| 1. |
- Bogdanova, Svetlana, et al.
(författare)
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Volgo-Uralia: The First U-Pb, Lu-Hf and Sm-Nd Isotopic Evidence of Preserved Paleoarchean Crust
- 2010
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Ingår i: American Journal of Science. - : American Journal of Science (AJS). - 0002-9599. ; 310:10, s. 1345-1383
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Tidskriftsartikel (refereegranskat)abstract
- The crustal segment Volgo-Uralia is the least known part of the East European Craton. Its crystalline crust is hidden beneath a thick Neoproterozoic to Phanerozoic cover but disclosed by thousands of drill holes. In conjunction with the recent "Tatseis" reflection seismic profile, we conducted the first isotopic study of the Bakaly granitoid block in eastern Volgo-Uralia, which represents a subsurface section of the layered upper-middle crust. The study included whole-rock Sm-Nd and ion-probe zircon U-Th-Pb (SIMS) and Lu-Hf (LA-ICPMS) analyses of granitoids from seven drill cores. The Bakaly block was also targeted because its rocks have never been subjected to granulite facies metamorphism, making it possible to date pristine, pre-metamorphic zircon. Our study showed that the four principal suites of granitoids in the Bakaly block are different in age, each corresponding to a particular stage of Archean crustal evolution between 3.3 and 2.6 Ga. The Tashliar monzonitic suite, belonging to an alkaline series yielded zircon ages of 3.3 and 3.2 Ga, which are the oldest ages yet found in Volgo-Urafia. The epsilon(Hf)(T) values of the dated zircon and the epsilon(Nd)(T) values of their host rocks indicate that a Paleo- to Eoarchean protolith with model T-DM ages up to 3.8 Ga had been involved in the formation of the Tashliar melts. Three Neoarchean rock suites, one comprising quartz dioritic and tonalitic gneisses (the Bak 1), another K-rich granodiorites, granites and migmatites (the Bak 2), and the third monzonitic granitoids (the Aktanysh suite) were formed sequentially between 2.72 and 2.60 Ga. The 2.72 Ga Bak 1 suite is chemically diverse. It includes granitoids of the TTG type related to slab/subduction melts as well as rocks formed by the re-melting of older crust with whole-rock Nd T-DM and Hf T-DM model ages of 3.4 to 3.2 Ga. The 2.69 to 2.65 Ga Bak 2 suite was probably associated with a major collisional event, which defined the stacked structure of the Archean crust in Volgo-Uralia and its seismic layering. Our data suggest that the Bak 2 melts originated partly from juvenile sources with epsilon(Hf)(T) zircon values up to +4.8, as well as mixed crustal and juvenile mantle materials. Some crustal contamination of the melts appears to have occurred as evidenced by incorporated xenocrystic zircon. The chemical compositions of Bak 2 granitoids from the different plutons, their zircon epsilon(Hf) values, and the Hf- and Nd T-DM ages all mirror a heterogeneous, collisional, crustal structure. During post-collisional extension at 2.6 Ga, the intrusion of Aktanysh monzonitic granitoids took place. These rocks also bear evidence of a long crustal pre-history with Nd and Hf T-DM model ages of 3.3 to 3.5 Ga. The Aktanysh rocks are coeval with the Tuymazy gabbro-norite-anorthosite intrusions, which are widely distributed along post-collisional shear zones in the Bakaly block. They could have provided the heat necessary to melt the crust at this stage. Altogether, the isotopic evidence suggests several episodes of crustal growth and recycling possibly reaching back to 3.6 and 3.8 Ga. Metamorphic zircon rims show that the Archean crust in the Bakaly block were subjected to several tectonothermal overprints in the Paleoproterozoic between 2.4 and 1.9 Ga ago.
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| 2. |
- Elsir, Tamador, et al.
(författare)
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A study of embryonic stem cell-related proteins in human astrocytomas : Identification of Nanog as a predictor of survival
- 2014
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 134:5, s. 1123-1131
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Tidskriftsartikel (refereegranskat)abstract
- Recent studies suggest that the regulatory networks controlling the functions of stem cells during development may be abnormally active in human cancers. An embryonic stem cell (ESC) gene signature was found to correlate with a more undifferentiated phenotype of several human cancer types including gliomas, and associated with poor prognosis in breast cancer. In the present study, we used tissue microarrays of 80 low-grade (WHO grade II) and 98 high-grade human gliomas (WHO grade III and IV) to investigate the presence of the ESC-related proteins Nanog, Klf4, Oct4, Sox2 and c-Myc by immunohistochemistry. While similar patterns of co-expressed proteins between low- and high-grade gliomas were present, we found up-regulated protein levels of Nanog, Klf4, Oct4 and Sox2 in high-grade gliomas. Survival analysis by Kaplan-Meier analysis revealed a significant shorter survival in the subgroups of low-grade astrocytomas (n=42) with high levels of Nanog protein (p=0.0067) and of Klf4 protein (p=0.0368), in high-grade astrocytomas (n=85) with high levels of Nanog (p=0.0042), Klf4 (p=0.0447), and c-Myc (p=0.0078) and in glioblastomas only (n=71) with high levels of Nanog (p=0.0422) and of c-Myc (p= 0.0256). In the multivariate model, Nanog was identified as an independent prognostic factor in the subgroups of low-grade astrocytomas (p=0.0039), high-grade astrocytomas (p=0.0124) and glioblastomas only (p=0.0544), together with established clinical variables in these tumors. These findings provide further evidence for the joint regulatory pathways of ESC-related proteins in gliomas and identify Nanog as one of the key players in determining clinical outcome of human astrocytomas.
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| 3. |
- Libard, Sylwia, et al.
(författare)
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Human cytomegalovirus tegument protein pp65 is detected in all intra- and extra-axial brain tumours independent of the tumour type or grade
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:9, s. e108861-
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Tidskriftsartikel (refereegranskat)abstract
- Human cytomegalovirus (HCMV) has been indicated being a significant oncomodulator. Recent reports have suggested that an antiviral treatment alters the outcome of a glioblastoma. We analysed the performance of commercial HCMV-antibodies applying the immunohistochemical (IHC) methods on brain sample obtained from a subject with a verified HCMV infection, on samples obtained from 14 control subjects, and on a tissue microarray block containing cores of various brain tumours. Based on these trials, we selected the best performing antibody and analysed a cohort of 417 extra- and intra-axial brain tumours such as gliomas, medulloblastomas, primary diffuse large B-cell lymphomas, and meningiomas. HCMV protein pp65 immunoreactivity was observed in all types of tumours analysed, and the IHC expression did not depend on the patient's age, gender, tumour type, or grade. The labelling pattern observed in the tumours differed from the labelling pattern observed in the tissue with an active HCMV infection. The HCMV protein was expressed in up to 90% of all the tumours investigated. Our results are in accordance with previous reports regarding the HCMV protein expression in glioblastomas and medulloblastomas. In addition, the HCMV protein expression was seen in primary brain lymphomas, low-grade gliomas, and in meningiomas. Our results indicate that the HCMV protein pp65 expression is common in intra- and extra-axial brain tumours. Thus, the assessment of the HCMV expression in tumours of various origins and pathologically altered tissue in conditions such as inflammation, infection, and even degeneration should certainly be facilitated.
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| 4. |
- Nord, Helena, et al.
(författare)
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Novel amplifications in pediatric medulloblastoma identified by genome-wide copy number profiling
- 2012
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Ingår i: Journal of Neuro-Oncology. - : Springer Science and Business Media LLC. - 0167-594X .- 1573-7373. ; 107:1, s. 37-49
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Tidskriftsartikel (refereegranskat)abstract
- Medulloblastoma (MB) is a WHO grade IV, invasive embryonal CNS tumor that mainly affects children. The aggressiveness and response to therapy can vary considerably between cases, and despite treatment, ~30% of patients die within 2 years from diagnosis. Furthermore, the majority of survivors suffer long-term side-effects due to severe management modalities. Several distinct morphological features have been associated with differences in biological behavior, but improved molecular-based criteria that better reflect the underlying tumor biology are in great demand. In this study, we profiled a series of 25 MB with a 32K BAC array covering 99% of the current assembly of the human genome for the identification of genetic copy number alterations possibly important in MB. Previously known aberrations as well as several novel focally amplified loci could be identified. As expected, the most frequently observed alteration was the combination of 17p loss and 17q gain, which was detected in both high- and standard-risk patients. We also defined minimal overlapping regions of aberrations, including 16 regions of gain and 18 regions of loss in various chromosomes. A few noteworthy narrow amplified loci were identified on autosomes 1 (38.89-41.97 and 84.89-90.76 Mb), 3 (27.64-28.20 and 35.80-43.50 Mb), and 8 (119.66-139.79 Mb), aberrations that were verified with an alternative platform (Illumina 610Q chips). Gene expression levels were also established for these samples using Affymetrix U133Plus2.0 arrays. Several interesting genes encompassed within the amplified regions and presenting with transcript upregulation were identified. These data contribute to the characterization of this malignant childhood brain tumor and confirm its genetic heterogeneity.
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| 5. |
- Popova, Svetlana N., et al.
(författare)
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Distribution of SLC10A4, a Synaptic Vesicle Protein in the Human Brain, and the Association of this Protein with Alzheimer's Disease-Related Neuronal Degeneration
- 2013
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 37:3, s. 603-610
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Tidskriftsartikel (refereegranskat)abstract
- Member 4 of the sodium/bile acid co-transporter family of proteins (SLC10A4) was discovered as a synaptic vesicle protein. The distribution of Slc10a4 protein in the brain has only so far been assessed in adult rats. Here, we assessed the regional distribution of SLC10A4 in aged human brain by immunohistochemistry. The protein was ubiquitously expressed, particularly in the cholinergic and monoaminergic neurons and in the lateral geniculate body. The protein expression was not influenced by the postmortem delay or fixation time. Synaptic alterations are reported to be seen in Alzheimer's disease (AD) and the suggested function of SLC10A4 as a vesicular transporter for cholinergic neurotransmitters proposes a link between this protein and AD. With increased severity of AD-related pathology, depletion of SLC10A4 expression was noted in the transentorhinal cortex. Intriguingly, in the most severely affected cases (Braak V), two patterns were noted, i. e., those with severe depletion of SLC10A4 and those with numerous neurons displaying SLC10A4. In conclusion, assessment of the expression of SLC10A4 by means of immunohistochemistry is feasible. The observed depletion of SLC10A4 with increase in the severity of AD-related neuronal degeneration is interesting and the observation that some subjects in Braak V displayed none and some displayed numerous SLC10A4 immunoreactive neurons is intriguing. Assessment of the SLC10A4 protein in neurodegenerative diseases or diseases affecting lateral geniculate body should be carried out to investigate whether alterations in the expression of SLC10A4 in synaptic vesicles might be used as a marker of transmitter deficits (cholinergic, monoaminorgic) or other synaptic pathology.
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| 6. |
- Popova, Svetlana N, et al.
(författare)
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Divergent clinical and neuropathological phenotype in a Gerstmann-Sträussler-Scheinker P102L family
- 2012
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Ingår i: Acta Neurologica Scandinavica. - : Hindawi Limited. - 0001-6314 .- 1600-0404. ; 126:5, s. 315-323
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES:Gerstmann-Sträussler-Scheinker syndrome belongs to the genetic prion diseases being associated with mutations in the prion protein gene (PRNP). The most common is the point mutation at codon 102, leading to the substitution of proline to leucine (P102L). Previous reports have indicated a phenotypic heterogeneity among individuals with this mutation. Here, we describe the clinical and pathological phenotype in members of the first Finnish kindred with the P102L mutation in the PNRP gene.MATERIALS AND METHODS:Genetic and clinical information was available in five members of a family, while a systematic histologic and immunohistochemical assessment of the post-mortem brain was carried out in three.RESULTS:Clinical presentation, disease duration and the clinical phenotype (ataxia vs dementia) varied between patients. There was a significant correlation between clinical symptoms and the neuroanatomical distribution of prion protein-immunoreactive aggregates, i.e. subtentorial predominance in ataxia vs cortical predominance in dementia. A significant concomitant Alzheimer is disease-related pathology was observed in the brain of one patient with dementia as onset symptom.CONCLUSIONS:This is the first Scandinavian family carrying the P102L mutation in the PRNP gene. Gerstmann-Sträussler-Scheinker syndrome should be considered in the differential diagnosis when handling with patients with ataxia and/or dementia of unclear aetiology.
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| 7. |
- Popova, Svetlana N, et al.
(författare)
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Subtyping of gliomas of various WHO grades by the application of immunohistochemistry
- 2014
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Ingår i: Histopathology. - : Wiley. - 0309-0167 .- 1365-2559. ; 64:3, s. 365-379
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Tidskriftsartikel (refereegranskat)abstract
- AimsIn 2010, four subtypes (classical, proneural, mesenchymal, and neural) of glioblastoma multiforme (GBM) were defined by molecular genetic analyses. The objective of this study was to assess whether gliomas, independently of the type and grade, could be subdivided into protein-based subtypes.Methods and resultsA tissue microarray (TMA) approach was applied to incorporate tissue samples of low-grade and high-grade gliomas into five TMAs. High expression levels of epidermal growth factor receptor (EGFR), CD44, c-MER proto-oncogene tyrosine kinase (MERTK), platelet-derived growth factor receptor α, p53, oligodendrocyte transcription factor 2 (OLIG2) and isocitrate dehydrogenase 1 with the R132H mutation were assessed using immunohistochemistry (IHC). Glioma could be subdivided into four subtypes by IHC. The majority of the low-grade gliomas were of the proneural subtype, i.e. high p53 expression (63% of grade II). The classical subtype, with high EGFR and low p53 expression, was most common in GBMs (39%), followed by the proneural (29%) and mesenchymal (with high CD44 and MERTK expression) (29%) subtypes, a frequency that is in line with previously published data based on molecular genetics.ConclusionsAssessment of the expression of the five proteins EGFR, CD44, MERTK, p53 and OLIG2 is sufficient for subtyping gliomas, and can be recommended for implementation in clinical practice for both low-grade and high-grade gliomas.
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| 8. |
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| 9. |
- Sooman, Linda, et al.
(författare)
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Vandetanib combined with a p38 MAPK inhibitor synergistically reduces glioblastoma cell survival
- 2013
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Ingår i: Medical Oncology. - : Springer Science and Business Media LLC. - 1357-0560 .- 1559-131X. ; 30:3, s. 638-
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Tidskriftsartikel (refereegranskat)abstract
- The survival for patients with high-grade glioma is poor, and only a limited number of patients respond to the therapy. The aim of this study was to analyze the significance of using p38 MAPK phosphorylation as a prognostic marker in high-grade glioma patients and as a therapeutic target in combination chemotherapy with vandetanib. p38 MAPK phosphorylation was analyzed with immunohistochemistry in 90 high-grade glioma patients. Correlation between p38 MAPK phosphorylation and overall survival was analyzed with Mann-Whitney U test analysis. The effects on survival of glioblastoma cells of combining vandetanib with the p38 MAPK inhibitor SB 203580 were analyzed in vitro with the median-effect method with the fluorometric microculture cytotoxicity assay. Two patients had phosphorylated p38 MAPK in both the cytoplasm and nucleus, and these two presented with worse survival than patients with no detectable p38 MAPK phosphorylation or phosphorylated p38 MAPK only in the nucleus. This was true for both high-grade glioma patients (WHO grade III and IV, n = 90, difference in median survival: 6.1 months, 95 % CI [0.20, 23], p = 0.039) and for the subgroup with glioblastoma patients (WHO grade IV, n = 70, difference in median survival: 6.1 months, 95 % CI [0.066, 23], p = 0.043). The combination of vandetanib and the p38 MAPK inhibitor SB 203580 had synergistic effects on cell survival for glioblastoma-derived cells in vitro. In conclusion, p38 MAPK phosphorylation may be a prognostic marker for high-grade glioma patients, and vandetanib combined with a p38 MAPK inhibitor may be useful combination chemotherapy for glioma patients.
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