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  • 1.
    Azar, Jimmy
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Simonsson, Martin
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Bengtsson, Ewert
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Hast, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Automated Classification of Glandular Tissue by Statistical Proximity Sampling2015In: International Journal of Biomedical Imaging, ISSN 1687-4188, E-ISSN 1687-4196, article id 943104Article in journal (Refereed)
    Abstract [en]

    Due to the complexity of biological tissue and variations in staining procedures, features that are based on the explicit extraction of properties from subglandular structures in tissue images may have difficulty generalizing well over an unrestricted set of images and staining variations. We circumvent this problem by an implicit representation that is both robust and highly descriptive, especially when combined with a multiple instance learning approach to image classification. The new feature method is able to describe tissue architecture based on glandular structure. It is based on statistically representing the relative distribution of tissue components around lumen regions, while preserving spatial and quantitative information, as a basis for diagnosing and analyzing different areas within an image. We demonstrate the efficacy of the method in extracting discriminative features for obtaining high classification rates for tubular formation in both healthy and cancerous tissue, which is an important component in Gleason and tubule-based Elston grading. The proposed method may be used for glandular classification, also in other tissue types, in addition to general applicability as a region-based feature descriptor in image analysis where the image represents a bag with a certain label (or grade) and the region-based feature vectors represent instances.

  • 2.
    Glimelius, Ingrid
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Qvarnström, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Simonsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Ekwall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Smedby, Karin E
    Molin, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Tissue microarray and digital image analysis: a methodological study with special reference to the microenvironment in Hodgkin lymphoma2012In: Histopathology, ISSN 0309-0167, E-ISSN 1365-2559, Vol. 61, no 1, p. 26-32Article in journal (Refereed)
    Abstract [en]

    Aim:  Cancer research has moved from solely investigating the tumour cells to also including analysis of the tumour microenvironment; however, the methods utilized have not been evaluated for this change. The aim of this study was to compare tissue microarrays (TMA) to whole tissue sections (WS) with regard to cells in the tumour microenvironment. Manual evaluation and digital image analyses (DIA) were utilized and also compared.

    Methods and results:  TMA slides from 117 Hodgkin lymphoma patients were immunostained for forkhead box protein 3 (FoxP3) [identifying regulatory T cells (T(reg) )], and 39 corresponding WS were also analysed. Manual evaluation and DIA were utilized for all patients on both the TMA and the WS. A correlation coefficient of 0.83 was obtained for the proportion of T(reg) in TMA versus WS using manual evaluation and a correlation coefficient of 0.77 with DIA. T(reg) counts using manual evaluation correlated in turn with DIA, with a coefficient of 0.79 for the 117 TMA sections and 0.65 for the 39 WS.

    Conclusion:  Because a high correlation was observed between TMA and WS, TMA can be utilized when evaluating cells in the tumour microenvironment. DIA appears to provide a reliable measurement method, provided that manual control of the tumour slides is conducted.

  • 3.
    Hedström, Gustav
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Thunberg, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Berglund, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Simonsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Low expression of microRNA-129-5p predicts poor clinical outcome in diffuse large B cell lymphoma (DLBCL)2013In: International Journal of Hematology, ISSN 0925-5710, E-ISSN 1865-3774, Vol. 97, no 4, p. 465-471Article in journal (Refereed)
    Abstract [en]

    Diffuse large B cell lymphoma (DLBCL) is a heterogeneous group of B cell lymphomas. MicroRNA expression provides a new and interesting tool for understanding the biology and clinical course of DLBCL. The present study presents microRNA-129-5p expression data from DLBCL patients treated with CHOP or R-CHOP. Patients with low microRNA-129-5p expression had a median survival of 23 months and a significantly shorter overall survival (P = 0.0042) compared to patients with high microRNA-129-5p expression, who had a median survival of 58 months. We also found that patients treated with R-CHOP only and displaying low microRNA-129-5p expression had a significantly shorter overall survival compared to patients with high microRNA-129-5p expression; all such patients were still alive at the time of last follow-up (P = 0.043). No significant difference was found among microRNA-129-5p expression in tumor tissue, the tissue surrounding the tumor, and normal controls. To our knowledge, this is the first report to show that the expression of microRNA-129-5p can affect the clinical outcome of DLBCL patients and that microRNA-129-5p may be involved in the biology of DLBCL development, although larger studies are necessary to confirm this. Further investigations may also help to elucidate the biological role of microRNA-129-5p in DLBCL.

  • 4.
    Issac Niwas, Swamidoss
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Kårsnäs, Andreas
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Uhlmann, Virginie
    Imaging Platform, Broad Institute of Harvard and MIT, Cambridge, Massachusetts MA, USA and Biomedical Imaging Group, École Polytechnique Fédérale de Lausanne (EPFL), Switzerland.
    Palanisamy, P.
    Dept. of Electronics and Communication Engineering (ECE), National Institute of Technology (NIT), Tiruchirappalli, India.
    Kampf, Caroline
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Simonsson, Martin
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wählby, Carolina
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Strand, Robin
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Automated classification of immunostaining patterns in breast tissue from the Human Protein Atlas2012In: Histopathology Image Analysis (HIMA): a MICCAI 2012 workshop, 2012Conference paper (Refereed)
    Abstract [en]

    Background:

    The Human Protein Atlas (HPA) is an effort to map the location of all human proteins (http://www.proteinatlas.org/ ). It contains a large number of histological images of sections from human tissue. Tissue micro arrays are imaged by a slide scanning microscope, and each image represents a thin slice of a tissue core with a dark brown antibody specific stain and a blue counter stain. When generating antibodies for protein profiling of the human proteome, an important step in the quality control is to compare staining patterns of different antibodies directed towards the same protein. This comparison is an ultimate control that the antibody recognizes the right protein. In this paper, we propose and evaluate different approaches for classifying sub-cellular antibody staining patterns in breast tissue samples.

    Methods and Material:

    The proposed methods include the computation of various features including gray level co-occurrence matrix (GLCM) features, complex wavelet co-occurrence matrix (CWCM) features and WND-CHARM-inspired features. The extracted features are used into two different multivariate classifiers (SVM and LDA classifier). Before extracting features, we use color deconvolution to separate different tissue components, such as the brownly stained positive regions and the blue cellular regions, in the immuno-stained TMA images of breast tissue.

    Results:

    Good results have been obtained by using the combinations of GLCM and wavelets and texture features, edge features, histograms, transforms, etc. (WND-CHARM). The proposed complex wavelet features and the WND-CHARM features have accuracy similar to that of a human expert.

    Conclusions:

    Both human experts and the proposed automated methods have difficulties discriminating between nuclear and cytoplasmic staining patterns. This is to a large extent due to mixed staining of nucleus and cytoplasm. Methods for quantification of staining patterns in histopathology have many applications, ranging from antibody quality control to tumour grading.

  • 5.
    Issac Niwas, Swamidoss
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Kårsnäs, Andreas
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Uhlmann, Virginie
    Imaging Platform, Broad Institute of Harvard and MIT, Cambridge, Massachusetts MA, USA and Biomedical Imaging Group, École Polytechnique Fédérale de Lausanne (EPFL), Switzerland.
    Ponnusamy, Palanisamy
    Dept. of Electronics and Communication Engineering (ECE), National Institute of Technology (NIT), Tiruchirappalli, India.
    Kampf, Caroline
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Molecular and Morphological Pathology.
    Simonsson, Martin
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Wählby, Carolina
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction. Uppsala University, Science for Life Laboratory, SciLifeLab. Broad Institute of Harvard and Massachusetts Institute Technology (MIT), Cambridge, Massachusetts, MA, USA, .
    Strand, Robin
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Automated classification of immunostaining patterns in breast tissue from the Human Protein Atlas2013In: Journal of Pathology Informatics, ISSN 2229-5089, E-ISSN 2153-3539, Vol. 4, no 14Article in journal (Refereed)
    Abstract [en]

    Background:

    The Human Protein Atlas (HPA) is an effort to map the location of all human proteins (http://www.proteinatlas.org/). It contains a large number of histological images of sections from human tissue. Tissue micro arrays (TMA) are imaged by a slide scanning microscope, and each image represents a thin slice of a tissue core with a dark brown antibody specific stain and a blue counter stain. When generating antibodies for protein profiling of the human proteome, an important step in the quality control is to compare staining patterns of different antibodies directed towards the same protein. This comparison is an ultimate control that the antibody recognizes the right protein. In this paper, we propose and evaluate different approaches for classifying sub-cellular antibody staining patterns in breast tissue samples.

    Materials and Methods:

    The proposed methods include the computation of various features including gray level co-occurrence matrix (GLCM) features, complex wavelet co-occurrence matrix (CWCM) features, and weighted neighbor distance using compound hierarchy of algorithms representing morphology (WND-CHARM)-inspired features. The extracted features are used into two different multivariate classifiers (support vector machine (SVM) and linear discriminant analysis (LDA) classifier). Before extracting features, we use color deconvolution to separate different tissue components, such as the brownly stained positive regions and the blue cellular regions, in the immuno-stained TMA images of breast tissue.

    Results:

    We present classification results based on combinations of feature measurements. The proposed complex wavelet features and the WND-CHARM features have accuracy similar to that of a human expert.

    Conclusions:

    Both human experts and the proposed automated methods have difficulties discriminating between nuclear and cytoplasmic staining patterns. This is to a large extent due to mixed staining of nucleus and cytoplasm. Methods for quantification of staining patterns in histopathology have many applications, ranging from antibody quality control to tumor grading.

  • 6.
    Qvarnström, Olov Fredrik
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Enheten för onkologi.
    Simonsson, Martin
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Enheten för onkologi.
    Johansson, Karl-Axel
    Nyman, Jan
    Turesson, Ingela
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Enheten för onkologi.
    DNA double strand break quantification in skin biopsies.2004In: Radiother Oncol, ISSN 0167-8140, Vol. 72, no 3, p. 311-7Article in journal (Other scientific)
  • 7.
    Seppänen, Henri
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Ångström Space Technology Centre, ÅSTC.
    Rauhala, Timo
    Kiprich, Sergiy
    Ukkonen, Jukka
    Simonsson, Martin
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kurppa, Risto
    Janhunen, Pekka
    Hæggström, Edward
    One kilometer (1 km) electric solar wind sail tether produced automatically2013In: Review of Scientific Instruments, ISSN 0034-6748, E-ISSN 1089-7623, Vol. 84, no 9, article id 095102Article in journal (Refereed)
    Abstract [en]

    We produced a 1 km continuous piece of multifilament electric solar wind sail tether of μm-diameter aluminum wires using a custom made automatic tether factory. The tether comprising 90 704 bonds between 25 and 50 μm diameter wires is reeled onto a metal reel. The total mass of 1 km tether is 10 g. We reached a production rate of 70 m/24 h and a quality level of 1‰ loose bonds and 2‰ rebonded ones. We thus demonstrated that production of long electric solar wind sail tethers is possible and practical.

  • 8.
    Simonsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Quantification of Radiation Induced DNA Damage Response in Normal Skin Exposed in Clinical Settings2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The structure, function and accessibility of epidermal skin provide aunique opportunity to study the DNA damage response (DDR) of a normaltissue. The in vivo response can be examined in detail, at a molecularlevel, and further associated to the structural changes, observed at atissue level. We collected an extensive skin biopsy material frompatients undergoing fractionated radiotherapy for 5 to 7 weeks. Several end-points inthe DDR pathways were examined before, during and after the treatment.

    Quantification of DNA double strand break (DSB) signalling focirevealed a hypersensitivity to doses below 0.3Gy. Furthermore, aconsiderable amount of foci persisted between fractions. The low dosehypersensitivity was observed throughout the treatment and was alsoobserved for several key parameters further downstream in the DDR-pathway, such as p21-associated checkpoint activation, apoptosisinduction and reduction in basal keratinocyte density (BKD).Furthermore, for dose fractions above 1.0 Gy, a distinct acceleration inDDR was observed half way into treatment. This was manifested as anaccelerated loss of basal keratinocytes, mirrored by a simultaneousincrease in DSBs and p21 expression.

    Quantifications of mitotic events revealed a pronounced suppression ofmitosis throughout the treatment which was clearly low dosehypersensitive. Thus, no evidence of accelerated repopulation could beobserved for fraction doses ranging from 0.05 to 2Gy.

    Our results suggest that the keratinocyte response primarily isdetermined by checkpoints, which leads to pre-mitotic cell elimination by permanent growth arrest and apoptosis.

    A comparison between the epidermal and dermal sub-compartments revealsa consistent up-regulation of the DDR response during treatment. Adifference was however observed in the recovery phase after treatment,where miR-34a and p21 remain up-regulated in dermis more persistentlythan in epidermis. Our observations suggest that the recovery phaseafter treatment can provide important clues to understand clinicalobservations such as the early and late effects observed in normaltissues during fractionated radiotherapy.

    List of papers
    1. Low-dose hypersensitive gammaH2AX response and infrequent apoptosis in epidermis from radiotherapy patients
    Open this publication in new window or tab >>Low-dose hypersensitive gammaH2AX response and infrequent apoptosis in epidermis from radiotherapy patients
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    2008 (English)In: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, Vol. 88, no 3, p. 388-397Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND AND PURPOSE: A low-dose hypersensitivity to radiation can be observed in vitro for many human cell types in terms of increased cell kill per dose unit for doses below 0.5Gy. Quantification of the double-strand break marker gammaH2AX in samples taken in clinical radiotherapy practice has the potential to provide important information about how induction and repair of severe DNA damage and apoptosis are linked to low-dose hypersensitivity. MATERIAL AND METHODS: The effects of exposure to low doses (0.05-1.1Gy) were investigated in skin biopsies taken from prostate cancer patients undergoing the first week of radiotherapy. gammaH2AX foci and apoptotic cells were visualised by immunohistochemistry and quantified by image analysis. RESULTS: The gammaH2AX foci pattern in biopsies taken 30min after a single fraction revealed a low-dose hypersensitivity below 0.3Gy (p=0.0009). The result was consistent for repeated fractions (p=0.00001). No decrease in foci numbers could be detected when comparing biopsies taken 30min and 2h after single fractions of 0.4 and 1.2Gy. The result was consistent for repeated fractions. Only 43 of 168,000 cells in total were identified as apoptotic, yet a dose dependency could be detected after 1week of radiotherapy (p=0.003). CONCLUSIONS: We describe a method based on gammaH2AX to study DNA damage response and apoptosis in a clinical setting. A gammaH2AX hypersensitive response to low doses can be observed in epidermal skin, already 30min following delivered fraction. A very low frequency of apoptosis in normal epithelium suggests that this effect is not an important part of the in vivo response to low doses.

    Keywords
    γH2AX, Hypersensitivity, Apoptosis, Epidermis, Normal tissue, Parp-1; DNA damage, DNA repair, Double strand breaks, DSB, Digital image analysis, Foci
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-17482 (URN)10.1016/j.radonc.2008.04.017 (DOI)000260203800012 ()18524402 (PubMedID)
    Available from: 2008-06-24 Created: 2008-06-24 Last updated: 2017-12-08Bibliographically approved
    2. A low-dose hypersensitive keratinocyte loss in response to fractionated radiotherapy is associated with growth arrest and apoptosis
    Open this publication in new window or tab >>A low-dose hypersensitive keratinocyte loss in response to fractionated radiotherapy is associated with growth arrest and apoptosis
    Show others...
    2010 (English)In: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, Vol. 94, no 1, p. 90-101Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND AND PURPOSE: The existence of a hypersensitive radiation response to doses below 0.5Gy is well established for many normal and tumour cell lines. There is also evidence for hypersensitive tissue responses in acute skin damage and kidney function in mice. Recently, we have identified that a hypersensitive gammaH2AX response exists in human epidermis. The aim of this study was to investigate the dose-response of basal clonogenic keratinocytes in normal skin to fractionated radiotherapy with low dose fractions. MATERIALS: Skin punch biopsies were taken before and during radiotherapy from prostate cancer patients undergoing radiotherapy with a curative intent. Areas of epidermis receiving daily fractions of approximately 0.1, 0.2, 0.45 and 1.1Gy were biopsied on the same occasion to determine dose-response for each individual patient. In total, 89 cases were assessed either at 1, 2.5, 3, 4, 5 or 6.5 weeks in the treatment course. Biopsy sampling of another 25 patients was performed from areas receiving 0.45 and 1.1Gy per fraction at regular intervals throughout the 7-week treatment period. The number of basal keratinocytes per mm of the interfollicular epidermis was determined. The DNA damage response of the basal keratinocytes was investigated by immunohistochemical staining for molecular markers of growth arrest, mitosis and cell death, using p21, phospho-H3 and gammaH2AX, respectively. The number of stained keratinocytes in the basal layer was counted manually. The p21 staining was also quantified by digital image analysis. RESULTS: The individual dose-response relationships revealed a low-dose hypersensitivity for reduction of basal keratinocytes throughout 7 weeks of radiotherapy (p<0.01). Growth arrest and cell proliferation assessed at 1 week and 6.5 weeks showed, in both cases, hypersensitive increase of p21 (p<0.01) and hypersensitive depression of mitosis (p<0.01). Manual counting and digital image analysis of p21 showed good agreement. Cell death was infrequent but increased significantly between 1 and 6.5 weeks and displayed a hypersensitive dose-response at the end of the treatment period. CONCLUSIONS: A low-dose hypersensitivity in basal skin keratinocyte reduction is present throughout 7 weeks of radiotherapy. A persistent hypersensitive growth arrest response and cell killing mediate this effect.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-134593 (URN)10.1016/j.radonc.2009.10.007 (DOI)000274889900014 ()19931928 (PubMedID)
    Available from: 2010-11-29 Created: 2010-11-29 Last updated: 2017-12-12Bibliographically approved
    3. Epidermal keratinocyte loss in response to daily 2 Gy fractions for 5 weeks of radiotherapy is associated with DSB-foci, growth arrest, apoptosis and lack of accelerated repopulation
    Open this publication in new window or tab >>Epidermal keratinocyte loss in response to daily 2 Gy fractions for 5 weeks of radiotherapy is associated with DSB-foci, growth arrest, apoptosis and lack of accelerated repopulation
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Background and purpose:

    Tissue-sparing due to repopulation is expected to occur in epithelial cell populations during a course of fractionated radiotherapy (RT). Recently, we established, in the clinical setting of RT, the dose response relationship of subtherapeutic doses in terms of epidermal keratinocyte loss in the basal layer throughout 7 weeks of RT. Surprisingly, in the case of daily dose fractions of 1.10Gy, the keratinocyte loss per dose unit  increases over the last 4 weeks of the treatment period rather than being constant or decreasing. The aim of the present study is to elaborate on the issue of germinal keratinocyte response to daily dose fractions of 2.0Gy for 5 weeks. Here, we present assessments of keratinocyte loss, DSB foci, growth arrest, mitosis and apoptosis using methods earlier described by us.

    Materials and Methods:

    In total 240 skin punch biopsies, collected from 31 breast cancer patients, before, during and after postmastectomy radiotherapy given to the thoracic wall with daily 2.0Gy fractions for 5 weeks, were investigated. The dose response for basal keratinocyte density of the interfollicular epidermis was determined. The DNA damage response of keratinocytes was studied by immunostaining for molecular markers of DNA DSBs, growth arrest, mitosis and cell death using 53BP1, p21, phospho-H3 and γH2AX (apoptosis), respectively. The stainings of keratinocytes were counted manually or by digital image analysis.

    Results:

    The dose-response relationship for the loss of basal keratinocytes over 5 weeks of RT revealed a biphasic shape. An initial radioresistant phase was followed by an increase in radiosensitivity in the second part of RT. The rate of keratinocyte loss reflected the significant changes determined by 53BP1 and γH2AX foci 30 minutes after dose fractions over the treatment period. The highest induction of DSB foci per cell was observed towards the end of treatment. The increase in the fraction of p21 stained cells was also more prominent during the second half of the treatment as compared to the first period of RT. The apoptotic frequency was generally low but increased dramatically towards the end of RT. The mitotic cell number was significantly suppressed over 5 weeks, and did not recover during the weekend treatment-gaps. Notably, the mitotic rate increased more than threefold compared to unexposed skin, 2 weeks after the end of RT, followed by a rapid decline one week later.

    Conclusion:

    The dose response for germinal keratinocyte loss as a result of daily dose fractions of 2.0Gy over 5 weeks treatment deviates significantly from an exponential curve fit. The effectiveness of each dose fraction was less in the first half of the treatment when compared with the second half. No accelerated repopulation could be revealed over the 5 weeks, but was evident after completion of radiotherapy. The changes in keratinocyte response were associated with changes in induction of DSB foci and p21 protein expression, as well as apoptotic events over the treatment period.  In particular, we highlight the existence of pre-mitotic apoptosis, which increased significantly towards the end of 5 weeks RT. These findings suggest that it is necessary to reconsider the current conceptions regarding DNA repair, cell-cycle redistribution and repopulation of normal epithelial cells to a long-lasting courses of fractionated radiotherapy.

    National Category
    Cancer and Oncology
    Research subject
    Oncology
    Identifiers
    urn:nbn:se:uu:diva-134594 (URN)
    Available from: 2010-11-29 Created: 2010-11-29 Last updated: 2011-01-13
    4. Mir-34a, mir-16 and mir-203 in the DNA damage response of epidermis and dermis to conventional radiotherapy
    Open this publication in new window or tab >>Mir-34a, mir-16 and mir-203 in the DNA damage response of epidermis and dermis to conventional radiotherapy
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Background:

    The cellular response to radiation induced DNA damage determines the outcome of radiotherapy. The skin is a normal tissue that is always affected in radiotherapy, and exhibits both early and late effects that can be dose-limiting. However, the molecular mechanisms behind the side effects are still poorly understood The DNA-damage response pathways consist of a network of genes activated to repair DNA insult and promote cell survival. MicroRNAs (miRNAs) are short non-protein-coding RNAs that regulate ~30% of all gene expressions. Many miRNAs are tumor suppressors and activated by DNA damage. The role of miRNAs in the response to radiation induced DNA damage could be crucial and contribute to the different side effects seen in normal tissues.

    Aim:

    The objective of the present clinical study is to elucidate the potential impact of miRNA regulation of DNA damage response in normal skin to radiotherapy given with daily fractions of 2 Gy over 5 weeks. We have focused on miR-34a, miR-16 and MiR-203, known to be upregulated by p53 upon various types of genotoxic exposure.

    Methods:

    A total of 141 punch skin biopsies from 15 breast cancer patients were collected before, during and after radiotherapy. The skin was microdissected into epidermis and dermis. Micro-RNA levels were determined for miR-34a, miR-16 and miR-203 by RT-QPCR. Associated protein levels of p21, Bcl-2 and p63 were determined by immunohistochemistry.

    Results:

    miR-34a was induced in a very similar pattern as p21 during  the radiotherapy course. Also the decline rate of the miR-34a expression following the end of radiotherapy was equal to that of p21. The relative expression levels of miR-34a and p21 increased both in epidermis and dermis, to the same degree for the two different tissues during the treatment period (p< 0.002). After completion of treatment the miR-34a and p21 levels declined faster in the epidermis compared to dermis (p<0.003). The expression levels in dermis remained elevated for weeks for both miR-34a and p21. No change could be observed for miR-16 neither in epidermis or dermis, as well as in the expression of Bcl-2. Notably, no induced changes in miR-203 and p63 were detectable in epidermis. Unexpectedly, there was a significant reduction of miR-203 in the dermis.

    Conclusion:

    This study is the first to show a significant up-regulation of miR-34a in various normal cell populations to the DNA damage inflicted by radiotherapy. The miR-34a induction is of equal degree in epidermis and dermis and mirrors that of p21, a well-known target protein of p53. Secondly, in contrast to the successive decline of p21 and miR-34a in epidermal keratinocytes after completion of treatment, retention lasting for weeks is characteristic for fibroblasts and endothelial cells in dermis. This diverging molecular resolution of the DNA damage reveals early mechanistic differences in the pathological processes behind acute reversible effects of epidermis and late progressive changes of dermis. Our findings highlight that the accessibility makes the skin to a unique clinical model to quantify markers of DNA damage response to repeated DNA insult as it is delivered in radiotherapy.

     

    National Category
    Cancer and Oncology
    Research subject
    Oncology
    Identifiers
    urn:nbn:se:uu:diva-134597 (URN)
    Available from: 2010-11-29 Created: 2010-11-29 Last updated: 2011-01-13
  • 9.
    Simonsson, Martin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Qvarnström, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Nyman, Jan
    Johansson, Karl-Axel
    Garmo, Hans
    Turesson, Ingela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Low-dose hypersensitive gammaH2AX response and infrequent apoptosis in epidermis from radiotherapy patients2008In: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, Vol. 88, no 3, p. 388-397Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND PURPOSE: A low-dose hypersensitivity to radiation can be observed in vitro for many human cell types in terms of increased cell kill per dose unit for doses below 0.5Gy. Quantification of the double-strand break marker gammaH2AX in samples taken in clinical radiotherapy practice has the potential to provide important information about how induction and repair of severe DNA damage and apoptosis are linked to low-dose hypersensitivity. MATERIAL AND METHODS: The effects of exposure to low doses (0.05-1.1Gy) were investigated in skin biopsies taken from prostate cancer patients undergoing the first week of radiotherapy. gammaH2AX foci and apoptotic cells were visualised by immunohistochemistry and quantified by image analysis. RESULTS: The gammaH2AX foci pattern in biopsies taken 30min after a single fraction revealed a low-dose hypersensitivity below 0.3Gy (p=0.0009). The result was consistent for repeated fractions (p=0.00001). No decrease in foci numbers could be detected when comparing biopsies taken 30min and 2h after single fractions of 0.4 and 1.2Gy. The result was consistent for repeated fractions. Only 43 of 168,000 cells in total were identified as apoptotic, yet a dose dependency could be detected after 1week of radiotherapy (p=0.003). CONCLUSIONS: We describe a method based on gammaH2AX to study DNA damage response and apoptosis in a clinical setting. A gammaH2AX hypersensitive response to low doses can be observed in epidermal skin, already 30min following delivered fraction. A very low frequency of apoptosis in normal epithelium suggests that this effect is not an important part of the in vivo response to low doses.

  • 10.
    Wu, Xuping
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Smavadati, Shirin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Nordfjäll, Katarina
    Karlsson, Krister
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Qvarnström, Fredrik
    Simonsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Bergqvist, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Gryaznov, Sergei
    Ekman, Simon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Paulsson-Karlsson, Ylva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Telomerase antagonist imetelstat inhibits esophageal cancer cell growth and increases radiation-induced DNA breaks2012In: Biochimica et Biophysica Acta. Molecular Cell Research, ISSN 0167-4889, E-ISSN 1879-2596, Vol. 1823, no 12, p. 2130-2135Article in journal (Refereed)
    Abstract [en]

    Telomerase is mainly active in human tumor cells, which provides an opportunity for a therapeutic window on telomerase targeting. We sought to evaluate the potential of the thio-phosphoramidate oligonucleotide inhibitor of telomerase, imetelstat, as a drug candidate for treatment of esophageal cancer. Our results showed that imetelstat inhibited telomerase activity in a dose-dependent manner in esophageal cancer cells. After only 1. week of imetelstat treatment, a reduction of colony formation ability of esophageal cancer cells was observed. Furthermore, long-term treatment with imetelstat decreased cell growth of esophageal cancer cells with different kinetics regarding telomere lengths. Short-term imetelstat treatment also increased γ-H2AX and 53BP1 foci staining in the esophageal cancer cell lines indicating a possible induction of DNA double strand breaks (DSBs). We also found that pre-treatment with imetelstat led to increased number and size of 53BP1 foci after ionizing radiation. The increase of 53BP1 foci number was especially pronounced during the first 1 h of repair whereas the increase of foci size was prominent later on. This study supports the potential of imetelstat as a therapeutic agent for the treatment of esophageal cancer.

1 - 10 of 10
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