200003 ()27874289 (PubMedID)
Available from: 2017-04-12 Created: 2017-04-12 Last updated: 2018-06-09Bibliographically approved
Hahn-Strömberg, V., Askari, S., Ahmad, A., Befekadu, R. & Nilsson, T. K. (2017). Expression of claudin 1, claudin 4, and claudin 7 in colorectal cancer and its relation with CLDN DNA methylation patterns. Tumor Biology, 39(4), Article ID 697569.
Open this publication in new window or tab >>Expression of claudin 1, claudin 4, and claudin 7 in colorectal cancer and its relation with CLDN DNA methylation patterns
Show others...
2017 (English)In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 39, no 4, article id 697569Article in journal (Refereed) Published
Abstract [en]

Altered claudin expression has been described in colon, prostatic, ovarian, and breast carcinoma. However, the role of epigenetic modifications in these genes and their role in colorectal cancer is unknown. We aimed our study to investigate whether claudin protein expression and methylation of CLDN can influence the tumorigenesis of colorectal cancer. A total of 31 patients diagnosed with colorectal carcinoma was used in this study. Immunohistochemical staining was used to study protein expression in both tumor and the adjacent nonneoplastic mucosa of claudin 1, 4, and 7. To detect the DNA methylation pattern of CLDN1, 4, and 7, genomic DNA was extracted from both the tumor and the adjacent nonneoplastic mucosa. Methylation analysis was carried out using bisulfite pyrosequencing. Cell membrane staining intensity of all claudins was found significantly lower in colorectal cancer tissues when compared to paired normal mucosa (p = 0.001). For claudin 4, the percentage of cells staining positively was also significantly reduced (p = 0.04). In normal mucosa, cytoplasm showed no staining for claudins in any patient, whereas in paired colorectal cancer tissues, significant cytoplasmic staining appeared both for claudin 1 (p = 0.04) and claudin 4 (p = 0.01). Tumor samples were significantly hypomethylated in CLDN1 (p < 0.05). In conclusion, our results show that CLDN1 is significantly hypomethylated in tumor samples and that the membrane staining intensity for claudin 1, 4, and 7 is significantly lower in colorectal cancer tissues than in adjacent nonneoplastic tissue. Colorectal cancer cells showed dystopic cytoplasmic location of claudins.

Place, publisher, year, edition, pages
Sage Publications, 2017
Keywords
Tight junction, methylation, colon cancer, claudin
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-136210 (URN)10.1177/1010428317697569 (DOI)000400268800047 ()
Available from: 2017-06-29 Created: 2017-06-29 Last updated: 2018-06-09Bibliographically approved
Johansson, K., Jansson, J.-H., Johansson, L., Bylesjö, I., Nilsson, T. K., Eliasson, M., . . . Lind, M. (2017). Factor XII as a Risk Marker for Hemorrhagic Stroke: A Prospective Cohort Study. Cerebrovascular diseases extra, 7(1), 84-94
Open this publication in new window or tab >>Factor XII as a Risk Marker for Hemorrhagic Stroke: A Prospective Cohort Study
Show others...
2017 (English)In: Cerebrovascular diseases extra, ISSN 1664-5456, Vol. 7, no 1, p. 84-94Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Coagulation factor XII (FXII) is involved in pathological thrombus formation and is a suggested target of anticoagulants. It is unclear whether FXII levels are correlated with cardiovascular risk factors and whether they are associated with myocardial infarction or ischemic or hemorrhagic stroke. The aim of this study was to investigate the correlation between FXII and cardiovascular risk factors in the general population. We also aimed to study the associations between FXII levels and future myocardial infarction and ischemic and hemorrhagic stroke.

METHODS: This prospective cohort study measured FXII levels in 1,852 randomly selected participants in a health survey performed in northern Sweden in 1994. Participants were followed until myocardial infarction, stroke, death, or until December 31, 2011.

RESULTS: During the median follow-up of 17.9 years, 165 individuals were diagnosed with myocardial infarction, 108 with ischemic stroke, and 30 with hemorrhagic stroke. There were weak correlations between FXII and body mass index, cholesterol, and hypertension. There was no association between FXII and myocardial infarction or ischemic stroke, neither in univariable Cox regression analysis nor after adjustment for age, sex, smoking, body mass index, cholesterol, hypertension, and diabetes. In univariable Cox regression analysis, the hazard ratio for the association between FXII levels and hemorrhagic stroke was 1.42 per SD (95% confidence interval: 0.99-2.05). In the multivariable model, higher levels of FXII were associated with increased risk of hemorrhagic stroke (hazard ratio 1.51 per SD; 95% confidence interval: 1.03-2.21).

CONCLUSION: We found an independent association between FXII levels and the risk of hemorrhagic stroke, but not between FXII levels and ischemic stroke or myocardial infarction.

Place, publisher, year, edition, pages
S. Karger, 2017
Keywords
Coagulation, Biomarkers, Intracranial hemorrhage, Cohort study, Cardiovascular disease
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:umu:diva-136401 (URN)10.1159/000468994 (DOI)000405098500004 ()28433996 (PubMedID)
Available from: 2017-06-16 Created: 2017-06-16 Last updated: 2018-06-09Bibliographically approved
Valencia, L., Randazzo, A., Engfeldt, P., Olsson, L. A., Chavez, A., Buckland, R. J., . . . Almon, R. (2017). Identification of novel genetic variants in the mutational hotspot region 14kb upstream of the LCT gene in a Mexican population. Scandinavian Journal of Clinical and Laboratory Investigation, 77(5), 311-314
Open this publication in new window or tab >>Identification of novel genetic variants in the mutational hotspot region 14kb upstream of the LCT gene in a Mexican population
Show others...
2017 (English)In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 77, no 5, p. 311-314Article in journal (Refereed) Published
Abstract [en]

Several polymorphic loci linked to lactase persistence (LP) have been described, all located in a small mutational hotspot region far upstream (approximate to 14kb) of the lactase (LCT) gene. One is typically found in Europeans, LCT -13910C>T, several others are found in East Africans and Arabs, e.g. LCT -13907C>G and LCT -13915T>G. The possibility of similar loci, specific to populations in South and Central America, has not received much attention so far. To identify possible novel polymorphisms in the mutational hotspot region, we sampled 158 subjects from a rural area in South-Central Mexico. DNA was isolated from serum, and Sanger sequencing of a 501bp region spanning the LCT -13910C>T hotspot was successfully performed in 150 samples. The frequency of the European-type LCT -13910T-allele was q=0.202, and 35% of the population was thus lactase-persistent (CT or TT). Sixteen novel genetic variants were found amongst 11 of the subjects, all were heterozygotes: seven of the subjects were also carriers of at least one LCT -13910T-allele. Thus, the mutational hotspot region is also a hotspot in the rural Mexican population: 11/150 subjects carried a total of 16 previously unknown private mutations but no novel polymorphism was found. The relationship between such novel genetic variants in Mexicans and lactase persistence is worthy of more investigation.

Place, publisher, year, edition, pages
TAYLOR & FRANCIS LTD, 2017
Keywords
Adult hypolactasia, DNA resequencing, lactose intolerance, lactase persistence, Latin America, SNP
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-138619 (URN)10.1080/00365513.2017.1318445 (DOI)000406760700001 ()
Available from: 2017-09-06 Created: 2017-09-06 Last updated: 2018-06-09Bibliographically approved
Makdoumi, K., Nilsson, T. K. & Crafoord, S. (2017). Levels of beta-trace protein in optic disc pit with macular detachment. Acta Ophthalmologica, 95(8), 815-819
Open this publication in new window or tab >>Levels of beta-trace protein in optic disc pit with macular detachment
2017 (English)In: Acta Ophthalmologica, ISSN 1755-375X, E-ISSN 1755-3768, Vol. 95, no 8, p. 815-819Article in journal (Refereed) Published
Abstract [en]

Background: To report beta-trace protein (bTP) levels in the subretinal fluid (SRF) of four patients with a macular detachment associated with optic disc pit (ODP).

Methods: Four patients with a serous retinal detachment involving the macula was operated by pars plana vitrectomy (PPV) with C2F6 gas tamponade and peeling of internal limiting membrane (ILM). Patients with a follow-up period exceeding one year postoperatively were included in the study. The SRF was drained using a fine cannula without laser photocoagulation, and the samples were analysed using particle-enhancing nephelometry. The levels of bTP were compared to 20 routine cerebrospinal fluid (CSF) samples.

Results: In four of the five samples from SRF had relatively low bTP levels, with a mean concentration of 6.6 mg/l (range 2.0 to 23.1 mg/l) compared to 16.0 mg/ l (range 6.3-26.8 mg/l) in CSF. The only SRF sample within the range corresponding to normal CSF was the first sample from patient 4, and the analysis of the renewed aspirate during the second operation was 2.8 mg/l. Postoperatively, the regression of SRF was slow, but regression of SRF in the foveal region took place in all cases; however, visual acuity (VA) was improved in only half of the patients.

Conclusion: The results from the analysed SRF regarding bTP concentration in these patients indicate that the SRF in ODP is not identical to CSF, as the concentrations of bTP differ.

Place, publisher, year, edition, pages
John Wiley & Sons, 2017
Keywords
beta trace, beta-trace protein, optic disc pit
National Category
Ophthalmology
Identifiers
urn:nbn:se:umu:diva-143571 (URN)10.1111/aos.13527 (DOI)000417645900036 ()28926186 (PubMedID)
Available from: 2018-01-04 Created: 2018-01-04 Last updated: 2018-06-09Bibliographically approved
Organisations

Search in DiVA

Show all publications