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Clinical studies of RNA as a prognostic and diagnostic marker for disease
Örebro University, School of Medical Sciences.ORCID iD: 0000-0003-4879-528X
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Technologies for RNA detection are evolving rapidly and gives an op-portunity for discovery of new markers for early detection of complex diseases. Today in clinical work we rely on signs and symptoms in com-bination with the measurement of protein levels for diagnosis. The quick turnaround time of mRNA synthesis may provide an earlier diagnostic signal than protein-based biomarkers assays, in acute dramatic condi-tions such as acute mesenteric ischemia (AMI), for early detection of cancer, as prognostic tool in cancer treatment and as an aid in difficult diagnosis of unknown origin.

The main goals of this thesis was to apply a whole genome approach to study different complex diseases to evaluate the applicability of RNA as a diagnostic or prognostic marker for disease, preferably from an easily accessible source such as peripheral blood. This was investigated in an animal model with induced AMI, a cohort of ovarian cancer patients and in a single-patient study of a girl with a severe inflammatory syn-drome.

Through this thesis we have gained insight into how gene expression is regulated in ischemic intestinal tissue.

We found that a peripheral blood test can distinguish between ovarian cancer patients with or without residual tumour mass after surgery with the help of expression analysis of six genes. We also found that gene expressions of three genes can predict overall survival in peripheral whole blood from ovarian cancer patients. And that gene expression profiles indeed can significantly distinguish between two groups of high and low risk ovarian cancer. In the single-patient study, we tried but failed to device a successful treatment before it was too late. Neverthe-less, the things we learned and the case studies that were published may serve as a diagnostic tool for clinicians facing similar syndromes.

Place, publisher, year, edition, pages
Örebro: Örebro University , 2017. , p. 57
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 168
Keywords [en]
gene expression, ovarian cancer, hypercalprotectinaemia, hyperzincaemia, ischemia, biomarker
National Category
Other Basic Medicine
Identifiers
URN: urn:nbn:se:oru:diva-61626ISBN: 978-91-7529-219-9 (print)OAI: oai:DiVA.org:oru-61626DiVA, id: diva2:1150127
Public defence
2017-12-15, Örebro universitet, Campus USÖ, hörsal C1, Södra Grev Rosengatan 32, Örebro, 09:15 (Swedish)
Opponent
Supervisors
Available from: 2017-10-18 Created: 2017-10-18 Last updated: 2018-01-13Bibliographically approved
List of papers
1. Altered mRNA Expression due to Acute Mesenteric Ischaemia in a Porcine Model
Open this publication in new window or tab >>Altered mRNA Expression due to Acute Mesenteric Ischaemia in a Porcine Model
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2011 (English)In: European Journal of Vascular and Endovascular Surgery, ISSN 1078-5884, E-ISSN 1532-2165, Vol. 41, no 2, p. 281-287Article in journal (Refereed) Published
Abstract [en]

Introduction: Messenger RNA (mRNA) changes in the small intestine in response to acute mesenteric ischaemia (AMI) could offer novel diagnostic possibilities, but have not been described. The aim was to characterize the mRNA response to experimental AMI. Materials and methods: Twelve pigs underwent catheterisation of the superior mesenteric artery with injection of polivinylalcohol embolisation particles or sodium chloride. Laparotomy and intestinal tissue sampling were performed. Microarray analysis was performed using the GeneChip (R) whole porcine genome array. Results: Seven down-regulated cellular pathways were associated with protein, lipid and carbohydrate metabolism. Seventeen up-regulated pathways were associated with inflammatory and immunological activity, regulation of extracellular matrix and decreased cellular proliferation. Thrombospondin (THS), monocyte chemoattractant protein 1(MCP-1) and gap junction alpha 1(GJA-1) were consistently up-regulated in all embolised pigs. Genes encoding earlier proposed biomarkers for AMI were up-regulated, such as lactate dehydrogenase and creatine kinase, or down-regulated, such as intestinal fatty acid binding protein and glutathione S-transferase. Conclusion: This study describes the intestinal tissue response on a gene expression level to AMI. THS, MCP-1 and GJA-1 were consistently up-regulated by ischaemia, whereas earlier proposed biomarkers for AMI were not. Gene expression may not be directly linked to the use of the corresponding proteins as potential clinical biomarkers. (C) 2010 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.

National Category
Medical and Health Sciences
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-18783 (URN)10.1016/j.ejvs.2010.09.012 (DOI)000288469000022 ()21095140 (PubMedID)2-s2.0-79651475389 (Scopus ID)
Available from: 2011-09-29 Created: 2011-09-29 Last updated: 2017-11-24Bibliographically approved
2. Whole blood RNA expression profiles in ovarian cancer patients with or without residual tumors after primary cytoreductive surgery
Open this publication in new window or tab >>Whole blood RNA expression profiles in ovarian cancer patients with or without residual tumors after primary cytoreductive surgery
2012 (English)In: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 27, no 5, p. 1331-1335Article in journal (Refereed) Published
Abstract [en]

Significant improvements in the treatment results of ovarian cancer have been achieved during the last decades, but further improvements require additional methods identifying signs of the disease and its biological behavior, preferably by a simple blood test. We hypothesized that peripheral blood leukocytes may express genes that carry such clinical information. Therefore, we studied the relative gene expressions of 168 cancer- and metastasis-specific genes in blood samples from ovarian cancer patients with different prognoses after primary cytoreductive surgery. Total RNA was extracted from whole blood and the relative gene expression profile of 168 genes were analyzed using real-time qPCR assays. Two groups of patients were analyzed; one group with residual tumor mass after primary surgery, and one group where the tumor was macroscopically radically resected, resulting in no visible tumor mass left behind. The group with the remaining tumor mass after surgery showed significantly different gene expression profiles compared to the group with no remaining tumor mass. Differences were noted for the metastasis associated 1 family, member 2 gene (MTA2), the TNF, alpha-catenin, interleukin 1 beta, the KiSS-1 metastasis suppressor and the matrix metalloproteinase 10 genes. All genes were downregulated with a fold-change between 1.15 to 1.57; there were no upregulated genes. Thus, a signature of genes involved in metastasis, invasion and inflammation was found to be significantly downregulated in native unstimulated blood leukocytes from ovarian cancer patients with a poor prognosis. Preoperatively it may serve as a guide to the biology of the tumor and postoperatively in the optimization of adjuvant treatment of ovarian cancer patients.

Place, publisher, year, edition, pages
Athens, Greece: Spandidos Publications Ltd., 2012
Keywords
Seropapillary ovarian cancer, residual tumor, leukocyte gene expression, whole blood RNA expression
National Category
Medical and Health Sciences Cancer and Oncology
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-23093 (URN)10.3892/or.2012.1680 (DOI)000302202600005 ()22322362 (PubMedID)2-s2.0-84858269622 (Scopus ID)
Note

Funding Agencies:

Lions' Cancer Research Foundation 

Research Committee of Orebro County Council 

Available from: 2012-05-31 Created: 2012-05-31 Last updated: 2017-12-07Bibliographically approved
3. Whole genome expression profiling of blood cells in ovarian cancer patients: prognostic impact of the CYP1B1, MTSS1, NCALD, and NOP14 genes
Open this publication in new window or tab >>Whole genome expression profiling of blood cells in ovarian cancer patients: prognostic impact of the CYP1B1, MTSS1, NCALD, and NOP14 genes
2014 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 5, no 12, p. 4040-4049Article in journal (Refereed) Published
Abstract [en]

Ovarian cancer patients with different tumor stages and cell differentiation might be distinguished from each other by gene expression profiles in whole blood cell mRNA by the Affymetrix Human Gene 1.0 ST Array. We also examined if there is any association with other clinical variables, response to therapy, and residual tumor burden after surgery. Patients were divided into two groups, one with poor prognosis, advanced stage and poorly differentiated tumors (n = 22), and one group with good prognosis, early stage and well-to medium differentiated tumors (n = 11). Six genes were found to be differentially expressed: the PDIA3, LYAR, NOP14, NCALD and MTSS1 genes were down-regulated and the CYP1B1 gene expression was up-regulated in the poor prognosis group, all with p value <0.05, adjusted for mass comparison. In survival analyses, CYP1B1, MTSS1, NCALD and NOP14 remained significantly different (p<0.05). Patient groups did not differ in any transcript related to acute phase or immune responses. This minimal gene expression signature of prognostic ovarian cancer-related genes opens up an avenue for more practicable monitoring of ovarian cancer patients by simple peripheral blood tests, which may evolve into a tool to guide selection of curative and postoperative supportive therapies.

Place, publisher, year, edition, pages
Impact press, 2014
Keywords
ovarian cancer, whole genome profiling, prognosis, mRNA, NCALD, MTSS1, PDA3, CYP1B1, NOP14, LYAR
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:oru:diva-36179 (URN)000339055200007 ()24961659 (PubMedID)2-s2.0-84905090787 (Scopus ID)
Note

Funding Agencies:

Research Committee of Örebro County Council

Foundation for Gynecological Oncology, Örebro

Lions' Cancer Research Foundation, Uppsala-Örebro

Available from: 2014-09-02 Created: 2014-08-28 Last updated: 2018-06-09Bibliographically approved
4. Tissue zinc levels in a child with hypercalprotectinaemia and hyperzincaemia: a case report and a review of the literature
Open this publication in new window or tab >>Tissue zinc levels in a child with hypercalprotectinaemia and hyperzincaemia: a case report and a review of the literature
2012 (English)In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 72, no 1, p. 34-38Article, review/survey (Refereed) Published
Abstract [en]

Background: A girl suffering from a rare syndrome of unknown aetiology, termed hypercalprotectinaemia, was evaluated for tissue zinc status, because calprotectin is a protein which chelates Zn at multiple binding-sites, which might have affected the distribution of Zn in her body.

Methods: Measurement of serum, urine, hair and nail zinc (Zn) concentration, complemented with measurement of total Zn in ultrafiltrates of plasma.

Results: Her serum Zn concentration was 105-133 mu mol/L. Zn levels in her hair (102 mu g/g), nail (90 mu g/g) and urine (3-12 mu mol/L; 20-80 mu g/dL) were all at the lower end of the reference intervals described in the sparse literature. Zn concentrations in ultrafiltrates of plasma were below the detection limit (<100 nmol/L). Thus, the elevated serum Zn did not translate into a similarly increased level of Zn in any of the tissues tested, nor in free Zn concentrations. Instead it appeared to be a result of Zn being chelated to binder proteins, most probably calprotectin.

Conclusion: Her grossly elevated serum calprotectin concentration is probably able to raise circulating total Zn concentrations without raising ionized concentrations, but this Zn remains confined to the circulating blood as well as to excreted body fluids, particularly faeces.

Place, publisher, year, edition, pages
London, United Kingdom: Informa Healthcare, 2012
Keywords
Tissue zinc, zinc excretion, calprotectin, inflammation, growth retardation
National Category
Medical Biotechnology Clinical Laboratory Medicine
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-21627 (URN)10.3109/00365513.2011.623177 (DOI)000299283700005 ()22017170 (PubMedID)2-s2.0-84856056036 (Scopus ID)
Available from: 2012-02-14 Created: 2012-02-14 Last updated: 2018-05-08Bibliographically approved
5. Whole genome microarray expression analysis in blood leucocytes identifies pathways linked to signs and symptoms of a patient with hypercalprotectinaemia and hyperzincaemia
Open this publication in new window or tab >>Whole genome microarray expression analysis in blood leucocytes identifies pathways linked to signs and symptoms of a patient with hypercalprotectinaemia and hyperzincaemia
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2018 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 191, no 2, p. 240-251Article in journal (Refereed) Published
Abstract [en]

A child, 2 years with the "hypercalprotectinemia with hyperzincemia" clinical syndrome presented with atypical symptoms and signs, notably persistent fever of around 38°C, thrombocythaemia of >700 x 10(9) /L, and a predominance of persistent intestinal symptoms. In an effort to find a cure by identifying the dysregulated pathways we analyzed whole-genome mRNA expression by the Affymetrix HG U133 PLUS 2.0 array on three occasions 3 to 5 months apart. Major upregulation was demonstrated for the JAK/STAT pathway including in particular CD177, S100A8, S100A9, and S100A12, accounting for the thrombocytosis; a large number of interleukins, their receptors, and activators, accounting for the febrile apathic state; and the HMBG1 gene, possibly accounting for part of the intestinal symptoms. These results show that gene expression array technology may assist the clinician in the diagnostic workup of individual patients with suspected syndromal states of unknown origin, and the expression data can guide the selection of optimal treatment directed at the identified target pathways.

Place, publisher, year, edition, pages
Wiley-Blackwell Publishing Inc., 2018
Keywords
expression array, fever, hypercalprotectinaemia, hyperzincaemia, thrombocytaemia
National Category
Medical Genetics Immunology in the medical area
Identifiers
urn:nbn:se:oru:diva-61444 (URN)10.1111/cei.13064 (DOI)000419624200012 ()28984903 (PubMedID)
Available from: 2017-11-02 Created: 2017-11-02 Last updated: 2018-09-14Bibliographically approved

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Isaksson, Helena

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