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  • 1.
    Andersson, Charlotta
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Oji, Yusuke
    Ohlson, Nina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wang, Sihan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Li, Xingru
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Ottander, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Sugiyama, Haruo
    Li, Aihong
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Prognostic significance of specific anti-WT1 IgG antibody level in plasma in patients with ovarian carcinoma2014In: Cancer Medicine, ISSN 2045-7634, E-ISSN 2045-7634, Vol. 3, no 4, p. 909-918Article in journal (Refereed)
    Abstract [en]

    Ovarian carcinoma (OC) has a poor prognosis and lack early effective screening markers. Wilm's tumor gene 1 (WT1) is overexpressed in OCs. Therefore, it is of great interest to investigate whether WT1-specific antibody (Ab) measurements in plasma can serve as a biomarker of anti-OC response, and is of importance in relation to patient prognosis. Peripheral blood samples were obtained from a total of 103 women with ovarian tumors with median being 1 day (range 0-48 days) before operation. WT1 IgG Ab levels were evaluated using enzyme-linked immunosorbent assay (ELISA). Immunohistochemical analysis of WT1 protein expression was performed on OC tissue samples. We found that low-WT1 Ab level in plasma was related to improved survival in patients diagnosed at stages III-IV and grade 3 carcinomas. Positive WT1 protein staining on OC tissue samples had a negative impact on survival in the entire cohort, both overall survival (OS) (P = 0.046) and progression-free survival (PFS) (P = 0.006), but not in the serous OC subtype. Combining WT1 IgG Ab levels and WT1 staining, patients with high-WT1 IgG Ab levels in plasma and positive WT1 protein staining in cancer tissues had shorter survival, with a significant association in PFS (P = 0.016). These results indicated that WT1 Ab measurements in plasma and WT1 staining in tissue specimens could be useful as biomarkers for patient outcome in the high-risk subtypes of OCs for postoperative individualized therapy.

  • 2. Falconer, Henrik
    et al.
    Palsdottir, Kolbrun
    Stalberg, Karin
    Dahm-Kahler, Pernilla
    Ottander, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences.
    Lundin, Evelyn Serreyn
    Wijk, Lena
    Kimmig, Rainer
    Jensen, Pernille Tine
    Eriksson, Ane Gerda Zahl
    Maenpaa, Johanna
    Persson, Jan
    Salehi, Sahar
    Robot-assisted approach to cervical cancer (RACC): an international multi-center, open-label randomized controlled trial2019In: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 29, no 6, p. 1072-1076Article in journal (Refereed)
    Abstract [en]

    Background Radical hysterectomy with pelvic lymphadenectomy represents the standard treatment for early-stage cervical cancer. Results from a recent randomized controlled trial demonstrate that minimally invasive surgery is inferior to laparotomy with regards to disease-free and overall survival. Primary Objective To investigate the oncologic safety of robot-assisted surgery for early-stage cervical cancer as compared with standard laparotomy. Study Hypothesis Robot-assisted laparoscopic radical hysterectomy is non-inferior to laparotomy in regards to recurrence-free survival with the advantage of fewer post-operative complications and superior patient-reported outcomes. Trial Design Prospective, multi-institutional, international, open-label randomized clinical trial. Consecutive women with early-stage cervical cancer will be assessed for eligibility and subsequently randomized 1:1 to either robot-assisted laparoscopic surgery or laparotomy. Institutional review board approval will be required from all participating institutions. The trial is coordinated from Karolinska University Hospital, Sweden. Major Inclusion/Exclusion Criteria Women over 18 with cervical cancer FIGO (2018) stages IB1, IB2, and IIA1 squamous, adenocarcinoma, or adenosquamous will be included. Women are not eligible if they have evidence of metastatic disease, serious co-morbidity, or a secondary invasive neoplasm in the past 5 years. Primary Endpoint Recurrence-free survival at 5 years between women who underwent robot-assisted laparoscopic surgery versus laparotomy for early-stage cervical cancer. Sample Size The clinical non-inferiority margin in this study is defined as a 5-year recurrence-free survival not worsened by >7.5%. With an expected recurrence-free survival of 85%, the study needs to observe 127 events with a one-sided level of significance (alpha) of 5% and a power (1-beta) of 80%. With 5 years of recruitment and 3 years of follow-up, the necessary number of events will be reached if the study can recruit a total of 768 patients. Estimated Dates for Completing Accrual and Presenting Results Trial launch is estimated to be May 2019 and the trial is estimated to close in May 2027 with presentation of data shortly thereafter.

  • 3.
    Hosokawa, K
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Ottander, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Wahlberg, P
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Ny, Tor
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Cajander, S
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Olofsson, Jan I
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Dominant expression and distribution of oestrogen receptor beta over oestrogen receptor alpha in the human corpus luteum2001In: Molecular human reproduction, ISSN 1360-9947, E-ISSN 1460-2407, Vol. 7, no 2, p. 137-145Article in journal (Refereed)
    Abstract [en]

    To investigate the potential importance of oestrogen as a local regulator of human corpus luteum function, the mRNA expression pattern and cellular localization of oestrogen receptors (ERs), ER-alpha and ER-beta, were studied in corpora lutea grouped according to age, where days 2-5 post-LH rise were designated as the early luteal phase, days 6-10 as mid-luteal and days 11-14 as the late luteal phase respectively. Northern blot analysis using an ER-beta probe in samples from whole ovarian tissue and isolated corpora lutea, revealed a major band at 7.5 kb and several minor bands between 4-10 kb, while no signals for ER-alpha mRNA were obtained. However, using a semi-quantitative reverse transcription-polymerase chain reaction followed by Southern blotting, ER-beta mRNA levels were found to be 63% lower (P: < 0.05, n = 39) in the mid-luteal phase compared with the early luteal phase, while ER-alpha mRNA expression showed no statistical differences between the different age groups. Using in-situ hybridization, ER-beta mRNA expression was localized to the steroidogenic luteal cells as well as perivascular cells and fibroblasts in the corpus luteum. Immunohistochemistry confirmed the localization of ER-beta protein, but no clear staining of luteal cells was found using antibodies against ER-alpha. Collectively, the findings of low to moderate expression of ER-beta mRNA and protein in the steroidogenic cells, and also in vascular endothelial cells of the corpus luteum, as opposed to diminutive amounts of ER-alpha mRNA, suggest that oestrogen activity is primarily transduced via ER-beta in the human corpus luteum.

  • 4.
    Idahl, Annika
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Jurstrand, Margaretha
    Kliniskt forskingscentrum, Örebro universitetssjukhus.
    Møller, Jens K
    Klinisk mikrobiologi, Århus universitetssjukhus, Skejby, Danmark.
    Marklund, Ingrid
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Lindgren, Peter
    Inst för kvinnors och barns hälsa, obstetrik och gynekologi, Uppsala universitet.
    Ottander, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Chlamydia trachomatis, Mycoplasma genitalium, Neisseria gonorrhoeae, human papillomavirus, and polyomavirus are not detectable in human tissue with epithelial ovarian cancer, borderline tumor, or benign conditions2010In: American Journal of Obstetrics and Gynecology, ISSN 0002-9378, E-ISSN 1097-6868, Vol. 202, no 1, p. 71.e1-71.e6Article in journal (Other academic)
    Abstract [en]

    OBJECTIVE: We sought to analyze the presence of the microorganisms Chlamydia trachomatis, Mycoplasma genitalium, Neisseria gonorrhoeae, human papillomavirus (HPV), and the polyomaviruses BK virus (BKV) and JC virus (JCV) in ovarian tissues of women with ovarian carcinomas, borderline tumors, and benign conditions. STUDY DESIGN: Ovarian tissue, snap-frozen and stored at -80 degrees C, from 186 women with benign conditions, borderline tumors, and epithelial ovarian cancer, as well as tissue from the contralateral ovary of 126 of these women, were analyzed regarding presence of C trachomatis and N gonorrhoeae (transcription mediated amplification), M genitalium (real-time polymerase chain reaction [PCR]), HPV (PCR), and BKV and JCV (PCR). RESULTS: All the tissue samples studied were found negative for the microorganisms analyzed. CONCLUSION: C trachomatis, M genitalium, N gonorrhoeae, HPV, and the polyomaviruses BKV and JCV are not detectable in ovarian tissues either from women with benign conditions and borderline tumors or from women with ovarian cancer.

  • 5.
    Idahl, Annika
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Jurstrand, Margaretha
    Clinical Research Centre, Örebro University Hospital.
    Kumlin, Urban
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Ohlson, Nina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Ottander, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Chlamydia trachomatis and Mycoplasma genitalium plasma antibodies in relation to epithelial ovarian tumors2011In: Infectious diseases in obstetrics and gynecology, ISSN 1064-7449, E-ISSN 1098-0997, Vol. 2011, p. 824627-Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To assess associations of Chlamydia trachomatis and Mycoplasma genitalium antibodies with epithelial ovarian tumors.

    METHODS: Plasma samples from 291 women, undergoing surgery due to suspected ovarian pathology, were analyzed with respect to C. trachomatis IgG and IgA, chlamydial Heat Shock Protein 60-1 (cHSP60-1) IgG and M. genitalium IgG antibodies. Women with borderline tumors (n=12), ovarian carcinoma (n=45), or other pelvic malignancies (n=11) were matched to four healthy controls each.

    RESULTS: Overall, there were no associations of antibodies with EOC. However, chlamydial HSP60-1 IgG antibodies were associated with type II ovarian cancer (P=.002) in women with plasma samples obtained >1 year prior to diagnosis (n=7). M. genitalium IgG antibodies were associated with borderline ovarian tumors (P=.01).

    CONCLUSION: Chlamydial HSP60-1 IgG and M. genitalium IgG antibodies are in this study associated with epithelial ovarian tumors in some subsets, which support the hypothesis linking upper-genital tract infections and ovarian tumor development.

  • 6.
    Idahl, Annika
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Jurstrand, Margaretha
    Kliniskt forskningscentrum, Örebro universitetssjukhus.
    Kumlin, Urban
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Elgh, Fredrik
    Hälsoakademin, Örebro universitet.
    Ohlson, Nina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Ottander, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Chlamydia trachomatis and Mycoplasma genitalium plasma antibodies in relation to epithelial ovarian tumorsArticle in journal (Other academic)
  • 7.
    Israelsson, Pernilla
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Labani-Motlagh, Alireza
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Nagaev, Ivan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Dehlin, Eva
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Nagaeva, Olga
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Ottander, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Assessment of cytokine mRNA expression profiles in tumor microenvironment and peripheral blood mononuclear cells of patients with high-grade serous carcinoma of the ovary2017In: Journal of Cancer Science & Therapy, ISSN 1948-5956, Vol. 9, no 5, p. 422-429Article in journal (Refereed)
    Abstract [en]

    Objective: Tumor establishment, metastatic spreading and poor survival in ovarian cancer is strongly associated with progressive derangement of the patient’s immune system. Accumulating evidence suggests that immune impairment is influenced by the production and presence of cytokines in the tumor microenvironment. Methods: Cytokine mRNA profiles in tumor tissue and peripheral blood mononuclear cells (PBMC) were analyzed in patients with high grade serous carcinoma (HGSC) of the ovary and compared it to patients with benign ovarian conditions and controls with normal ovaries. Cytokine assessment was done by real-time quantitative RT-PCR and specific primers and probes for 12 cytokines-IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-15, TNF-α, TNF-β/LTA, TGF-β1, and GM-CSF chosen to distinguish between cytotoxic Th1, humoral Th2, regulatory Th3/Tr1 and inflammatory responses. Results: The cytokine mRNA response in the HGSC patients was significantly up regulated compared to patients with benign ovarian conditions and normal ovary controls confirming the immunogenicity of HGSC and implying immune recognition and reaction locally in the tumor microenvironment and systemically in the peripheral blood.There was an up-regulation of inflammatory and inhibitory cytokine mRNA promoting tumor progression, T-regulatory cell priming and T-regulatory cell-mediated immune suppression. In contrast, there was an inability to mount the crucially important IFN gamma response needed for upregulation of the cytotoxic anti-tumor response in the local microenvironment. In addition, systemic IL-4- mediated Th2 response prevailed in the peripheral blood deviating the systemic defense towards humoral immunity. Conclusions: Taken together, these results suggest local and systemic cytokine cooperation promoting tumor survival, progression and immune escape. Our study confirms and extends previous investigations and contributes to the evaluation of potential cytokine candidates for diagnostic cytokine mRNA profiles and for future therapeutic interventions based on cytokine inhibition.

  • 8.
    Jagarlamudi, Krishna
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Liu, Lian
    Department of Chemotherapy, Cancer Center, Qilu Hospital, Shandong University, Jinan, China.
    Adhikari, Deepak
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Reddy, Pradeep
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Ottander, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Liu, Kui
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Oocyte-specific deletion of Pten in mice reveals a stage-specific function of PTEN/PI3K signaling in oocytes in controlling follicular activation2009In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 4, no 7, p. e6186-Article in journal (Refereed)
    Abstract [en]

    Immature ovarian primordial follicles are essential for maintenance of the reproductive lifespan of female mammals. Recently, it was found that overactivation of the phosphatidylinositol 3-kinase (PI3K) signaling in oocytes of primordial follicles by an oocyte-specific deletion of Pten (phosphatase and tensin homolog deleted on chromosome ten), the gene encoding PI3K negative regulator PTEN, results in premature activation of the entire pool of primordial follicles, indicating that activation of the PI3K pathway in oocytes is important for control of follicular activation. To investigate whether PI3K signaling in oocytes of primary and further developed follicles also plays a role at later stages in follicular development and ovulation, we conditionally deleted the Pten gene from oocytes of primary and further developed follicles by using transgenic mice expressing zona pellucida 3 (Zp3) promoter-mediated Cre recombinase. Our results show that Pten was efficiently deleted from oocytes of primary and further developed follicles, as indicated by the elevated phosphorylation of the major PI3K downstream component Akt. However, follicular development was not altered and oocyte maturation was also normal, which led to normal fertility with unaltered litter size in the mutant mice. Our data indicate that properly controlled PTEN/PI3K-Akt signaling in oocytes is essential for control of the development of primordial follicles whereas overactivation of PI3K signaling in oocytes does not appear to affect the development of growing follicles. This suggests that there is a stage-specific function of PTEN/PI3K signaling in mouse oocytes that controls follicular activation.

  • 9.
    Labani-Motlagh, Alireza
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Israelsson, Pernilla
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Ottander, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Nagaev, Ivan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Nagaeva, Olga
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Dehlin, Eva
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Baranov, Vladimir
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Differential expression of ligands for NKG2D and DNAM-1 receptors by epithelial ovarian cancer-derived exosomes and its influence on NK cell cytotoxicity2016In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 37, no 4, p. 5455-5466Article in journal (Refereed)
    Abstract [en]

    Cancers constitutively produce and secrete into the blood and other biofluids 30-150 nm-sized endosomal vehicles called exosomes. Cancer-derived exosomes exhibit powerful influence on a variety of biological mechanisms to the benefit of the tumors that produce them. We studied the immunosuppressive ability of epithelial ovarian cancer (EOC) exosomes on two cytotoxic pathways of importance for anticancer immunity-the NKG2D receptor-ligand pathway and the DNAM-1-PVR/nectin-2 pathway. Using exosomes, isolated from EOC tumor explant and EOC cell-line culture supernatants, and ascitic fluid from EOC patients, we studied the expression of NKG2D and DNAM-1 ligands on EOC exosomes and their ability to downregulate the cognate receptors. Our results show that EOC exosomes differentially and constitutively express NKG2D ligands from both MICA/B and ULBP families on their surface, while DNAM-1 ligands are more seldom expressed and not associated with the exosomal membrane surface. Consequently, the NKG2D ligand-bearing EOC exosomes significantly downregulated the NKG2D receptor expression on peripheral blood mononuclear cells (PBMC) while the DNAM-1 receptor was unaffected. The downregulation of NKG2D receptor expression was coupled to inhibition of NKG2D receptor-ligand-mediated degranulation and cytotoxicity measured in vitro with OVCAR-3 and K562 cells as targets. The EOC exosomes acted as a decoy impairing the NKG2D mediated cytotoxicity while the DNAM-1 receptor-ligand system remained unchanged. Taken together, our results support and explain the mechanism behind the recently reported finding that in EOC, NK-cell recognition and killing of tumor cells was mainly dependent on DNAM-1 signaling while the contribution of the NKG2D receptor-ligand pathway was complementary and uncertain.

  • 10. Liu, Lian
    et al.
    Rajareddy, Singareddy
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Reddy, Pradeep
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Jagarlamudi, Krishna
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Du, Chun
    Shen, Yan
    Guo, Yongzhi
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Boman, Karin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Lundin, Eva
    Patologi.
    Ottander, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Selstam, Gunnar
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Liu, Kui
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Phosphorylation and inactivation of glycogen synthase kinase-3 by soluble kit ligand in mouse oocytes during early follicular development.2007In: Journal of Molecular Endocrinology, ISSN 0952-5041, E-ISSN 1479-6813, Vol. 38, no 1-2, p. 137-146Article in journal (Refereed)
    Abstract [en]

    Communication between mammalian oocytes and their surrounding granulosa cells through the Kit-Kit ligand (KL, or stem cell factor, SCF) system has been shown to be crucial for follicular development. Our previous studies (Reddy et al. 2005, Liu et al. 2006) have indicated that the intra-oocyte KL-Kit-PI3 kinase (PI3K)-Akt-Foxo3a cascade may play an important role in follicular activation and early development. In the present study, using in situ hybridization and in vitro culture of growing oocytes from 8-day-old postnatal mice, we have demonstrated that another Akt substrate, glycogen synthase kinase-3 (GSK-3), is expressed in growing oocytes. Also, treatment of cultured mouse oocytes with soluble KL not only leads to increased Akt kinase activity in the oocytes, which can phosphorylate recombinant GSK-3 in vitro, but also leads to phosphorylation of oocyte GSK-3alpha and GSK-3beta, which can result in the inactivation of GSK-3 function in oocytes. In addition, we have shown that the regulation of GSK-3alpha and GSK-3beta in cultured oocytes by soluble KL is accomplished through PI3K, since the PI3K-specific inhibitor LY294002 completely abolished the KL-induced phosphorylation of GSK-3alpha and GSK-3beta. Moreover, blockage of the Kit signaling pathway by a Kit function-blocking antibody, ACK2, resulted in reduced phosphorylation of GSK-3. Taken together, our data suggest that the cascade from granulosa cell-derived KL to Kit-PI3K-Akt-GSK-3 in oocytes may take part in regulation of oocyte growth and early ovarian follicular development.

  • 11.
    Ofverman, Charlotte
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Stefansson, Kristina
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Ottander, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Lindquist, David
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    CASE SERIES OF PATIENTS WITH LEIOMYOSARCOMA OF THE UTERUS TREATED WITH TRABECTEDIN IN NORTHERN SWEDEN2016In: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 26, no Supplement 3, p. 1046-1046, article id IGCS-0142Article in journal (Refereed)
  • 12.
    Olofsson, Jan I
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Poromaa, I S
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Ottander, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Kjellberg, Lennart
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Damber, M G
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Clinical and pregnancy outcome following ectopic pregnancy: a prospective study comparing expectancy, surgery and systemic methotrexate treatment2001In: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412, Vol. 80, no 8, p. 744-749Article in journal (Refereed)
    Abstract [en]

    Systemic single-dose methotrexate treatment is a safe treatment option with a reasonably high success rate, with similar probability of a later intrauterine pregnancy as conventional surgical treatment.

  • 13.
    Ottander, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Intraovarian mechanisms influencing the human corpus luteum2000Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Introduction: The human corpus luteum (CL) is a transient endocrine gland, only functionally active for about 14 days. Its principal function is to produce and secrete progesterone and thereby support the endometrium for implantation of a blastocyst and prevent rejection of the developing embryo. In the event of a non-conceptive cycle, functional and structural demise of the CL follows and a new ovulatory cycle begins. The aims of the thesis were to study different mechanisms involved in the extrinsic and intrinsic regulation of the CL and correlate these findings to available clinical investigations tools.

    Materials and methods: Sixty women volunteered to donate their CL prior to scheduled surgery due to benign conditions. They were grouped according to CL-age, based on the occurrence of a preovulatory luteinizing hormone (LH) surge where days 2-5 post LH surge were designated as early luteal phase, days 6-9 as mid luteal phase and days 11-14 as late luteal phase. The CL bearing ovary was investigated using transvaginal ultrasonographical B-mode and color Doppler imaging prior to surgery. Following excision, the CL was further characterized using anatomical and morphological measurements, in vivo and in vitro hormone synthesis, isolation and cultures of steroidogenic luteal cells. Moreover, active transcription of putative regulatory genes of interest was targeted using semi-quantitative reverse-transcription polymerase chain reaction, in situ hybridization and Northern blots, and these genes' respective translation products were characterized by immunocytochemistry.

    Results: The bulk of progesterone is stimulated by human chorionic gonadotropin (hCG) in the peripheral (steroidogenic) layer of the CL, where the LH/hCG receptor, as well as progesterone receptor (PR) isoform A/B and estrogen receptor type β (ER-β), but not ER-α, was localized. The sesitivity towards hCG was highest during the mid luteal phase in concordance with the value of LH/hCG receptor coding mRNAs. During this phase, despite low levels of PR-B mRNA, hCG treatment initiated a significant rise in progesterone output which could be blunted by the PR antagonist mifepristone. Increased amounts of prostaglandin (PG) F and its respective receptor (FP) mRNA were detected during the later developmental stages of the CL. However, steroidogenic luteal cells were unresponsive to added PGF until late luteal phase, indicative of an acquisition of sensitivity to the proposed luteolytic signal during this stage. Intraluteal vascular density was highest in early luteal phase and dramatically decreased during the course of CL development, a finding which was inversely correlated to resistance to blood flow in intraovarian blood vessels supplying the CL. Furthermore, a high degree of agreement between ultrasonographical and anatomical measurements of the CL was found.

    Conclusions: Based on the novel findings herein, the hypothesis of steroid influence, acting within or near the steroidogenic luteal cells is confirmed. Alongside the classical extrinsic signals (e.g. hCG) and locally produced factors (e.g. PGF) these findings may further explain their modulatory roles during luteolysis or very early pregnancy. Furthermore, transvaginal ultrasonography in combination with color Doppler measurements may serve as a clinical tool to evaluate CL function.

  • 14.
    Ottander, Ulrika
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Högberg, Ulf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Löfgren, Mats
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    [A case report. Sepsis in connection with levonorgestrel IUD]1995In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 92, no 48, p. 4555-4557Article in journal (Refereed)
  • 15.
    Ottander, Ulrika
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Hosokawa, Kenichi
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Liu, Kui
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Ny, Tor
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Olofsson, Jan I
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    A putative stimulatory role of progesterone acting via progesterone receptors in the steroidogenic cells of the human corpus luteum2000In: Biology of Reproduction, ISSN 0006-3363, E-ISSN 1529-7268, Vol. 62, no 3, p. 655-663Article in journal (Refereed)
    Abstract [en]

    To further explore the proposed auto-regulatory role of progesterone action in the human corpus luteum (CL), the expression and functional roles of progesterone receptor (PR) isoforms A and B during the luteal phase (LP) of the menstrual cycle were investigated. A total of 27 otherwise healthy patients previously scheduled for surgery were recruited after informed consent. An LH rise was detected, and CL were grouped according to age (Days 2-5 post-LH-rise, early LP; Days 6-10, mid LP; Days 11-14, late LP). Using a semiquantitative reverse transcription-polymerase chain reaction assay, the PR-B mRNA levels, which were 100- to 1000-fold lower than PR-A/B mRNA, were 46% lower (P < 0.05, n = 24) in mid LP, compared to early and late LP. CL tissue levels of progesterone and PR-A/B protein levels were inversely correlated to increasing CL age; i.e., significantly reduced levels were observed in the late LP (r(2) = 0.34, P < 0.01, n = 23). Expression of PR-A/B mRNA as well as PR-A/B protein were detected by in situ hybridization and immunohistochemistry, respectively. Both methods revealed a clear and distinct localization to cells in the steroidogenic layer of the CL. Freshly obtained mid-luteal CL cells were cultured in vitro, and media were analyzed for progesterone concentrations after treatment by incremental doses of hCG and the stable PR antagonist mifepristone, alone or in combination. Mifepristone did not per se alter progesterone synthesis, but when it was added in conjunction with hCG, a dose-related inhibitory response was seen, with a maximal 47% reduction in progesterone output at a 10 microM addition (P < 0.05, n = 3). Collectively, these data implicate a stimulatory role of progesterone receptor-mediated action in the steroidogenic cells of the human CL, which may serve as an important pathway for maintaining functional homeostasis during early pregnancy.

  • 16.
    Ottander, Ulrika
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Leung, Constant HB
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Olofsson, Jan I
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Functional evidence for divergent receptor activation mechanisms of luteotrophic and luteolytic events in the human corpus luteum1999In: Molecular human reproduction, ISSN 1360-9947, E-ISSN 1460-2407, Vol. 5, no 5, p. 391-395Article in journal (Refereed)
    Abstract [en]

    Using a dispersed human luteal cell culture model, progesterone synthesis following treatment by incremental doses of human chorionic gonadotrophin (HCG) and the stable prostaglandin F2alpha (PGF2alpha) analogue cloprostenol, alone or in combination, was related to corpora lutea (CL) mRNA transcript abundance coding for the luteinizing hormone (LH)/HCG receptor (LH-R) and PGF2alpha-receptor (FP) by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) in 33 otherwise healthy women, scheduled for surgery due to benign conditions. CL were grouped according to age, based on the occurrence of a preovulatory LH surge where post-LH days 2-5 were designated as early luteal phase, days 6-10 as mid-luteal phase and days 11-14 as late luteal phase. When exposed to HCG, maximal progesterone output was raised 2.2-fold (P = 0.08, n = 5) compared with untreated controls in the early CL, while it increased 5.7- and 4.6-fold in the mid- and late groups respectively (P<0.05, n = 4 mid-luteal phase, n = 3 late luteal phase). This stimulation pattern was found to be concordant with the value of mRNA coding for LH-R in all groups (n = 6 early luteal phase, n = 5 mid-luteal phase, n = 6 late luteal phase). The integrated response to HCG and cloprostenol showed a dose-dependent 60% inhibition of progesterone production; but only in late luteal phase luteal cells (P<0.01, n = 3). FP mRNA values were lowest in early luteal phase, and increased with the age of the CL. Interestingly, lowest CL tissue concentrations of the natural FP agonist PGF2alpha were found during mid-luteal phase while it increased again 1.6-fold during late luteal phase (P<0.05, n = 8 versus mid-luteal phase, n = 6). Collectively, these data demonstrate that (i) the extrinsic functional control (or rescue of CL in the event of pregnancy) occurs when the sensitivity towards LH/HCG is maximal; and (ii) the demise of CL function is mediated via an acquisition of sensitivity towards the intrinsic luteolytic signal, PGF2alpha in the ageing CL.

  • 17.
    Ottander, Ulrika
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Nakata, M
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Liu, K
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Ny, Tor
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Olofsson, J I
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Compartmentalization of human chorionic gonadotrophin sensitivity and luteinizing hormone receptor mRNA in different subtypes of the human corpus luteum1997In: Human Reproduction, ISSN 0268-1161, E-ISSN 1460-2350, Vol. 12, no 5, p. 1037-1042Article in journal (Refereed)
    Abstract [en]

    The relationship was investigated between different ultrasonographically defined subtypes of the human corpus luteum and progesterone production. Twenty-one women in the mid-luteal phase who underwent laparotomy for benign uterine conditions volunteered for this study. The corpus luteum was identified by preoperative ultrasound and classified into four types according to earlier established criteria, where types a and c were centrally hypoechoic, types b and d were centrally echogenic, types a and b had thin surrounding 'walls' (<3 mm) and types c and d had thick walls (<3 mm). After luteectomy, the theca externa capsule was removed and tissue from directly beneath the surface ('peripheral region') and the layer immediately beneath ('inner region') minced into 4-6 mg pieces. Following preincubation, pieces were incubated for 3 h at 37 degrees C in HEPES-minimal essential medium buffer with or without human chorionic gonadotrophin (HCG; 10 IU/ml), and subsequently progesterone accumulation in the medium was determined by radioimmunoassay. The highest progesterone production was consistently seen in the peripheral region. Type a had a significantly (P > 0.01) lower progesterone production (3.2 +/- 1.5 nmol/g tissue wet weight, mean +/- SEM, n = 4) than that of types b, c and d (17.7 +/- 3.5 nmol/g tissue wet weight, n = 9). All types responded to HCG with an almost two-fold increase in progesterone production. However, the maximal progesterone produced following stimulation by HCG in the type a corpus luteum was <50% of the basal (unstimulated) progesterone synthesis of any other type of corpus luteum. Using in-situ hybridization, with a primate RNA probe complementary to the region coding the extracellular part of the luteinizing hormone (LH) receptor, a highly localized expression of LH receptor mRNA to the peripheral region was found. Negligible or low levels of expression were found in the theca externa capsule and the inner region. No obvious correlations between the different subtypes of corpora lutea and LH receptor mRNA expression were seen. Thus, the ultrasonographic detection of a thin-walled and centrally hypoechoic corpus luteum correlates well with reduced progesterone secretion. The underlying cellular mechanism does not appear to involve a diminished sensitivity to the gonadotrophic stimulation by LH or HCG.

  • 18.
    Ottander, Ulrika
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Poromaa, Inger Sundström
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bjurulf, Erik
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Skytt, Asa
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Olofsson, Jan I
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Allopregnanolone and pregnanolone are produced by the human corpus luteum.2005In: Mol Cell Endocrinol, ISSN 0303-7207, Vol. 239, no 1-2, p. 37-44Article in journal (Refereed)
  • 19.
    Ottander, Ulrika
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Solensten, Nils Gunnar
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Olofsson, Jan I
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Intraovarian blood flow measured with color doppler ultrasonography inversely correlates with vascular density in the human corpus luteum of the menstrual cycle2004In: Fertility and Sterility, ISSN 0015-0282, E-ISSN 1556-5653, Vol. 81, no 1, p. 154-159Article in journal (Refereed)
    Abstract [en]

    Objective

    To evaluate the morphologic characteristics underlying the ultrasonographic appearance and blood flow dynamics in the human corpus luteum (CL) of the menstrual cycle.

    Design

    Cross-sectional study.

    Setting

    Umeå University Hospital, Umeå, Sweden.

    Patient(s)

    Twenty-six otherwise healthy women with proven fertility and a history of regular menstrual cycles, scheduled for elective hysterectomy or tubal sterilization.

    Intervention(s)

    An ovulatory LH rise in urine was established and the CL age was determined according to the day after the LH rise. Before surgery, a standardized ultrasonographic examination of the CL, including B-mode and color Doppler ultrasonography measurements, was performed. Upon commencing the minilaparotomy, the CL was excised and measured using a digital slide-caliper. The volume density (percentage of CL volume occupied by blood vessels) of factor VIII–related antigen immunostained endothelial cells was determined.

    Main outcome measure(s)

    Pulsatility index obtained from intraovarian blood vessels supplying the CL and volume density of blood vessels in CL tissue. The CL maximal and minimal outer and inner dimensions were measured in vivo by ultrasonography and ex vivo by a digital slide caliper.

    Result(s)

    A statistically significant decrease of blood vessel density and an increased resistance to blood flow, as indicated by pulsatility index, was established during the course of corpus luteum development. An inverse correlation between pulsatility index and volume density of blood vessels was found. A high degree of agreement between ultrasonographic and anatomic measurements of surgically removed CL was found.

    Conclusion(s)

    Transvaginal ultrasonography in combination with intraovarian color Doppler flow measurements is a simple and reliable method to evaluate the size and vascularization of the human CL.

  • 20.
    Reddy, Pradeep
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Liu, Lian
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Ren, Chong
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Lindgren, Peter
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Boman, Karin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Shen, Yan
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Ottander, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Rytinki, Miia
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Liu, Kui
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Formation of E-cadherin-mediated cell-cell adhesion activates AKT and mitogen activated protein kinase via phosphatidylinositol 3 kinase and ligand-independent activation of epidermal growth factor receptor in ovarian cancer cells2005In: Mol Endocrinol, ISSN 0888-8809, Vol. 19, no 10, p. 2564-2578Article in journal (Refereed)
  • 21.
    Reddy, Pradeep
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Shen, Lijun
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Ren, Chong
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Boman, Karin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Ottander, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Lindgren, Peter
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Liu, Yi-Xun
    Sun, Qing-Yuan
    Liu, Kui
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Activation of Akt (PKB) and suppression of FKHRL1 in mouse and rat oocytes by stem cell factor during follicular activation and development2005In: Dev Biol, ISSN 0012-1606, Vol. 281, no 2, p. 160-170Article in journal (Refereed)
  • 22.
    Vaskivuo, Tommi E
    et al.
    Department of Obstetrics and Gynecology, University of Oulu, Oulu, Finland.
    Ottander, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Oduwole, Olayiwola
    Research Center for Molecular Endocrinology, WHO Collaborating Center, University of Oulu, Oulu, Finland.
    Isomaa, Veli
    Research Center for Molecular Endocrinology, WHO Collaborating Center, University of Oulu, Oulu, Finland.
    Vihko, Pirkko
    Research Center for Molecular Endocrinology, WHO Collaborating Center, University of Oulu, Oulu, Finland.
    Olofsson, Jan I
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Tapanainen, Juha S
    Department of Obstetrics and Gynecology, University of Oulu, Oulu, Finland.
    Role of apoptosis, apoptosis-related factors and 17beta-hydroxysteroid dehydrogenases in human corpus luteum regression2002In: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 194, no 1-2, p. 191-200Article in journal (Refereed)
    Abstract [en]

    The human corpus luteum (CL) is a transient endocrine organ with a life span of 14-16 days. Apoptosis has been suggested to be the mechanism of CL regression and the possible regulatory role of the bcl-2 family in this process has been studied in animals and, to some extent, in humans. In the present study, apoptosis was studied in the human CL and in luteinised granulosa cells by in situ 3'-end labelling and gel electrophoretic DNA fragmentation analysis. The apoptosis-regulating factors Bcl-2, Bax and TNF-alpha, transcription factor NF-kappaB and Caspase-3, a key executioner protein in apoptotic cell death, were studied by immunohistochemistry and in situ hybridisation. Furthermore, we analysed expression of 17beta hydroxysteroid dehydrogenase (17HSD) type 1 and 2, key enzymes in the estrogen metabolism. Apoptosis was found in the CL throughout the luteal phase, but a marked increase of apoptotic luteal cells was observed during the late luteal phase (CL day 11-14). This was preceded by a clear increase of 17HSD type 1 expression. The apoptosis-regulating proteins Bcl-2 and Bax were expressed constantly in the CL throughout the luteal phase. TNF-alpha expression was constant during the early and mid-luteal phases, but in the late luteal phase, some specimens showed increased immunostaining. NF-kappaB and Caspase-3 were present in the CL throughout the luteal phase and in individual specimens, the expression of Caspase-3 was associated with a high rate of apoptosis in the late luteal phase. In conclusion, apoptosis is involved in human luteal regression and estradiol (E(2)) may function as a trigger for this process. The expression of the pro- and anti-apoptotic factors studied in the CL suggest their part in this process, but the conclusive evidence for the exact molecular mechanisms remains open.

  • 23.
    Vinnars, Marie-Therese
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Björk, Emma
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Nagaev, Ivan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Ottander, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Bremme, Katarina
    Holmlund, Ulrika
    Sverremark-Ekström, Eva
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Enhanced Th1 and inflammatory mRNA responses upregulate NK cell cytotoxicity and NKG2D ligand expression in human pre-eclamptic placenta and target it for NK cell attack2018In: American Journal of Reproductive Immunology, ISSN 1046-7408, E-ISSN 1600-0897, Vol. 80, no 1, article id e12969Article in journal (Refereed)
    Abstract [en]

    Problem: Pre-eclampsia (PE), a severe human pregnancy disorder, is associated with exaggerated systemic inflammation, enhanced cytokine production, and increased shedding of microvesicles leading to endothelial dysfunction, coagulopathy, and extensive placenta destruction. The cause of PE is still unclear. Evidence suggests that its origin lies in the placenta and that the maternal immune system is involved. A shift in cytokine production in PE pregnancy promotes NK cell activation, suggested to be important in PE pathogenesis. In line with this suggestion, we studied NK cell cytotoxicity in peripheral blood of PE patients and controls and the mRNA expression of cytokines and of the NKG2D receptor and its ligands MICA/B and ULBP1-3 in PE- and normal placenta.

    Method of study: The cytotoxic capacity of peripheral blood NK cells was analyzed using K562 target cells. The cytokine mRNA profiles and the mRNA expression of the NKG2D receptor and its ligands MICA/B and ULBP 1-3 in PE placenta were assessed and compared to those in normal placenta using real-time quantitative RT-PCR.

    Results: The cytotoxicity of peripheral blood NK cells was upregulated in PE cases. Further, we found an enhanced inflammatory cytokine mRNA response combined with a dysregulated regulatory response and a significant mRNA overexpression of NKG2D receptor and its ligands MICA/B and ULBP in PE placenta.

    Conclusion: The destruction of chorionic villi observed in PE placenta might be conveyed by an enhanced local cytotoxic response through the NKG2D receptor-ligand pathway, which in turn might be promoted by an intense inflammatory response not counteracted by regulatory cytokine responses.

1 - 23 of 23
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