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Al-Khalili Szigyarto, CristinaORCID iD iconorcid.org/0000-0001-6990-1905
Alternative names
Publications (10 of 36) Show all publications
Spitali, P., Hettne, K., Tsonaka, R., Charrout, M., van den Bergen, J., Koeks, Z., . . . Aartsma-Rus, A. (2018). Tracking disease progression non-invasively in Duchenne and Becker muscular dystrophies. Journal of Cachexia, Sarcopenia and Muscle, 9(4), 715-726
Open this publication in new window or tab >>Tracking disease progression non-invasively in Duchenne and Becker muscular dystrophies
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2018 (English)In: Journal of Cachexia, Sarcopenia and Muscle, ISSN 2190-5991, E-ISSN 2190-6009, Vol. 9, no 4, p. 715-726Article in journal (Refereed) Published
Abstract [en]

Background Analysis of muscle biopsies allowed to characterize the pathophysiological changes of Duchenne and Becker muscular dystrophies (D/BMD) leading to the clinical phenotype. Muscle tissue is often investigated during interventional dose finding studies to show in situ proof of concept and pharmacodynamics effect of the tested drug. Less invasive readouts are needed to objectively monitor patients' health status, muscle quality, and response to treatment. The identification of serum biomarkers correlating with clinical function and able to anticipate functional scales is particularly needed for personalized patient management and to support drug development programs. Methods A large-scale proteomic approach was used to identify serum biomarkers describing pathophysiological changes (e.g. loss of muscle mass), association with clinical function, prediction of disease milestones, association with in vivo(31)P magnetic resonance spectroscopy data and dystrophin levels in muscles. Cross-sectional comparisons were performed to compare DMD patients, BMD patients, and healthy controls. A group of DMD patients was followed up for a median of 4.4years to allow monitoring of individual disease trajectories based on yearly visits. Results Cross-sectional comparison enabled to identify 10 proteins discriminating between healthy controls, DMD and BMD patients. Several proteins (285) were able to separate DMD from healthy, while 121 proteins differentiated between BMD and DMD; only 13 proteins separated BMD and healthy individuals. The concentration of specific proteins in serum was significantly associated with patients' performance (e.g. BMP6 serum levels and elbow flexion) or dystrophin levels (e.g. TIMP2) in BMD patients. Analysis of longitudinal trajectories allowed to identify 427 proteins affected over time indicating loss of muscle mass, replacement of muscle by adipose tissue, and cardiac involvement. Over-representation analysis of longitudinal data allowed to highlight proteins that could be used as pharmacodynamic biomarkers for drugs currently in clinical development. Conclusions Serum proteomic analysis allowed to not only discriminate among DMD, BMD, and healthy subjects, but it enabled to detect significant associations with clinical function, dystrophin levels, and disease progression.

Place, publisher, year, edition, pages
Wiley-VCH Verlagsgesellschaft, 2018
Keywords
Biomarker, Duchenne muscular dystrophy, Becker muscular dystrophy, Longitudinal analysis, Proteomics, Sarcopenia
National Category
Clinical Laboratory Medicine
Identifiers
urn:nbn:se:kth:diva-234633 (URN)10.1002/jcsm.12304 (DOI)000442345000009 ()29682908 (PubMedID)2-s2.0-85052068809 (Scopus ID)
Note

QC 20180913

Available from: 2018-09-13 Created: 2018-09-13 Last updated: 2018-09-13Bibliographically approved
Danielsson, F., Fasterius, E., Sullivan, D., Hases, L., Sanli, K., Zhang, C., . . . Lundberg, E. (2018). Transcriptome profiling of the interconnection of pathways involved in malignant transformation and response to hypoxia. OncoTarget, 9(28), 19730-19744
Open this publication in new window or tab >>Transcriptome profiling of the interconnection of pathways involved in malignant transformation and response to hypoxia
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2018 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 9, no 28, p. 19730-19744Article in journal (Refereed) Published
Abstract [en]

In tumor tissues, hypoxia is a commonly observed feature resulting from rapidly proliferating cancer cells outgrowing their surrounding vasculature network. Transformed cancer cells are known to exhibit phenotypic alterations, enabling continuous proliferation despite a limited oxygen supply. The four-step isogenic BJ cell model enables studies of defined steps of tumorigenesis: the normal, immortalized, transformed, and metastasizing stages. By transcriptome profiling under atmospheric and moderate hypoxic (3% O2) conditions, we observed that despite being highly similar, the four cell lines of the BJ model responded strikingly different to hypoxia. Besides corroborating many of the known responses to hypoxia, we demonstrate that the transcriptome adaptation to moderate hypoxia resembles the process of malignant transformation. The transformed cells displayed a distinct capability of metabolic switching, reflected in reversed gene expression patterns for several genes involved in oxidative phosphorylation and glycolytic pathways. By profiling the stage-specific responses to hypoxia, we identified ASS1 as a potential prognostic marker in hypoxic tumors. This study demonstrates the usefulness of the BJ cell model for highlighting the interconnection of pathways involved in malignant transformation and hypoxic response.

Place, publisher, year, edition, pages
Impact Journals LLC, 2018
Keywords
Hypoxia, Malignant transformation, Transcriptomics
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:kth:diva-227616 (URN)10.18632/oncotarget.24808 (DOI)2-s2.0-85045315705 (Scopus ID)
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

QC 20180522

Available from: 2018-05-22 Created: 2018-05-22 Last updated: 2018-09-05Bibliographically approved
Fasterius, E., Raso, C., Kennedy, S., Rauch, N., Lundin, P., Kolch, W., . . . Al-Khalili Szigyarto, C. (2017). A novel RNA sequencing data analysis method for cell line authentication. PLoS ONE, 12(2), Article ID e0171435.
Open this publication in new window or tab >>A novel RNA sequencing data analysis method for cell line authentication
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2017 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 2, article id e0171435Article in journal (Refereed) Published
Abstract [en]

We have developed a novel analysis method that can interrogate the authenticity of biological samples used for generation of transcriptome profiles in public data repositories. The method uses RNA sequencing information to reveal mutations in expressed transcripts and subsequently confirms the identity of analysed cells by comparison with publicly available cell-specific mutational profiles. Cell lines constitute key model systems widely used within cancer research, but their identity needs to be confirmed in order to minimise the influence of cell contaminations and genetic drift on the analysis. Using both public and novel data, we demonstrate the use of RNA-sequencing data analysis for cell line authentication by examining the validity of COLO205, DLD1, HCT15, HCT116, HKE3, HT29 and RKO colorectal cancer cell lines. We successfully authenticate the studied cell lines and validate previous reports indicating that DLD1 and HCT15 are synonymous. We also show that the analysed HKE3 cells harbour an unexpected KRAS-G13D mutation and confirm that this cell line is a genuine KRAS dosage mutant, rather than a true isogenic derivative of HCT116 expressing only the wild type KRAS. This authentication method could be used to revisit the numerous cell line based RNA sequencing experiments available in public data repositories, analyse new experiments where whole genome sequencing is not available, as well as facilitate comparisons of data from different experiments, platforms and laboratories.

Place, publisher, year, edition, pages
PUBLIC LIBRARY SCIENCE, 2017
National Category
Biological Sciences
Identifiers
urn:nbn:se:kth:diva-204084 (URN)10.1371/journal.pone.0171435 (DOI)000394423800024 ()28192450 (PubMedID)2-s2.0-85012231859 (Scopus ID)
Note

QC 20170329

Available from: 2017-03-29 Created: 2017-03-29 Last updated: 2018-09-05Bibliographically approved
Lourbakos, A., Yau, N., de Bruijn, P., Hiller, M., Kozaczynska, K., Jean-Baptiste, R., . . . Spitali, P. (2017). Evaluation of serum MMP-9 as predictive biomarker for antisense therapy in Duchenne. Scientific Reports, 7, Article ID 17888.
Open this publication in new window or tab >>Evaluation of serum MMP-9 as predictive biomarker for antisense therapy in Duchenne
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2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 17888Article in journal (Refereed) Published
Abstract [en]

Duchenne Muscular Dystrophy (DMD) is a severe muscle disorder caused by lack of dystrophin. Predictive biomarkers able to anticipate response to the therapeutic treatments aiming at dystrophin re-expression are lacking. The objective of this study is to investigate Matrix Metalloproteinase-9 (MMP-9) as predictive biomarker for Duchenne. Two natural history cohorts were studied including 168 longitudinal samples belonging to 66 patients. We further studied 1536 samples obtained from 3 independent clinical trials with drisapersen, an antisense oligonucleotide targeting exon 51: an open label study including 12 patients; a phase 3 randomized, double blind, placebo controlled study involving 186 patients; an open label extension study performed after the phase 3. Analysis of natural history cohorts showed elevated MMP-9 levels in patients and a significant increase over time in longitudinal samples. MMP-9 decreased in parallel to clinical stabilization in the 12 patients involved in the open label study. The phase 3 study and subsequent extension study clarified that the decrease in MMP-9 levels was not predictive of treatment response. These data do not support the inclusion of serum MMP-9 as predictive biomarker for DMD patients.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2017
National Category
Clinical Laboratory Medicine
Identifiers
urn:nbn:se:kth:diva-220826 (URN)10.1038/s41598-017-17982-y (DOI)000418388700008 ()2-s2.0-85038627721 (Scopus ID)
Note

QC 20180111

Available from: 2018-01-11 Created: 2018-01-11 Last updated: 2018-02-20Bibliographically approved
Uhlén, M., Fagerberg, L., Hallström, B. M., Lindskog, C., Oksvold, P., Mardinoglu, A., . . . Pontén, F. (2015). Tissue-based map of the human proteome. Science, 347(6220), 1260419
Open this publication in new window or tab >>Tissue-based map of the human proteome
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2015 (English)In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 347, no 6220, p. 1260419-Article in journal (Refereed) Published
Abstract [en]

Resolving the molecular details of proteome variation in the different tissues and organs of the human body will greatly increase our knowledge of human biology and disease. Here, we present a map of the human tissue proteome based on an integrated omics approach that involves quantitative transcriptomics at the tissue and organ level, combined with tissue microarray-based immunohistochemistry, to achieve spatial localization of proteins down to the single-cell level. Our tissue-based analysis detected more than 90% of the putative protein-coding genes. We used this approach to explore the human secretome, the membrane proteome, the druggable proteome, the cancer proteome, and the metabolic functions in 32 different tissues and organs. All the data are integrated in an interactive Web-based database that allows exploration of individual proteins, as well as navigation of global expression patterns, in all major tissues and organs in the human body.

Keywords
isoprotein, membrane protein, protein, proteome, tumor protein
National Category
Biological Sciences
Identifiers
urn:nbn:se:kth:diva-160035 (URN)10.1126/science.1260419 (DOI)000348225800036 ()25613900 (PubMedID)2-s2.0-84925582323 (Scopus ID)
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscienceKnut and Alice Wallenberg Foundation
Note

QC 20150216

Available from: 2015-02-13 Created: 2015-02-13 Last updated: 2017-12-04Bibliographically approved
Fagerberg, L., Hallström, B. M., Oksvold, P., Kampf, C., Djureinovic, D., Odeberg, J., . . . Uhlén, M. (2014). Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Molecular & Cellular Proteomics, 13(2), 397-406
Open this publication in new window or tab >>Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics
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2014 (English)In: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 13, no 2, p. 397-406Article in journal (Refereed) Published
Abstract [en]

Global classification of the human proteins with regards to spatial expression patterns across organs and tissues is important for studies of human biology and disease. Here, we used a quantitative transcriptomics analysis (RNA-Seq) to classify the tissue-specific expression of genes across a representative set of all major human organs and tissues and combined this analysis with antibody- based profiling of the same tissues. To present the data, we launch a new version of the Human Protein Atlas that integrates RNA and protein expression data corresponding to 80% of the human protein-coding genes with access to the primary data for both the RNA and the protein analysis on an individual gene level. We present a classification of all human protein-coding genes with regards to tissue-specificity and spatial expression pattern. The integrative human expression map can be used as a starting point to explore the molecular constituents of the human body.

Keywords
article, gene expression, human, human tissue, immunohistochemistry, priority journal, protein analysis, protein expression, proteomics, spermatogenesis, transcriptomics
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:kth:diva-142992 (URN)10.1074/mcp.M113.035600 (DOI)000331369000002 ()24309898 (PubMedID)2-s2.0-84893276590 (Scopus ID)
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscienceKnut and Alice Wallenberg FoundationEU, FP7, Seventh Framework Programme, HEALTH-F4-2008-201648/PROSPECTS
Note

QC 20140314

Available from: 2014-03-14 Created: 2014-03-14 Last updated: 2017-12-05Bibliographically approved
Lourbakos, A., Hiller, M., Kozaczynska, K., Baptiste, R. J., Reza, M., Niks, E., . . . Spitali, P. (2014). MMP-9 serum levels increase over time in Duchenne muscular dystrophy patients and decrease upon treatment with drisapersen. Paper presented at ESGCT and NVGCT Collaborative Congress; The Hague, NETHERLANDS, OCT 23-26, 2014. Human Gene Therapy, 25(11), A27-A28
Open this publication in new window or tab >>MMP-9 serum levels increase over time in Duchenne muscular dystrophy patients and decrease upon treatment with drisapersen
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2014 (English)In: Human Gene Therapy, ISSN 1043-0342, E-ISSN 1557-7422, Vol. 25, no 11, p. A27-A28Article in journal, Meeting abstract (Other academic) Published
National Category
Microbiology Genetics
Identifiers
urn:nbn:se:kth:diva-158414 (URN)000344774700085 ()
Conference
ESGCT and NVGCT Collaborative Congress; The Hague, NETHERLANDS, OCT 23-26, 2014
Note

QC 20150107

Available from: 2015-01-07 Created: 2015-01-07 Last updated: 2017-12-05Bibliographically approved
Wein, N., Vulin, A., Falzanaro, M. S., Szigyarto, C.-K. A., Maiti, B., Findlay, A., . . . Flanigan, K. M. (2014). Successful Use of Out-of-Frame Exon 2 Skipping Induces IRES-Driven Expression of the N-Truncated Dystrophin Isoform: Promising Approach for Treating Other 5 ' Dystrophin Mutations. Paper presented at 17th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT), MAY 21-24, 2014, Washington, DC. Molecular Therapy, 22, S294-S295
Open this publication in new window or tab >>Successful Use of Out-of-Frame Exon 2 Skipping Induces IRES-Driven Expression of the N-Truncated Dystrophin Isoform: Promising Approach for Treating Other 5 ' Dystrophin Mutations
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2014 (English)In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 22, p. S294-S295Article in journal, Meeting abstract (Other academic) Published
National Category
Biological Sciences
Identifiers
urn:nbn:se:kth:diva-148261 (URN)000337231300753 ()
Conference
17th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT), MAY 21-24, 2014, Washington, DC
Note

QC 20140813

Available from: 2014-08-13 Created: 2014-08-04 Last updated: 2017-12-05Bibliographically approved
Wein, N., Vulin, A., Falzarano, M. S., Szigyarto, C.-K. A., Maiti, B., Findlay, A., . . . Flanigan, K. M. (2014). Translation from a DMD exon 5 IRES results in a functional dystrophin isoform that attenuates dystrophinopathy in humans and mice. Nature Medicine, 20(9), 992-1000
Open this publication in new window or tab >>Translation from a DMD exon 5 IRES results in a functional dystrophin isoform that attenuates dystrophinopathy in humans and mice
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2014 (English)In: Nature Medicine, ISSN 1078-8956, E-ISSN 1546-170X, Vol. 20, no 9, p. 992-1000Article in journal (Refereed) Published
Abstract [en]

Most mutations that truncate the reading frame of the DMD gene cause loss of dystrophin expression and lead to Duchenne muscular dystrophy. However, amelioration of disease severity has been shown to result from alternative, translation initiation beginning in DMD exon 6 that leads to expression of a highly functional N-truncated dystrophin. Here we demonstrate that this isoform results from usage of an internal ribosome entry site (IRES) within exon 5 that is glucocorticoid inducible. We confirmed IRES activity by both peptide sequencing and ribosome profiling in muscle from individuals with minimal symptoms despite the presence of truncating mutations. We generated a truncated reading frame upstream of the IRES by exon skipping, which led to synthesis of a functional N-truncated isoform in both human subject derived cell lines and in a new DMD mouse model, where expression of the truncated isoform protected muscle from contraction-induced injury and corrected muscle force to the same level as that observed in control mice. These results support a potential therapeutic approach for patients with mutations within the 5' exons of DMD.

National Category
Cell and Molecular Biology Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:kth:diva-153266 (URN)10.1038/nm.3628 (DOI)000341404000011 ()2-s2.0-84908315048 (Scopus ID)
Note

QC 20141009

Available from: 2014-10-09 Created: 2014-10-03 Last updated: 2018-01-11Bibliographically approved
Cepeda, D., Ng, H.-F. -., Sharifi, H. R., Mahmoudi, S., Cerrato, V. S., Fredlund, E., . . . Sangfelt, O. (2013). CDK-mediated activation of the SCFFBXO28 ubiquitin ligase promotes MYC-driven transcription and tumourigenesis and predicts poor survival in breast cancer. EMBO Molecular Medicine, 5(7), 999-1018
Open this publication in new window or tab >>CDK-mediated activation of the SCFFBXO28 ubiquitin ligase promotes MYC-driven transcription and tumourigenesis and predicts poor survival in breast cancer
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2013 (English)In: EMBO Molecular Medicine, ISSN 1757-4676, E-ISSN 1757-4684, Vol. 5, no 7, p. 999-1018Article in journal (Refereed) Published
Abstract [en]

SCF (Skp1/Cul1/F-box) ubiquitin ligases act as master regulators of cellular homeostasis by targeting key proteins for ubiquitylation. Here, we identified a hitherto uncharacterized F-box protein, FBXO28 that controls MYC-dependent transcription by non-proteolytic ubiquitylation. SCFFBXO28 activity and stability are regulated during the cell cycle by CDK1/2-mediated phosphorylation of FBXO28, which is required for its efficient ubiquitylation of MYC and downsteam enhancement of the MYC pathway. Depletion of FBXO28 or overexpression of an F-box mutant unable to support MYC ubiquitylation results in an impairment of MYC-driven transcription, transformation and tumourigenesis. Finally, in human breast cancer, high FBXO28 expression and phosphorylation are strong and independent predictors of poor outcome. In conclusion, our data suggest that SCFFBXO28 plays an important role in transmitting CDK activity to MYC function during the cell cycle, emphasizing the CDK-FBXO28-MYC axis as a potential molecular drug target in MYC-driven cancers, including breast cancer. FBXO28 is identified as part of a SCF complex acting as a regulator of tumor cell proliferation and an important modifier of MYC function. FBXO28 may be a new prognostic factor in breast cancer and a new potential drug target in MYC- driven tumors.

Keywords
Breast cancer, CDK, F-box protein, FBXO28, MYC
National Category
Medical Biotechnology
Identifiers
urn:nbn:se:kth:diva-134164 (URN)10.1002/emmm.201202341 (DOI)000325942300009 ()2-s2.0-84880026012 (Scopus ID)
Funder
Swedish Cancer SocietySwedish Research CouncilKnut and Alice Wallenberg Foundation
Note

QC 20131120

Available from: 2013-11-20 Created: 2013-11-18 Last updated: 2017-12-06Bibliographically approved
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Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-6990-1905

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