[Show abstract][Hide abstract] ABSTRACT: Ovarian cancer still represents a challenge in gynecological oncology. Most patients are diagnosed in an advanced tumor stage. No specific screening or prevention strategies for ovarian cancer exist as of yet.
Interleukin 8 (IL-8) is a pro-inflammatory chemokine known for its angiogenetic activity, and is supposedly responsible for tumor-associated angiogenesis in several malignant tumors.
The aim of the study was to investigate the susceptibility of patients with an IL-8 gene polymorphism to developing ovarian cancer.
Four single nucleotide polymorphisms (SNPs) (IL-8 −251, IL-8 +781, IL-8 +1633 and IL-8 +2767) of the IL-8 gene were screened, using the PCR method in 268 patients with ovarian cancer and 426 healthy women as a control group. Significant associations were noted in patients with the IL-8 +781 (T/T) genotype (p = 0.0048) with increased frequencies of ovarian cancer, while women with the IL-8 +781 (C/C) allele suffer from ovarian cancer significantly less frequently (p = 0.0003). Furthermore, the IL-8 +2767 (T/T) genotype is also associated with a higher risk of ovarian cancer (p = 0.0177).
Our results indicate, for the first time, that IL-8 polymorphism is associated with ovarian cancer.
[Show abstract][Hide abstract] ABSTRACT: In the luteal phase, human endometrial stromal cells (HESCs) undergo proliferation, migration and differentiation during the decidualization process under the control of the ovarian steroids progesterone and estrogen. Proper decidualization of stromal cells is required for blastocyst implantation and the development of pregnancy. The proliferation, migration and differentiation of HESCs in decidualization do not require the presence of a blastocyst but are greatly accelerated during implantation. Lysophosphatidic acid (LPA) and Sphingosine-1-phosphate (S1P) are potent bioactive lysophospholipids that have critical roles in various physiological and pathophysiological processes including inflammation, angiogenesis and cancer. The expression of the enzymes involved in LPA and S1P turnover and their receptors in HESCs during decidualization has not been characterized yet. We found that the LPAR1 and LPAR6 and S1PR3 receptors are highly expressed in HESCs. LPAR1, autotaxin (ATX), an LPA producing enzyme and lipid phosphate phosphatase 3 (LPP3) were upregulated during decidualization. Interestingly, the expression of all S1P receptor subtypes and LPA receptors (LPAR2-6) mRNA was downregulated after decidualization. We found that SPHK1 is highly expressed in HESCs, and is upregulated during decidualization. S1P phosphatase SGPP1 and S1P lyase SGPL1 are highly expressed in HESCs. SGPP1 mRNA expression was significantly upregulated in decidualized HESCs. In conclusion, this study shows the first time that specific LPA and S1P receptors and their metabolizing enzymes are highly regulated in HESCs during decidualization. Furthermore, we suggest that LPAR1 receptor-mediated signaling in HESCs may be crucial in decidualization process. SPHK1 activity and high turnover of S1P and LPA might be essential for precise regulation of their signaling during decidualization of human endometrium and implantation.
Molecular Human Reproduction 07/2014; 20(10). DOI:10.1093/molehr/gau051 · 3.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The management of high-risk endometrial cancer (HREC) remains controversial. We conducted a prospective multicenter phase-II clinical trial to evaluate an adjuvant chemotherapy (CT) with sequential radiotherapy (RT) in patients with HREC.
Patients with HREC from 8 institutions in Germany were enrolled. After surgery, patients received four cycles of paclitaxel 175 mg/m² (P) and carboplatin AUC5 (C) (d1, q21d) and subsequent external pelvic radiation therapy (1.8 Gy/d, d1-5) at a total dose of 45 Gy with vaginal brachytherapy (3 × 5 Gy). Quality of life (QoL) was assessed using the EORTC-QLQ-C30 questionnaire. Primary endpoints were tolerability, toxicity and QoL. Progression-free survival (PFS) was defined as secondary endpoint.
Thirty-five patients were enrolled from 2004 through 2008. Median follow-up was 24 months (range 3-24 months). All patients received 4 cycles of P and C and completed RT. Overall, grade 3/4 haematological toxicity was 25.6 %. Three cycles were delayed because of leukopenia. Grade 3/4 non-haematologic toxicities were rare (≤3 %). No overall change in QoL occurred during treatment. Two-year median PFS and OS rates were both 75.8 %.
Adjuvant combination CT with P + C and sequential RT is well tolerated and a feasible regimen in patients with HREC. Subsequent phase-III trials are warranted.
Cancer Chemotherapy and Pharmacology 09/2013; DOI:10.1007/s00280-013-2276-9 · 2.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Various cytokines derived from placental cells are essential for normal placenta development and successful pregnancy. Interleukin-6 (IL-6) is a multifunctional cytokine produced by extravillous and cytotrophoblasts regulating the functions of these cells e.g. migration, invasion, trophoblast differentiation, and proliferation. In macrophages, newly synthesized IL-6 accumulates in the Golgi complex and exits in tubulovesicular carriers fused with recycling endosomes and secreted as a soluble protein. Sphingosine-1-phosphate (S1P) induces various cytokine secretions including IL-6 in different cell types. The signaling mechanisms regulating the IL-6 secretion are unknown. In this study, we found that S1PR2 was the major S1P receptor being expressed in BeWo cells. S1P regulated IL-6 protein secretion in early phase (6 hours) and gene expression in later phase (24 hours). IL-6 secretion was completely inhibited via inhibitor of transcription (Actinomycin D) or protein synthesis (Cycloheximide) confirming that IL-6 releases constitutively from BeWo cells. By using specific S1PR2 inhibitor JTE-013 and S1PR2 gene silencing, we found that S1PR2 was the main receptor that regulates IL-6 secretion. Furthermore, S1P induced RhoGTPases dependent pathways that are required for IL-6 secretion. Pretreatment of cells with specific Rho-kinase inhibitor (Y27632) and Rac1 inhibitor (NSC23766) drastically inhibited S1P-induced IL-6 secretion. By using a specific Phosphoinositide 3-kinase (PI3 K) inhibitor (LY294002), we found that basal activity of PI3 K was required for secretion but was independent of S1P/S1PR2 axis activation. In summary, we report first time that binding of S1P to S1PR2 activates multiple RhoGTPases dependent pathways that coordinate with PI3 K pathway for secretion of IL-6 in BeWo cells.
Molecular Human Reproduction 03/2013; 19(8). DOI:10.1093/molehr/gat023 · 3.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Die Geschichte der naturwissenschaftlichen Forschung im Bereich der Geburtshilfe ist, mit wenigen Ausnahmen, verhältnismäßig jung. Die letzten Jahre haben einen signifikanten Wechsel in den Strukturen der Forschung mit sich gebracht. Heute findet fundierte wissenschaftliche Tätigkeit in Forschungsverbünden und -Clustern statt. Sie kann nur dann erfolgreich werden, wenn sie auf den Prinzipien der Multizentrizität, Translation und Interdisziplinarität aufbaut. Bei der Betrachtung der wissenschaftlichen Schwerpunkte des Fachs Geburtshilfe ist besonders wichtig, zwischen den Schwerpunkten in der klinischen Medizin und in der Grundlagenforschung einerseits sowie der Ausrichtung der Forschung in den Industrie- und Schwellenländern zu differenzieren. Die zukünftigen Schwerpunkte in diesen Bereichen unterscheiden sich signifikant, werden aber durch das übergeordnete Ziel der kindlichen und der maternalen Gesundheit zusammengefasst. Der vorliegende Beitrag stellt die wichtigsten Ansätze vor.
Over 120 years of basic research in obstetrics and perinatal medicine provide a strong scientific background for this clinical discipline. In the forthcoming years there will be a strong need for developing networks of collaborating researchers and institutions in this field. Additionally, political activities of research organisations and societies as well as individuals involved (scientists and clinicians) are needed to promote knowledge of the major topics and issues of research and place them at the global forefront. As there is only minimal interest of industrial and pharmaceutical sectors in this field, interdisciplinary and translational projects on maternal, fetal and perinatal diseases have to compete for major founding from governmental bodies [e.g. the DFG (German Research Society) in Germany, the European Union] and foundations. The future focus of perinatal research will concentrate on fetal programming, its impact on health, possible preventive measures and interventions. The role of the placenta as a key organ in fetal growth and development will be further studied. Also the role of the placenta in drug delivery and fetal exposure to xenobiotics, infectious and toxic agents needs further evaluation. In terms of reproductive biology and medicine: individualized, patient-focused stimulation protocols, in vitro maturation of gametes and uterus transplantation are going to play an important role. Future research in and for developing countries will additionally focus on the infection-related pathology, fetal and maternal morbidity and mortality caused by malaria, human immunodeficiency virus (HIV) and other pathogens. Scientific attention will also be given to socioeconomic inequalities and the impact on feto-maternal health, e.g. nutrition, micronutrient deficiency, domestic violence and psychiatric diseases.
Der Gynäkologe 09/2012; 45(9):690-694. DOI:10.1007/s00129-012-2965-1
[Show abstract][Hide abstract] ABSTRACT: The establishment of an appropriate fetomaternal vessel system is a prerequisite for prevention of pregnancy associated pathologies. Notch receptors and ligands are manifoldly involved in vascular development and angiogenesis. To further characterize the process of human placental vasculo- and angiogenesis we investigated the expression pattern of Notch receptors and their ligands during pregnancy. Real time RT-PCR, immunohistochemistry and flow cytometry analysis were performed in early (6-12) weeks of gestation (w.o.g.) and late placenta (37-41 w.o.g.). To specify the exact cellular localization immunofluorescent labelling of epithelial and endothelial cells (EC), respectively, with cytokeratin-7 and vonWillebrand factor (vWF) was done. One placenta from a patient with Alagille syndrome (AGS) was examined with real time RT-PCR and immunohistochemistry. The receptors Notch2, -3, -4 and their ligands Jagged1, -2 and Delta1, -4 were detected at both the mRNA and protein level in early and late placenta. Notch1 was only detected at protein level. The expression was found mainly in the stromal compartment: placental EC expressed Notch1, Delta4, Jagged1 and Delta1. A strong Jagged1 expression was found in the endothelium of arteries and veins supporting a role in differentiation of capillaries. Hofbauer cells (HC) primarily displayed the receptors Notch2, -3 and -4. Placental stromal cells (SC) were positive for Jagged2. The syncytiotrophoblast (ST) and cytotrophoblast (CT) cells revealed a weak but detectable co-localization with cytokeratin-7 and Notch1, -3 and Delta1. These results were verified by flow cytometry of freshly isolated placental cells of placental tissue. Interestingly Jagged1 expression was absent in endothelial cells from an AGS placenta. The Notch receptors and their ligands are expressed in human placental ST, CT, EC, SC and HC. The distribution pattern of Notch receptors and their ligands suggests their involvement in the process of placental vasculo- and angiogenesis via cell-cell communication between trophoblast, -stroma and endothelial cells.
[Show abstract][Hide abstract] ABSTRACT: This prospective study aimed to compare sonoelastography, B-mode ultrasonography, and mammography in terms of their ability to distinguish benign from malignant breast lesions. We also assessed how the diagnostic value of sonoelastography differs between palpable and clinically occult lesions.
Evaluation revealed a total of 97 lesions (66 benign; 31 malignant) without histological confirmation at the time of the initial examination. The sensitivity, specificity, positive (PPV) and negative predictive value (NPV) as well as efficiency were calculated. These parameters were separately assessed for palpable lesions and for non-palpable lesions. We subsequently compared these results.
Sonography had a sensitivity of 97% and a specificity of 82% (PPV: 71 %, NPV: 98%, efficiency: 87%). For mammography, the respective figures were 84% and 89% (PPV: 79%, NPV: 92%, efficiency: 88%). Sonoelastography had a sensitivity of 71% and a specificity of 48% (PPV: 39%, NPV: 78%, efficiency: 56%). The combination of sonography and sonoelastography yielded a sensitivity of 100% and a specificity of 38% (PPV: 43%, NPV: 100%, efficiency: 58%). The sensitivity and specificity were not statistically different between the groups of palpable and non-palpable lesions.
Sonoelastography is easily performed and not very time-consuming. Used by itself, the method is not more efficacious than alternative techniques. When used in conjunction with B-mode ultrasonography, the latter's sensitivity was increased, albeit at the expense of specificity.
Ultraschall in der Medizin 12/2010; 31(6):596-603. DOI:10.1055/s-0029-1245526 · 4.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Both exogenous and endogenous factors during pregnancy may impact placental vascular development and cause different malformations of placental vessels. In humans, consequences of abnormal vascular development have been associated with different pregnancy-related pathologies ranging from miscarriage to intrauterine growth restriction or preeclampsia. Pregnancy-associated exposure to bacterial or viral infections or pharmacologic or toxic agents may also influence vascular development of the placenta and lead to preterm labor and delivery. Several steps of vascular adaptation on both the fetal and maternal side are necessary and include such events as uterine vasodilation, remodeling by extravillous trophoblast, as well as vasculogenesis and angiogenesis within the placenta. Ubiquitous as well as pregnancy-specific angiogenic factors are involved. Morphologic and stereologic approaches, as well as experiments in established laboratory animals, cannot be applied to large domestic animals or humans without hesitation. Thus, further studies into the different aspects of this process will require an appropriate in vitro model of placental vascular development. Reflecting the core of placental vascular development, the in vitro model should facilitate the interactions between trophoblast and stromal cells with endothelial progenitor cells. The effects of viral or bacterial infection as well as pharmacologic or toxic agents may be studied more closely in the process. This report reviews major aspects of vascular development in the placenta and describes the establishment of a three-dimensional in vitro model of human placental vascular development.
[Show abstract][Hide abstract] ABSTRACT: The official birth statistics are regarded as a reliable data source on births and birth rate in the German population. However, they show methodological limitations with respect to the identification of first-time mothers and the number of children per mother. The mothers' social and economical background is not assessed. The goal of the present analysis was (a) to describe demographic and socio-economic variables of all births in a defined region over a fixed time-frame and (b) to make a comparison on the basis of parity and gravidity.
From 2004-2007 4,982 children were born in the region and data from n=4,788 children were assessed (96%); n=3,505 (73%) of these mothers consented to a more detailed assessment.
The fertility rate in the SniP region is low. There are fewer children per 1,000 women and born per women in general. The average age of primiparae was 25 and 26 years. As can be expected there is a significant difference between primiparae and multiparae with respect to age. There is also a difference in occupational status. 17% of the primiparae have been multigravidae.
For the first time in Germany, the SNiP collected comprehensive population-based data on the age and socio-demographic variables of children and their mothers in a defined geographical region. A significant discrepancy for average age of primiparae between the study results and the official statistics is discussed in the light of methodological and regional issues. Our results require the continuation of comprehensive population-based data assessment. Furthermore, the SniP region could serve as a model region for future research. In international comparisons Germany's reproductive behaviour has proved to be unfavourable, which is accentuated in the region under examination.
Zeitschrift für Geburtshilfe und Neonatologie 01/2010; 214(1):15-23. DOI:10.1055/s-0029-1243625 · 0.46 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Undisturbed development and growth of the fetus depends on an adequate vascular development in the fetomaternal unit. Several steps of vascular adaptation both on fetal and maternal side are necessary and involve uterine vasodilation and remodelling by extravillous trophoblast as well as vasculo- and angiogenesis within the placenta. Ubiquitous (e. g. VEGF, bFGF) as well as pregnancy specific (PlGF, hCG, IGF-II, AFP) angiogenic factors are involved. Consequences of abnormal vascular development have been associated with different pregnancy-related pathologies ranging from miscarriage to intrauterine growth restriction or preeclampsia. Pregnancy-associated exposure to bacterial and viral infections or toxic agents (e. g. alcohol, nicotine or drugs) may also influence vascular development of the placenta and often lead to preterm labour and delivery. Different methods of study placental vascular development exist. Morphological and stereological approaches as well as animal models reveal significant limitations and can not be applied to in vivo human situation without hesitation. There is a need to design in vitro models of human placental vascular development allowing studies into the different aspects of this process including: trophoblast and stromal cells, interaction with endothelial progenitor cells, influence of viral or bacterial infection of trophoblast as well as influence of toxic agents. Our manuscript reviews major aspects of vascular development in the placenta and describes author's efforts to establish a three-dimensional model of this process in vitro.
Zeitschrift für Geburtshilfe und Neonatologie 07/2009; 213(3):96-100. DOI:10.1055/s-0029-1224141 · 0.46 Impact Factor