Publications by authors named "Sabine Dekan"

20 Publications

  • Page 1 of 1

PD-1 and PD-L1 expression on TILs in peritoneal metastases compared to ovarian tumor tissues and its associations with clinical outcome.

Sci Rep 2021 03 18;11(1):6400. Epub 2021 Mar 18.

Department of Obstetrics and Gynecology, Comprehensive Cancer Center (CCC), Medical University of Vienna, Vienna, Austria.

The therapeutic potential of immune checkpoint inhibitors is currently being investigated in epithelial ovarian cancer (EOC), but immunological effects of the programmed cell death protein 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) axis in EOC still remain poorly understood. The aim of this study was thus to compare infiltration rates of PD-1 and PD-L1 expressing tumor infiltrating leucocytes (TILs) in primary ovarian tumor tissue and metastatic intraperitoneal implants and to investigate its impact on overall survival (OS). Tumor specimens (ovarian tumor tissues and intraperitoneal metastases) of 111 patients were used to investigate the PD-1, PD-L1 and CD8 expression rates on TILs and PD-L1 expression rate of tumor cells. The percentages of CD8, PD-1, and PD-L1 expressing subpopulations of TILs differ in primary ovarian tumor tissues and metastatic intraperitoneal implants. High PD-1 among TILs in peritoneal metastases were associated with favorable OS. High PD-L1 expression in TILs was associated with poor OS. Combining both factors in peritoneal metastases revealed an unfavorable prognosis. Primary ovarian tumor tissue and intraperitoneal metastatic tissues in EOC might have different strategies to evade immune control. Those findings are of importance for the process of biomarker assessment to predict patients' response to immunotherapy.
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http://dx.doi.org/10.1038/s41598-021-85966-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973418PMC
March 2021

RANK links thymic regulatory T cells to fetal loss and gestational diabetes in pregnancy.

Nature 2021 01 23;589(7842):442-447. Epub 2020 Dec 23.

Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna, Austria.

Successful pregnancies rely on adaptations within the mother, including marked changes within the immune system. It has long been known that the thymus, the central lymphoid organ, changes markedly during pregnancy. However, the molecular basis and importance of this process remain largely obscure. Here we show that the osteoclast differentiation receptor RANK couples female sex hormones to the rewiring of the thymus during pregnancy. Genetic deletion of Rank (also known as Tnfrsf11a) in thymic epithelial cells results in impaired thymic involution and blunted expansion of natural regulatory T (T) cells in pregnant female mice. Sex hormones, in particular progesterone, drive the development of thymic T cells through RANK in a manner that depends on AIRE medullary thymic epithelial cells. The depletion of Rank in the mouse thymic epithelium results in reduced accumulation of natural T cells in the placenta, and an increase in the number of miscarriages. Thymic deletion of Rank also results in impaired accumulation of T cells in visceral adipose tissue, and is associated with enlarged adipocyte size, tissue inflammation, enhanced maternal glucose intolerance, fetal macrosomia, and a long-lasting transgenerational alteration in glucose homeostasis, which are all key hallmarks of gestational diabetes. Transplantation of T cells rescued fetal loss, maternal glucose intolerance and fetal macrosomia. In human pregnancies, we found that gestational diabetes also correlates with a reduced number of T cells in the placenta. Our findings show that RANK promotes the hormone-mediated development of thymic T cells during pregnancy, and expand the functional role of maternal T cells to the development of gestational diabetes and the transgenerational metabolic rewiring of glucose homeostasis.
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http://dx.doi.org/10.1038/s41586-020-03071-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116618PMC
January 2021

Densities of decidual high endothelial venules correlate with T-cell influx in healthy pregnancies and idiopathic recurrent pregnancy losses.

Hum Reprod 2020 11;35(11):2467-2477

Department of Obstetrics and Gynecology, Reproductive Biology Unit, Medical University of Vienna, Vienna, Austria.

Study Question: Do high endothelial venules (HEVs) appear in the uterus of healthy and pathological pregnancies?

Summary Answer: Our study reveals that HEVs are present in the non-pregnant endometrium and decidua parietalis (decP) but decline upon placentation in decidua basalis (decB) and are less abundant in decidual tissues from idiopathic, recurrent pregnancy losses (RPLs).

What Is Known Already: RPL is associated with a compromised decidual vascular phenotype.

Study Design, Size, Duration: Endometrial (n = 29) and first trimester decidual (n = 86, 6-12th week of gestation) tissue samples obtained from endometrial biopsies or elective pregnancy terminations were used to determine the number of HEVs and T cells. In addition, quantification of HEVs and immune cells was performed in a cohort of decidual tissues from RPL (n = 25).

Participants/materials, Setting, Methods: Position and frequency of HEVs were determined in non-pregnant endometrial as well as decidual tissue sections using immunofluorescence (IF) staining with antibodies against E-selectin, intercellular adhesion molecule, von Willebrand factor, ephrin receptor B4, CD34 and a carbohydrate epitope specific to HEVs (MECA-79). Immune cell distribution and characterization was determined by antibodies recognizing CD45 and CD3 by IF staining- and flow cytometry-based analyses. Antibodies against c-c motif chemokine ligand 21 (CCL21) and lymphotoxin-beta were used in IF staining and Western blot analyses of decidual tissues.

Main Results And The Role Of Chance: Functional HEVs are found in high numbers in the secretory endometrium and decP but decline in numbers upon placentation in decB (P ≤ 0.001). Decidua parietalis tissues contain higher levels of the HEV-maintaining factor lymphotoxin beta and decP-associated HEVs also express CCL21 (P ≤ 0.05), a potent T-cell chemoattractant. Moreover, there is a positive correlation between the numbers of decidual HEVs and the abundance of CD3+ cells in decidual tissue sections (P ≤ 0.001). In-depth analysis of a RPL tissue collection revealed a decreased decB (P ≤ 0.01) and decP (P ≤ 0.01) HEV density as well as reduced numbers of T cells in decB (P ≤ 0.05) and decP (P ≤ .001) sections when compared with age-matched healthy control samples. Using receiver-operating characteristics analyses, we found significant predictive values for the ratios of CD3/CD45 (P < 0.001) and HEVs/total vessels (P < 0.001) for the occurrence of RPL.

Limitations, Reasons For Caution: Analyses were performed in first trimester decidual tissues from elective terminations of pregnancy or non-pregnant endometrium samples from patients diagnosed with non-endometrial pathologies including cervical polyps, ovarian cysts and myomas. First trimester decidual tissues may include pregnancies which potentially would have developed placental disorders later in gestation. In addition, our cohort of non-pregnant endometrium may not reflect the endometrial vascular phenotype of healthy women. Finally, determination of immune cell distributions in the patient cohorts studied may be influenced by the different modes of tissue derivation. Pregnancy terminations were performed by surgical aspiration, endometrial tissues were obtained by biopsies and RPL tissues were collected after spontaneous loss of pregnancy.

Wider Implications Of The Findings: In this study, we propose an inherent mechanism by which the endometrium and in particular the decidua control T-cell recruitment. By demonstrating reduced HEV densities and numbers of T cells in decB and decP tissues of RPL samples we further support previous findings reporting an altered vascular phenotype in early pregnancy loss. Altogether, the findings provide important information to further decipher the etiologies of unexplained RPL.

Study Funding/competing Interest(s): This study was supported by the Austrian Science Fund (P31470 B30 to M.K.) and by the Austrian National Bank (17613ONB to J.P.). There are no competing interests to declare.

Trial Registration Number: N/A.
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http://dx.doi.org/10.1093/humrep/deaa234DOI Listing
November 2020

Markers of vitality in ovaries of transmen after long-term androgen treatment: a prospective cohort study.

Mol Med 2020 09 5;26(1):83. Epub 2020 Sep 5.

Department of Obstetrics and Gynecology, Clinical Division of Gynecologic Endocrinology and Reproductive Medicine, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria.

Background: Gender-affirming hormone therapy has been hypothesized to reduce the patient's reproductive potential in transmen, although the exact long-term effects on future fertility are unknown.

Methods: In this prospective cohort study we aimed to evaluate ovaries of 20 transmen by using hormone serum levels, histomorphological analysis and fluorescence activated cells sorting (FACS) analysis - in order to assess the amount of vital cells.

Results: The median total number of follicles per field of view was 39 (IQR 12-122). Of all follicles (n = 1661), the vast majority was primordial (n = 1505, 90.6%), followed by primary (n = 76, 4.6%), abnormal (n = 63, 3.8%) and secondary follicles (n = 17, 1.0%). FACS analysis was available for 13 samples (65.0%) and the median frequency of vital cells was 87.5% (IQR, 77.7-95.4%). Both a higher age (p = 0.032) and a lower BMI (p = 0.003) were significantly associated with a higher frequency of vital cells.

Conclusion: The majority of ovarian cells after long-term androgen treatment were vital in FACS analysis and histomorphological evaluation revealed a normal cortical follicle distribution. These results are currently exploratory, but might be promising for issues on fertility preservation.

Trial Registration: The study was approved by the ethics committee of the Medical University of Vienna (EK 2240/2016) and was retrospectively registered in the Current Controlled Trials Register (registration number NCT03649087 , date of registration: 28.08.2018).
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http://dx.doi.org/10.1186/s10020-020-00214-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487795PMC
September 2020

A Global Gene Body Methylation Measure Correlates Independently with Overall Survival in Solid Cancer Types.

Cancers (Basel) 2020 Aug 12;12(8). Epub 2020 Aug 12.

Department of Obstetrics and Gynecology, Comprehensive Cancer Center (CCC) Vienna, Medical University of Vienna, 1090 Vienna, Austria.

Epigenetics, CpG methylation of CpG islands (CGI) and gene bodies (GBs), plays an important role in gene regulation and cancer biology, the former established as a transcription regulator. Genome wide CpG methylation, summarized over GBs and CGIs, was analyzed for impact on overall survival (OS) in cancer. The averaged GB and CGI methylation status of each gene was categorized into methylated and unmethylated (defined) or undefined. Differentially methylated GBs and genes associated with their GB methylation status were compared to the corresponding CGI methylation states and biologically annotated. No relevant correlations of GB and CGI methylation or GB methylation and gene expression were observed. Summarized GB methylation showed impact on OS in ovarian, breast, colorectal, and pancreatic cancer, and glioblastoma, but not in lung cancer. In ovarian, breast, and colorectal cancer more defined GBs correlated with unfavorable OS, in pancreatic cancer with favorable OS and in glioblastoma more methylated GBs correlated with unfavorable OS. The GB methylation of genes were similar over different samples and even over cancer types; nevertheless, the clustering of different cancers was possible. Gene expression differences associated with summarized GB methylation were cancer specific. A genome-wide dysregulation of gene-body methylation showed impact on the outcome in different cancers.
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http://dx.doi.org/10.3390/cancers12082257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464642PMC
August 2020

NECTIN4 (PVRL4) as Putative Therapeutic Target for a Specific Subtype of High Grade Serous Ovarian Cancer-An Integrative Multi-Omics Approach.

Cancers (Basel) 2019 May 20;11(5). Epub 2019 May 20.

Section for Clinical Biometrics, Center for Medical Statistics, Informatics, and Intelligent Systems (CeMSIIS), Medical University of Vienna, 1090 Vienna, Austria.

In high grade serous ovarian cancer patients with peritoneal involvement and unfavorable outcome would benefit from targeted therapies. The aim of this study was to find a druggable target against peritoneal metastasis. We constructed a planar-scale free small world-co-association gene expression network and searched for clusters with hub-genes associated to peritoneal spread. Protein expression and impact was validated via immunohistochemistry and correlations of deregulated pathways with comprehensive omics data were used for biological interpretation. A cluster up-regulated in miliary tumors with NECTIN4 as hub-gene was identified and impact on survival validated. High Nectin 4 protein expression was associated with unfavorable survival and (i) reduced expression of HLA genes (mainly MHC I); (ii) with reduced expression of genes from chromosome 22q11/12; (iii) higher BCAM in ascites and in a high-scoring expression cluster; (iv) higher Kallikrein gene and protein expressions; and (v) substantial immunologic differences; locally and systemically; e.g., reduced CD14 positive cells and reduction of different natural killer cell populations. Each three cell lines with high (miliary) or low NECTIN4 expression (non-miliary) were identified. An anti-Nectin 4 antibody with a linked antineoplastic drug-already under clinical investigation-could be a candidate for a targeted therapy in patients with extensive peritoneal involvement.
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http://dx.doi.org/10.3390/cancers11050698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562934PMC
May 2019

Pregnancy-associated diamine oxidase originates from extravillous trophoblasts and is decreased in early-onset preeclampsia.

Sci Rep 2018 04 20;8(1):6342. Epub 2018 Apr 20.

Department of Obstetrics and Gynaecology, Reproductive Biology Unit, Medical University of Vienna, Vienna, Austria.

Human extravillous trophoblast (EVT) invasion of the pregnant uterus constitutes a pivotal event for the establishment of the maternal-fetal interface. Compromised EVT function manifesting in inadequate arterial remodeling is associated with the severe pregnancy disorder early-onset preeclampsia (eoPE). Recent studies suggest that EVTs invade the entire uterine vasculature including arteries, veins and lymphatics in the first trimester of pregnancy. We therefore hypothesized that EVT-derived factors accumulate in the circulation of pregnant women early in gestation and may serve to predict eoPE. In contrast to published literature, we demonstrate that placenta-associated diamine oxidase (DAO) is not expressed by maternal decidual cells but solely by EVTs, especially when in close proximity to decidual vessels. Cultures of primary EVTs express and secret large amounts of bioactive DAO. ELISA measurements indicate a pregnancy-specific rise in maternal DAO plasma levels around gestational week (GW) 7 coinciding with vascular invasion of EVTs. Strikingly, DAO levels from eoPE cases were significantly lower (40%) compared to controls in the first trimester of pregnancy but revealed no difference at mid gestation. Furthermore, DAO-containing pregnancy plasma rapidly inactivates pathophysiologically relevant histamine levels. This study represents the first proof of concept suggesting EVT-specific signatures as diagnostic targets for the prediction of eoPE.
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http://dx.doi.org/10.1038/s41598-018-24652-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5910386PMC
April 2018

Extravillous trophoblast invasion of venous as well as lymphatic vessels is altered in idiopathic, recurrent, spontaneous abortions.

Hum Reprod 2017 06;32(6):1208-1217

Department of Obstetrics and Gynecology, Reproductive Biology Unit, Medical University of Vienna, Währinger Gürtel 18-20, 5Q, 1090 Vienna, Austria.

Study Question: Do extravillous trophoblasts (EVTs) invade non-arterial decidual vessels in healthy and pathological pregnancies?

Summary Answer: Our results reveal that trophoblast invasion of venous and lymphatic vessels is a frequent event during the first trimester of pregnancy and is compromised in  recurrent spontaneous abortion (RSA). In addition, the present data suggest that EVTs populate regional lymph nodes during pregnancy.

What Is Already Known: Human trophoblasts remodel and invade decidual spiral arteries. In addition, a recent report demonstrates that trophoblasts contact and invade decidual veins.

Study Design, Size, Duration: Tissue samples of human first trimester deciduae basalis (n = 54, 6th-13th weeks of gestation) obtained from elective pregnancy terminations were used to study trophoblast invasion into veins and lymphatics, in comparison to arteries. Age-matched cases of idiopathic, recurrent spontaneous abortions tissue samples (n = 23) were assessed for cell numbers of EVTs in these decidual vessels. In addition, lymph nodes of four pregnant women were analysed for the presence of EVTs.

Participants/materials, Setting, Methods: Localization, frequency and EVT-mediated targeting and invasion of arterial, venous as well as lymphatic vessels were determined in first trimester decidua basalis tissue sections using immunofluorescence staining with antibodies against CD31, CD34, ephrin B2 (EFNB2), ephrin receptor B4 (EPHB4), HLA-G, podoplanin, prospero-related homeobox 1 (Prox-1), alpha-smooth muscle actin 2 (ATCTA2), von willebrand factor (vWF) and proteoglycan 2 (PRG2). Arterial, venous and lymphatic-associated EVTs were further characterized according to their position in the vascular structure and classified as intramural (im) or intraluminal (il).

Main Results And The Role Of Chance: EVTs, specifically expressing PRG2, target and invade veins and lymphatics in first trimester decidua basalis since HLA-G+ trophoblast were detected in the vascular wall (intramural EVT, imEVTs) and in the lumen of these vessels (intraluminal EVT, ilEVTs). In total, 276 arteries, 793 veins and 113 lymphatics were analysed. While EVTs contact and invade arteries and veins to a similar extent we found that lymphatics are significantly less affected by EVTs (P = 0.001). Moreover, ilEVTs were detected in the lumen of venous and lymphatic vessels, whereas ilEVTs were only found occasionally in the lumen of arteries. Interestingly, RSA tissue sections contained significantly more arterial (P = 0.037), venous (P = 0.002) and lymphatic vessels (P < 0.001), compared to healthy controls. However, while RSA-associated arterial remodeling was unchanged (P = 0.39) the ratios of EVT-affected versus total number of veins (P = 0.039) and lymphatics (P < 0.001) were significantly lower in RSA compared to age-matched healthy decidual sections. Finally, HLA-G+/PRG2+/CD45-EVTs can be detected in regional lymph nodes of pregnant women diagnosed with cervical cancer.

Large Scale Data: N/A.

Limitations, Reasons For Caution: In this study, first trimester decidual tissues from elective terminations of pregnancies have been examined and used as a reference for healthy pregnancy. However, this collective may also include pregnancies which would have developed placental disorders later in gestation. Due to limitations in tissue availability our staining results for EVT-specific marker expression in regional lymph nodes of pregnant women are based on four cases only.

Wider Implications Of The Findings: In this study, we propose migration of HLA-G+ cells into regional lymph nodes during pregnancy suggesting that the human EVT is capable of infiltrating maternal tissues via the blood stream. Moreover, the description of compromised EVT invasion into the venous and lymphatic vasculature in RSA may help to better understand the pathological characteristics of idiopathic recurrent pregnancy loss.

Study Funding/competing Interest(s): This study was supported by the Austrian Science Fund (grant P-25187-B13 to J.P. and grant P-28417-B30 to M.K.). There are no competing interests to declare.
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http://dx.doi.org/10.1093/humrep/dex058DOI Listing
June 2017

Absence of PD-L1 on tumor cells is associated with reduced MHC I expression and PD-L1 expression increases in recurrent serous ovarian cancer.

Sci Rep 2017 03 7;7:42929. Epub 2017 Mar 7.

Section for Clinical Biometrics, Center for Medical Statistics, Informatics, and Intelligent Systems (CeMSIIS), Medical University of Vienna, Vienna, Austria.

Immune-evasion and immune checkpoints are promising new therapeutic targets for several cancer entities. In ovarian cancer, the clinical role of programmed cell death receptor ligand 1 (PD-L1) expression as mechanism to escape immune recognition has not been clarified yet. We analyzed PD-L1 expression of primary ovarian and peritoneal tumor tissues together with several other parameters (whole transcriptomes of isolated tumor cells, local and systemic immune cells, systemic cytokines and metabolites) and compared PD-L1 expression between primary tumor and tumor recurrences. All expressed major histocompatibility complex (MHC) I genes were negatively correlated to PD-L1 abundances on tumor tissues, indicating two mutually exclusive immune-evasion mechanisms in ovarian cancer: either down-regulation of T-cell mediated immunity by PD-L1 expression or silencing of self-antigen presentation by down-regulation of the MHC I complex. In our cohort and in most of published evidences in ovarian cancer, low PD-L1 expression is associated with unfavorable outcome. Differences in immune cell populations, cytokines, and metabolites strengthen this picture and suggest the existence of concurrent pathways for progression of this disease. Furthermore, recurrences showed significantly increased PD-L1 expression compared to the primary tumors, supporting trials of checkpoint inhibition in the recurrent setting.
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http://dx.doi.org/10.1038/srep42929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5339797PMC
March 2017

Epigenetic Alterations Affecting Transcription Factors and Signaling Pathways in Stromal Cells of Endometriosis.

PLoS One 2017 26;12(1):e0170859. Epub 2017 Jan 26.

Institute for Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York, United States of America.

Endometriosis is characterized by growth of endometrial-like tissue outside the uterine cavity. Since its pathogenesis may involve epigenetic changes, we used Illumina 450K Methylation Beadchips to profile CpG methylation in endometriosis stromal cells compared to stromal cells from normal endometrium. We validated and extended the Beadchip data using bisulfite sequencing (bis-seq), and analyzed differential methylation (DM) at the CpG-level and by an element-level classification for groups of CpGs in chromatin domains. Genes found to have DM included examples encoding transporters (SLC22A23), signaling components (BDNF, DAPK1, ROR1, and WNT5A) and transcription factors (GATA family, HAND2, HOXA cluster, NR5A1, OSR2, TBX3). Intriguingly, among the TF genes with DM we also found JAZF1, a proto-oncogene affected by chromosomal translocations in endometrial stromal tumors. Using RNA-Seq we identified a subset of the DM genes showing differential expression (DE), with the likelihood of DE increasing with the extent of the DM and its location in enhancer elements. Supporting functional relevance, treatment of stromal cells with the hypomethylating drug 5aza-dC led to activation of DAPK1 and SLC22A23 and repression of HAND2, JAZF1, OSR2, and ROR1 mRNA expression. We found that global 5hmC is decreased in endometriotic versus normal epithelial but not stroma cells, and for JAZF1 and BDNF examined by oxidative bis-seq, found that when 5hmC is detected, patterns of 5hmC paralleled those of 5mC. Together with prior studies, these results define a consistent epigenetic signature in endometriosis stromal cells and nominate specific transcriptional and signaling pathways as therapeutic targets.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0170859PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5268815PMC
August 2017

Integrative Systemic and Local Metabolomics with Impact on Survival in High-Grade Serous Ovarian Cancer.

Clin Cancer Res 2017 04 19;23(8):2081-2092. Epub 2016 Oct 19.

Section for Clinical Biometrics, Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria.

Cancer metabolism is characterized by alterations including aerobic glycolysis, oxidative phosphorylation, and need of fuels and building blocks. Targeted metabolomics of preoperative and follow-up sera, ascites, and tumor tissues, RNA sequencing of isolated tumor cells, local and systemic chemokine, and local immune cell infiltration data from up to 65 high-grade serous ovarian cancer patients and 62 healthy controls were correlated to overall survival and integrated in a Systems Medicine manner. Forty-three mainly (poly)unsaturated glycerophospholipids and four essential amino acids (citrulline) were significantly reduced in patients with short compared with long survival and healthy controls. The glycerophospholipid fingerprint is identical to the fingerprint from isolated (very) low-density lipoproteins (vLDL), indicating that the source of glycerophospholipids consumed by tumors is (v)LDL. A glycerophospholipid-score (HR, 0.46; = 0.007) and a 100-gene signature (HR, 0.65; = 0.004) confirmed the independent impact on survival in training ( = 65) and validation ( = 165) cohorts. High concentrations of LDLs and glycerophospholipids were independently predictors for favorable survival. Patients with low glycerophospholipids presented with more systemic inflammation (C-reactive protein and fibrinogen negatively and albumin positively correlated) but less adaptive immune cell tumor infiltration (lower tumor and immune cell PD-L1 expression), less oxygenic respiration and increased triglyceride biosynthesis in tumor cells, and lower histone expressions, correlating with higher numbers of expressed genes and more transcriptional noise, a putative neo-pluripotent tumor cell phenotype. Low serum phospholipids and essential amino acids are correlated with worse outcome in ovarian cancer, accompanied by a specific tumor cell phenotype. .
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http://dx.doi.org/10.1158/1078-0432.CCR-16-1647DOI Listing
April 2017

Small RNAs and the competing endogenous RNA network in high grade serous ovarian cancer tumor spread.

Oncotarget 2016 Jun;7(26):39640-39653

Department of Obstetrics and Gynecology, Comprehensive Center Center (CCC), Medical University of Vienna, Vienna, Austria.

High grade serous ovarian cancer (HGSOC) is among the most deadly malignancies in women, frequently involving peritoneal tumor spread. Understanding molecular mechanisms of peritoneal metastasis is essential to develop urgently needed targeted therapies. We described two peritoneal tumor spread types in HGSOC apparent during surgery: miliary (numerous millet-sized implants) and non-miliary (few big, bulky implants). The former one is defined by a more epithelial-like tumor cell characteristic with less immune cell reactivity and with significant worse prognosis, even if corrected for typical clinicopathologic factors.23 HGSOC patients were enrolled in this study. Isolated tumor cells from fresh tumor tissues of ovarian and peritoneal origin and from ascites were used for ribosomal RNA depleted RNA and small RNA sequencing. RT-qPCR was used to validate results and an independent cohort of 32 patients to validate the impact on survival. Large and small RNA sequencing data were integrated and a new gene-miRNA set analysis method was developed.Thousands of new small RNAs (miRNAs and piwi-interacting RNAs) were predicted and a 13 small RNA signature was developed to predict spread type from formalin-fixed paraffin-embedded tissues. Furthermore, integrative analyses of RNA sequencing and small RNA sequencing data revealed a global upregulation of the competing endogenous RNA network in tumor tissues of non-miliary compared to miliary spread, i.e. higher expression of circular RNAs and long non-coding RNAs compared to coding RNAs but unchanged abundance of small RNAs. This global deregulated expression pattern could be co-responsible for the spread characteristic, miliary or non-miliary, in ovarian cancer.
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http://dx.doi.org/10.18632/oncotarget.9243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5129959PMC
June 2016

Trophoblast subtype-specific EGFR/ERBB4 expression correlates with cell cycle progression and hyperplasia in complete hydatidiform moles.

Hum Reprod 2015 Apr 3;30(4):789-99. Epub 2015 Mar 3.

Department of Obstetrics and Fetal-Maternal Medicine, Reproductive Biology Unit, Medical University of Vienna, Währinger Gürtel 18-20, 5Q, 1090, Vienna, Austria

Study Question: Do trophoblast subtypes differ in their expression of erythroblastic leukaemia viral oncogene homologue (ERBB) receptor family members and responsiveness towards specific growth factor ligands?

Summary Answer: Our data reveal a reciprocal expression pattern of epidermal growth factor receptor (EGFR)/ERBB4 in proliferative and ERBB2/ERBB3 in invasive trophoblast subtypes, as well as a restricted responsiveness to epidermal growth factor (EGF) and heparin-binding (HB)-EGF.

What Is Known Already: EGFR is expressed by villous cytotrophoblasts (vCTBs), but absent from extravillous trophoblasts (EVTs), which specifically up-regulate ERBB2.

Study Design, Size, Duration: Tissue samples of human first trimester placentae (n = 50) and deciduae (n = 5) obtained from elective pregnancy terminations were used to study trophoblast subtype-specific ERBB receptor expression and responsiveness to recombinant human EGF and HB-EGF. Age-matched complete hydatidiform mole (CHM) placentae (n = 12) were assessed for EGFR and ERBB4 expression in proliferation-competent regions.

Participants/materials, Setting, Methods: ERBB receptor expression was analysed in primary trophoblast cell isolates by means of microarray, quantitative real-time PCR and western blotting, as well as immunofluorescence stainings of placental and decidual tissue sections. EGF and HB-EGF were tested for their potential to activate ERBB receptors in purified EGFR(+) and HLA-G(+) trophoblasts. 5-Ethynyl-2'-deoxyuridine incorporation assays were performed to study the effect of both ligands on the proliferative capacity of primary trophoblasts as well as of vCTBs and proximal cell column trophoblasts (pCCTs) in placental floating explants. Finally, the average number of EGFR(+) vCTB and pCCT layers was determined in CHM placentae and compared with healthy age-matched controls.

Main Results And The Role Of Chance: Proliferative vCTBs and pCCTs co-express EGFR and ERBB4, but are devoid of ERBB2 and ERBB3. In contrast, HLA-G(+) trophoblast subtypes exhibit an EGFR/ERBB4(-) and ERBB2/ERBB3(+) phenotype. EGF and HB-EGF activate EGFR, ERBB4, AKT and extracellular signal-regulated kinase 1/2 in EGFR(+) primary trophoblasts; however, they do not show an effect on HLA-G(+) EVTs. Both ligands strongly induce cell cycle progression in primary trophoblasts (P < 0.05) and placental explant-associated vCTBs (P < 0.05) and pCCTs (P < 0.05). Notably, EGFR(+) vCTB (P < 0.0001) and pCCT (P < 0.0001) layers are significantly expanded in CHM placentae when compared with healthy controls.

Limitations, Reasons For Caution: Cells were removed from their physiological context and may therefore respond differently to various stimuli.

Wider Implications Of The Findings: In this study we define EGFR as a marker for proliferative trophoblast subtypes within the human placenta. Manipulation of EGFR signalling might thus offer a promising therapeutic avenue for the treatment of molar pregnancies associated with trophoblast hyperplasia.

Study Funding/competing Interests: This study was supported by the Austrian Science Fund (grant P-25187-B13 to J.P.). There are no competing interests to declare.
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http://dx.doi.org/10.1093/humrep/dev027DOI Listing
April 2015

Placental pathologies on fetal MRI are associated with high impairment rates: a prospective long-term outcome study.

J Matern Fetal Neonatal Med 2015 Jul 14;28(10):1219-23. Epub 2014 Aug 14.

a Department of Pediatrics and Adolescent Medicine .

Objective: Placental anomalies visualized at midgestation by MRI are shown to be related to pregnancy outcome. We performed a prospective cohort study to investigate the influence of placental pathologies diagnosed with fetal MRI on long-term neurodevelopmental outcome.

Methods: In our hospital-based, cross-sectional study, all fetal MRI examinations of pregnancies with vascular placental pathology (i.e. infarction with/without hemorrhage, subchorionic thrombi/hemorrhages, intervillous thrombi/hemorrhages or retroplacental hematoma) between 2003 and 2007 were included. The extent of the pathology was expressed as the percentage of abnormality related to the whole placental volume. Pathohistological reports were correlated to MRI findings. Infants were prospectively investigated using Bayley developmental scales at the age of 2-3.5 years. Impairment was categorized as a Bayley scale two SDs below normal (<85 points).

Results: There were 31 singletons and 25 offspring of multiple pregnancies included in the analyses. Impairment rates were 32.2% in singletons and 32.0% in multiple births. No correlation between neuro/motor developmental outcome at 2-3.5 years and the type, extent or gestational week at the time of diagnoses of placental vascular pathologies was found.

Conclusion: The long-term outcome of children with vascular placental pathologies on fetal MRI was associated with a high impairment rate after 2-3.5 years, both on motor- and neurodevelopmental Bayley scales. Neurological impairment did not correlate with the extent of placental involvement, intrauterine growth restriction, gestational age at birth or multiple state.
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http://dx.doi.org/10.3109/14767058.2014.947952DOI Listing
July 2015

Extravillous trophoblast-associated ADAM12 exerts pro-invasive properties, including induction of integrin beta 1-mediated cellular spreading.

Biol Reprod 2014 May 2;90(5):101. Epub 2014 Apr 2.

Department of Obstetrics and Fetal-Maternal Medicine, Reproductive Biology Unit, Medical University of Vienna, Austria

ADAM12, consisting of a membrane-bound (ADAM12L) and a secreted (ADAM12S) form, is expressed exclusively in regenerating and developing tissue as well as in certain cancer types. Strong ADAM12 expression levels have been noticed in the human placenta, and deregulated ADAM12S levels were associated with various pregnancy-related disorders including pre-eclampsia and intrauterine growth restriction. However, the role of ADAM12 in trophoblast motility has not been investigated so far. Hence, the present study aimed to investigate the specific function of the protease by using different primary trophoblast cell models. Immunofluorescence and Western blot analyses of first trimester placental tissue and differentiating primary first trimester cytotrophoblasts (CTBs) indicated strong upregulation of both of the ADAM12 isoforms during extravillous trophoblast differentiation. Functional assays involving short interfering RNA (siRNA)-mediated knockdown studies in primary CTBs and first trimester explant cultures revealed a significant repression of trophoblast motility upon partial loss of ADAM12. Conversely, isoform-specific overexpression in the ADAM12-negative trophoblast cell line SGHPL-5 enhanced the invasive capacity of these cells. We further confirmed proteolytic activity of trophoblast-derived ADAM12S by demonstrating its potential to degrade insulin-like growth factor-binding protein 3. Finally, we suggest that ADAM12S exerts its pro-migratory function in trophoblasts by inducing integrin beta 1-mediated cellular spreading.
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http://dx.doi.org/10.1095/biolreprod.113.115279DOI Listing
May 2014

Automated REcognition of tissue-associated erythrocytes (ARETE)-a new tool in tissue cytometry.

Cytometry A 2013 Apr 11;83(4):363-74. Epub 2013 Feb 11.

Department of Pathophysiology and Allergy Research, Medical University Vienna, Vienna, Austria.

Automated microscopic image analysis of immunofluorescence-stained targets on tissue sections is challenged by autofluorescent elements such as erythrocytes, which might interfere with target segmentation and quantification. Therefore, we developed an automated system (Automated REcognition of Tissue-associated Erythrocytes; ARETE) for in silico exclusion of erythrocytes. To detect erythrocytes in transmission images, a cascade of boosted decision trees of Haar-like features was trained on 8,640/4,000 areas (15 × 15 pixels) with/without erythrocytes from images of placental sections (4 µm). Ground truth data were generated on 28 transmission images. At least two human experts labelled the area covered by erythrocytes. For validation, output masks of human experts and ARETE were compared pixel-wise against a mask obtained from majority voting of human experts. F1 score, specificity, and Cohen's κ coefficients were calculated. To study the influence of erythrocyte-derived autofluorescence, we investigated the expression levels of a protein (receptor for advanced glycated end products; RAGE) in placenta and number of Ki-67-positive/cytokeratin 8-positive epithelial cells in colon sections. ARETE exhibited high sensitivity (99.87%) and specificity (99.81%) on a training-subset and processed transmission images (1,392 × 1,024 pixels) within 4 sec. ARETE and human expert's F1-scores were 0.55 versus 0.76, specificities 0.85 versus 0.92 and Cohen's κ coefficients 0.41 versus 0.68. A ranking of Cohen's κ coefficient by the scale of Fleiss certified "good agreement" between ARETE and the human experts. Applying ARETE, we demonstrated 4-14% false-positive RAGE-expression in placenta, and 18% falsely detected proliferative epithelial cells in colon, caused by erythrocyte-autofluorescence. ARETE is a fast system for in silico reduction of erythrocytes, which improves automated image analysis in research and diagnostic pathology.
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http://dx.doi.org/10.1002/cyto.a.22258DOI Listing
April 2013

Lung transplantation for bronchiolitis obliterans after allogeneic hematopoietic stem cell transplantation: a single-center experience.

Transplantation 2013 Feb;95(4):623-8

Department of Medicine I, Bone Marrow Transplantation Unit, Medical University Vienna, Währinger Gürtel 18-20 A-1090 Vienna, Austria.

Background: Bronchiolitis obliterans (BO) is a detrimental late pulmonary complication after allogeneic hematopoietic stem cell transplantation (HCT) associated with chronic graft-versus-host disease (cGvHD). When systemic immunosuppressive treatment fails to improve, severe BO patients should be considered for lung transplantation (LuTX). We present seven patients undergoing LuTX for severe refractory BO after HCT.

Methods: Seven patients with hematologic malignancies developed severe cGvHD with lung involvement presenting as BO after allogeneic HCT. Evaluation for LuTX was initiated after failure of a median of 4 immunosuppressive regimens.

Results: Between 1996 and 2012, seven patients with severe refractory BO were evaluated for LuTX. The median time from HCT to diagnosis of chronic lung GvHD was 8.2 months (range, 3.7-16.6). At a median time of 18.1 months (range, 6-120) after diagnosis of BO, six patients received a bilateral sequential LuTX, and one patient received a single LuTX. Six postoperative courses were uneventful; the patient with single LuTX died from septic multiorgan failure. Three LuTX recipients had a mild acute rejection after one to three months after LuTX, and one patient experienced fatal chronic rejection and hemolytic uremic syndrome. At present, three (43%) LuTX recipients remain alive at a median observation time of 26 months (range, 1 month-16 years) after LuTX. The median overall survival from LuTX was 24 months (95% CI, 0.5-78); the median overall survival time after allogeneic HCT is 98 months (95% CI, 46-198).

Conclusion: This case series illustrates that LuTX is a possible therapeutic option for selected patients with severe treatment-refractory BO.
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http://dx.doi.org/10.1097/TP.0b013e318277e29eDOI Listing
February 2013

MRI of the placenta - a short review.

Wien Med Wochenschr 2012 May;162(9-10):225-8

Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.

While ultrasound is still the gold standard method of placental investigation, magnetic resonance imaging (MRI) has certain benefits. In advanced gestational age, obese women, and posterior placental location, MRI is advantageous due to the larger field of view and its multiplanar capabilities. Some pathologies are seen more clearly in MRI, such as infarctions and placental invasive disorders. The future development is towards functional placental MRI. Placental MRI has become an important complementary method for evaluation of placental anatomy and pathologies contributing to fetal problems such as intrauterine growth restriction.
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http://dx.doi.org/10.1007/s10354-012-0073-4DOI Listing
May 2012

Placental magnetic resonance imaging in monochorionic twin pregnancies.

J Matern Fetal Neonatal Med 2012 Aug 30;25(8):1419-22. Epub 2011 Nov 30.

Division of Neonatology, Pediatric Intensive Care and Neuropediatrics, Medical University of Vienna, Wien, Austria.

Objective: Twin-twin transfusion syndrome (TTTS) is a severe complication of monochorionic pregnancies. Placental hydrops might be a marker for TTTS. The purpose of this study was to evaluate whether differences in the placental parenchyma due to TTTS can be seen with fetal MRI.

Methods: In a retrospective study, 34 monochorionic pregnancies were investigated on a 1.5 Tesla MR. Seventeen pregnancies were affected by TTTS, and 17 showed no clinical signs of TTTS. Placental maturation and vascular pathologies, as well as the extent of the placental findings and allocation of placental tissue to each twin, were investigated. Placental findings were reported for origin, size, maturation, and placental thickness, and were correlated with the presence of TTTS.

Results: All placentas affected by TTTS showed abnormal maturation on MR scans, but only 64.7% of the non-TTTS group (p = 0.018). Vascular placental pathologies did not differ significantly between the TTTS and non-TTTS group.

Conclusions: MR-signs of placental maturity in monochorionic twin pregnancies may indicate a lower risk of development of TTTS.
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http://dx.doi.org/10.3109/14767058.2011.636106DOI Listing
August 2012

Towards a versatile automated cell-detection system for science and diagnostics.

Annu Int Conf IEEE Eng Med Biol Soc 2010 ;2010:3045-8

Medical University of Vienna, Department of Pathophysiology and Allergy Research, Austria.

Analyzing in-situ tissue structures with complex shapes and textures such as multinuclear cells or cells without nuclei is still a challenge for currently available imageprocessing software. This work aims to provide a versatile system to solve such tasks provided that the structures of interests were detected by immunofluorescence microscopy. Images were automatically acquired using slide-based microscopy. Human domain-experts manually marked up tissue samples to evaluate the performance of the computer generated masks. From precision and recall a balanced F-score was computed to measure the correlation between experts and algorithm output. Exhaustive parameter optimization was conducted to ensure that the optimal input parameters were applied during evaluation of the developed algorithm. This procedure significantly increased the performance compared to manually chosen input parameters. We present an approach that can handle huge tissue areas and does not rely on nuclei detection. Once a markup has been created, the algorithm can be parameter-optimized on ground-truth data for the chosen tissue sample. Thereafter, the resulting settings could be applied automatically to the respective stitched image. Concluding, we provide new insights in physiological and pathopysiological cellular mechanisms by automating the in-situ analysis of proteins in intact tissues.
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http://dx.doi.org/10.1109/IEMBS.2010.5626140DOI Listing
March 2011
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