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Popova, Svetlana
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Publications (10 of 13) Show all publications
Lundström, Y., Lundström, P., Popova, S., Lindblom, R. P. .. & Alafuzoff, I. (2019). Detection of Changes in Immunohistochemical Stains Caused by Postmortem Delay and Fixation Time. Applied immunohistochemistry & molecular morphology (Print), 27(3), 238-245
Open this publication in new window or tab >>Detection of Changes in Immunohistochemical Stains Caused by Postmortem Delay and Fixation Time
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2019 (English)In: Applied immunohistochemistry & molecular morphology (Print), ISSN 1541-2016, E-ISSN 1533-4058, Vol. 27, no 3, p. 238-245Article in journal (Refereed) Published
Abstract [en]

In this study, we have systematically assessed the influence of postmortem delay (PMD) and fixation time (FT) on the immunohistochemical (IHC) staining outcome. The IHC method is frequently applied on surgical and postmortem samples in diagnostics and research. To replicate the routine situation, brain tissues from pigs were exposed to either storage in a refrigerator (+8°C), that is, PMD (1 to 168 h), or fixed in 10% buffered formalin, that is, FT (18 to 94 d). Subsequently, the tissue was routinely processed into paraffin blocks to enable construction of tissue microarrays (TMA). Sections cut from the TMA blocks were stained applying 13 different antibodies directed against neuronal and glial antigens. Immunoreactivity applying 5 antibodies was influenced by prolonged PMD and applying 2 antibodies by prolonged FT. None of the staining outcomes related to the PMD or FT were predictable. Loss of TMA cores during processing was primarily influenced by pretreatment and by tissue characteristics (gray/white matter). The test model described here confirmed that these 2 variables, PMD and FT, indeed influence the IHC outcome. The PMD and FT are particularly of importance while assessing tissue samples obtained at autopsy. The result above is also of importance while comparing the IHC outcomes seen in the postmortem setting (various PMD/FT) with surgical samples or with IHC outcome seen in experimental animal setting (controlled PMD/FT). Thus, we suggest that the test model described here is considered when assessing the reliability of the IHC outcome when analyzing tissues with various characteristics.

Keywords
immunohistochemistry, tissue microarray, fixation time, postmortem delay
National Category
Other Basic Medicine Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-369701 (URN)10.1097/PAI.0000000000000658 (DOI)000462177700013 ()29912765 (PubMedID)
Funder
Hans-Gabriel och Alice Trolle-Wachtmeisters stiftelse för medicinsk forskning
Available from: 2018-12-16 Created: 2018-12-16 Last updated: 2019-04-24Bibliographically approved
Lindblom, R. P., Tovedal, T., Norlin, B., Hillered, L., Popova, S., Alafuzoff, I. & Thelin, S. (2017). Mechanical reperfusion with leucocyte-filtered blood does not prevent injury following global cerebral ischaemia. European Journal of Cardio-Thoracic Surgery, 51(4), 773-781
Open this publication in new window or tab >>Mechanical reperfusion with leucocyte-filtered blood does not prevent injury following global cerebral ischaemia
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2017 (English)In: European Journal of Cardio-Thoracic Surgery, ISSN 1010-7940, E-ISSN 1873-734X, Vol. 51, no 4, p. 773-781Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES: Prolonged global cerebral ischaemia leads to irreversible injury, often with lethal outcome. Brain injuries are partly caused by the uncontrolled reperfusion that occurs once the circulation is re-established. Recent animal experiments suggest that controlled reperfusion following lengthy ischaemia might prevent severe brain injury. This study aimed at further exploring cerebral alterations and outcome following prolonged global cerebral ischaemia and mechanically manipulated reperfusion.

METHODS: Three groups of pigs were included; one sham operated (n = 3) and two that underwent 30-min global cerebral ischaemia. All vessels that supply the brain were isolated intrathoracically, after which they were occluded for 30 min in the ischaemic groups. In one of the ischaemic groups uncontrolled reperfusion was applied (URep, n = 6), i.e. normal circulation was restored 30 min after arrested cerebral circulation. The second ischaemic group received mechanical reperfusion (MRep, n = 6) with leucocyte-filtered blood at constant flow and pressure for 20 min using extracorporeal circulation following the 30-min ischaemia, after which normal blood flow resumed. All animals were monitored for 3 h after start of uncontrolled reperfusion. Haemodynamic parameters, arterial and sagittal sinus blood gases, cerebral oxygen extraction rates and intraparenchymal biomarkers using microdialysis were measured. Brain histology was performed post-mortem.

RESULTS: Global brain ischaemia led to the same extent of severe morphological changes at the level of light microscopy in the two ischaemic experimental groups, regardless of reperfusion protocol. Furthermore, no significant differences were found between the URep and MRep groups regarding cerebral blood gases or microdialysis biomarkers.

CONCLUSIONS: Mechanical reperfusion following the current protocol does not modify brain alterations caused by 30 min of arrested cerebral circulation.

National Category
Basic Medicine
Identifiers
urn:nbn:se:uu:diva-315862 (URN)10.1093/ejcts/ezw367 (DOI)000398558800026 ()28007877 (PubMedID)
Available from: 2017-02-21 Created: 2017-02-21 Last updated: 2018-01-13Bibliographically approved
Leino, M., Popova, S. & Alafuzoff, I. (2017). Transactive DNA Binding Protein 43 Rather Than Other Misfolded Proteins in the Brain is Associated with Islet Amyloid Polypeptide in Pancreas in Aged Subjects with Diabetes Mellitus. Journal of Alzheimer's Disease, 59(1), 43-56
Open this publication in new window or tab >>Transactive DNA Binding Protein 43 Rather Than Other Misfolded Proteins in the Brain is Associated with Islet Amyloid Polypeptide in Pancreas in Aged Subjects with Diabetes Mellitus
2017 (English)In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 59, no 1, p. 43-56Article in journal (Refereed) Published
Abstract [en]

A link between diabetes mellitus (DM) related islet amyloid polypeptide (IAPP) and Alzheimer's disease (AD) related amyloid-beta (A beta) has been suggested in epidemiological and clinical studies. In 2017, proof for existing interaction between type 2 DM and AD on a molecular level was provided based on research carried out in experimental animal models. We assessed aging-related neurodegenerative lesions, i.e., misfolded proteins, associated with dementia such as hyperphosphorylated tau (HP tau), A beta, alpha-synuclein (alpha S), and phosphorylated transactive DNA binding protein 43 (pTDP43) seen in the brain and IAPP seen in the pancreas in subjects with and without DM applying immunohistochemical techniques. HP tau in the brain and IAPP in the pancreas were observed in most subjects. The prevalence and the extent of all misfolded proteins increased with age but this increase was not influenced by DM. Interestingly the extent of misfolded proteins in the brain was higher in non-diabetics when compared with diabetics in demented. A significant correlation was observed between HP tau, A beta, alpha S, and pTDP43, whereas IAPP showed no association with HP tau, A beta, and alpha S. In subjects with DM, the extent of pTDP43 in brain correlated with the extent of IAPP in pancreas. Thus, there is no evidence of a link between AD-related pathology and DM in humans, whereas an association was found between pTDP43 and IAPP in DM. TDP43 is ubiquitously expressed in all organs but whether TDP43 is phosphorylated in other organs in DM or whether the phosphorylation of TDP43 is influenced by glucose metabolism is yet unknown.

Place, publisher, year, edition, pages
IOS Press, 2017
Keywords
alpha-synuclein, amyloid-beta, diabetes mellitus, islet amyloid polypeptide, hyperphosphorylated tau, phosphorylated transactive DNA binding protein 43
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-330074 (URN)10.3233/JAD-170192 (DOI)000404876400006 ()28582864 (PubMedID)
Available from: 2017-10-19 Created: 2017-10-19 Last updated: 2018-01-13Bibliographically approved
Elobeid, A., Libard, S., Leino, M., Popova, S. & Alafuzoff, I. (2016). Altered proteins in the aging brain. Journal of Neuropathology and Experimental Neurology, 75(4), 316-325
Open this publication in new window or tab >>Altered proteins in the aging brain
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2016 (English)In: Journal of Neuropathology and Experimental Neurology, ISSN 0022-3069, E-ISSN 1554-6578, Vol. 75, no 4, p. 316-325Article in journal (Refereed) Published
Abstract [en]

We assessed the prevalence of common altered brain proteins in 296 cognitively unimpaired subjects ranging from age 50 to 102 years. The incidence and the stage of hyperphosphorylated-tau (HP tau), beta-amyloid, alpha-synuclein (alpha S), and transactive response DNA (TDP) binding protein 43 (TDP43)-immunoreactivity (-IR) increased with age. HP tau-IR was observed in 98% of the subjects; the locus coeruleus was solely affected in 46%, and 79% of the subjects were in Braak stages a to II. beta-Amyloid was seen in 47% of subjects and the Thal phase correlated with the HP tau Braak stage and age. Intermediate Alzheimer disease-related pathology (ADRP) was seen in 12%; 52% of the subjects with HP tau-IR fulfilled criteria for definite primary age-related tauopathy (PART). The incidence of concomitant pathology (alpha S, TDP43) did not differ between those with PART and those with ADRP but the former were younger. TDP43-IR was observed in 36%; the most frequently affected region was the medulla; alpha S-IR was observed in 19% of subjects. In 41% of the subjects from 80 to 89 years at death, 3 altered proteins were seen in the brain. Thus, altered proteins are common in the brains of cognitively unimpaired aged subjects; this should be considered while developing diagnostic biomarkers, particularly for identifying subjects at early stages of neurodegenerative diseases.

Place, publisher, year, edition, pages
Oxford University Press, 2016
Keywords
alpha-Synuclein; beta-Amyloid; Aging; Cognition; Hyperphosphorylated-tau; Immunohistochemistry; Transactive response DNA binding protein 43
National Category
Neurology Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-277213 (URN)10.1093/jnen/nlw002 (DOI)000375797000004 ()26979082 (PubMedID)
Available from: 2016-02-18 Created: 2016-02-18 Last updated: 2019-04-02Bibliographically approved
Alafuzoff, I., Popova, S. N., Wanders, A. & Veress, B. (2016). Neuronal Protein Alteration in Enteric Dysmotility Syndrome. Journal of Alzheimer’s Disease & Parkinsonism, 6(1), Article ID 1000212.
Open this publication in new window or tab >>Neuronal Protein Alteration in Enteric Dysmotility Syndrome
2016 (English)In: Journal of Alzheimer’s Disease & Parkinsonism, ISSN 2161-0460, Vol. 6, no 1, article id 1000212Article in journal (Other academic) Published
National Category
Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-319176 (URN)10.4172/2161-0460.1000212 (DOI)
Available from: 2017-03-31 Created: 2017-03-31 Last updated: 2017-04-03Bibliographically approved
Elsir, T., Edqvist, P.-H., Carlson, J., Ribom, D., Bergqvist, M., Ekman, S., . . . Smits, A. (2014). A study of embryonic stem cell-related proteins in human astrocytomas: Identification of Nanog as a predictor of survival. International Journal of Cancer, 134(5), 1123-1131
Open this publication in new window or tab >>A study of embryonic stem cell-related proteins in human astrocytomas: Identification of Nanog as a predictor of survival
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2014 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 134, no 5, p. 1123-1131Article in journal (Refereed) Published
Abstract [en]

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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-207784 (URN)10.1002/ijc.28441 (DOI)000328246700011 ()24037901 (PubMedID)
Note

De två (2) sista författarna delar sistaförfattarskapet.

Available from: 2013-09-18 Created: 2013-09-18 Last updated: 2017-12-06Bibliographically approved
Sandgren, J., Pfeifer, S., Popova, S., Alafuzoff, I. & de Stahl, T. D. (2014). Bi-Allelic Mismatch Repair Msh6 Gene Mutations in a Patient Surviving a Childhood Malignant Brain Tumor. Paper presented at 16th International Symposium on Pediatric Neuro-Oncology (ISPNO), JUN 28-JUL 02, 2014, Singapore, SINGAPORE. Neuro-Oncology, 16, 53-53
Open this publication in new window or tab >>Bi-Allelic Mismatch Repair Msh6 Gene Mutations in a Patient Surviving a Childhood Malignant Brain Tumor
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2014 (English)In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 16, p. 53-53Article in journal, Meeting abstract (Other academic) Published
National Category
Cancer and Oncology Pediatrics
Identifiers
urn:nbn:se:uu:diva-229383 (URN)000337924200201 ()
Conference
16th International Symposium on Pediatric Neuro-Oncology (ISPNO), JUN 28-JUL 02, 2014, Singapore, SINGAPORE
Available from: 2014-08-06 Created: 2014-08-06 Last updated: 2017-12-05Bibliographically approved
Libard, S., Popova, S. N., Amini, R.-M., Kärjä, V., Pietiläinen, T., Hämäläinen, K. M., . . . Alafuzoff, I. (2014). Human cytomegalovirus tegument protein pp65 is detected in all intra- and extra-axial brain tumours independent of the tumour type or grade. PLoS ONE, 9(9), e108861
Open this publication in new window or tab >>Human cytomegalovirus tegument protein pp65 is detected in all intra- and extra-axial brain tumours independent of the tumour type or grade
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2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 9, p. e108861-Article in journal (Refereed) Published
Abstract [en]

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.

National Category
Cancer and Oncology Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-237109 (URN)10.1371/journal.pone.0108861 (DOI)000343671700180 ()25268364 (PubMedID)
Available from: 2014-11-26 Created: 2014-11-26 Last updated: 2019-04-02Bibliographically approved
Popova, S. N., Bergqvist, M., Dimberg, A., Edqvist, P.-H., Ekman, S., Hesselager, G., . . . Alafuzoff, I. (2014). Subtyping of gliomas of various WHO grades by the application of immunohistochemistry. Histopathology, 64(3), 365-379
Open this publication in new window or tab >>Subtyping of gliomas of various WHO grades by the application of immunohistochemistry
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2014 (English)In: Histopathology, ISSN 0309-0167, E-ISSN 1365-2559, Vol. 64, no 3, p. 365-379Article in journal (Refereed) Published
Abstract [en]

Aims

In 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 results

A 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.

Conclusions

Assessment 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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-215836 (URN)10.1111/his.12252 (DOI)000330638700005 ()
Available from: 2014-01-17 Created: 2014-01-17 Last updated: 2017-12-06Bibliographically approved
Popova, S. N. & Alafuzoff, I. (2013). Distribution of SLC10A4, a Synaptic Vesicle Protein in the Human Brain, and the Association of this Protein with Alzheimer's Disease-Related Neuronal Degeneration. Journal of Alzheimer's Disease, 37(3), 603-610
Open this publication in new window or tab >>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 (English)In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 37, no 3, p. 603-610Article in journal (Refereed) Published
Abstract [en]

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.

Keywords
Alzheimer's disease, hyperphosphorylated tau, immunohistochemistry, SLC10A4, synaptic vesicles
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-211120 (URN)10.3233/JAD-130548 (DOI)000324918300016 ()
Available from: 2013-11-20 Created: 2013-11-20 Last updated: 2017-12-06Bibliographically approved
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