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Purpose: The aim of this study was to investigate characteristics associated with ectopic pregnancy (EP) that could be utilized for predicting morbidity or mortality.
Methods: This was a retrospective analysis of pregnancy-related records from a tertiary center over a period of ten years. Data on age, gravidity, parity, EP risk, amenorrhea duration, abdominal pain presence and location, β-human chorionic gonadotropin (β-HCG) level, ultrasound findings, therapeutic intervention, exact EP implantation site and length of hospital stay (LOS) were obtained from the database. The LOS was used as a proxy for morbidity and was tested for an association with all variables. All statistical analyses were conducted with Stata® (ver. 16.1, Texas, USA).
Results: The incidence of EP in a cohort of 30,247 pregnancies over a ten-year period was 1.05%. Patients presented with lower abdominal pain in 87.9% of cases, and the likelihood of experiencing pain was tenfold higher if fluid was detectable in the pouch of Douglas. Only 5.1% of patients had a detectable embryonic heartbeat, and 18.15% had one or more risk factors for EP. While most EPs were tubal, 2% were ovarian. The LOS was 1.9 days, and laparoscopic intervention was the main management procedure. The cohort included one genetically proven dizygotic heterotopic pregnancy (incidence, 3.3 × 10− 5) that was diagnosed in the 7th gestational week. The only association found was between the β-HCG level and LOS, with a linear regression β coefficient of 0.01 and a P-value of 0.04.
Conclusion: EP is a relatively common condition affecting approximately 1% of all pregnancies. β-HCG correlates with EP-related morbidity, but the overall morbidity rate of EP is low regardless of the implantation site. Laparoscopic surgery is an effective therapeutic procedure that is safe for managing EP, even in cases of heterotopic pregnancy.
Evaluation of 2‑methoxyestradiol serum levels as a potential prognostic marker in malignant melanoma
(2021)
Experimental findings indicated that 2‑methoxyestradiol (2‑ME), an endogenous metabolite of 17β‑estradiol, may exhibit anti‑tumorigenic properties in various types of tumour, such as melanoma and endometrial carcinoma. In patients with endometrial cancer, the serum levels of 2‑ME are decreased compared with those in healthy controls, and this finding has been associated with a poor outcome. The aim of the present study was to examine whether the serum levels of 2‑ME are decreased in patients with melanoma, and whether this decrease may be correlated with disease stage and, therefore, serve as a prognostic indicator. ELISA was used to detect serum levels of 2‑ME in patients with stage I‑IV malignant melanoma (MM). A cohort of 78 patients with MM was analysed, along with 25 healthy controls, among whom 15 were women in the second trimester of pregnancy (positive control). As expected, significantly elevated levels of serum 2‑ME were observed in pregnant control patients compared with those in patients with MM and healthy controls. There was no observed correlation between 2‑ME serum levels in patients with MM and disease stage, tumour thickness, lactate dehydrogenase or S100 calcium‑binding protein B levels. In addition, the 2‑ME levels of patients with MM did not differ significantly from those of normal healthy controls. Overall, the findings of the present study indicated that the 2‑ME serum levels in patients with MM were not decreased, and there was no correlation with early‑ or advanced‑stage disease. Therefore, in contrast to published results on endometrial cancer, endogenous serum 2‑ME levels in MM were not found to be correlated with tumour stage and did not appear to be a suitable prognostic factor in MM.
Introduction: Cesarean section (CS) rates are increasing worldwide. One constant indication is the breech presentation at term. By offering external cephalic version (ECV) and vaginal breech delivery CS rates can be further reduced. Objective: This study aimed to analyze the ECV at 38 weeks of gestation with the associate uptake rate, predicting factors, success rate, and complications at a tertiary healthcare provider in Germany specializing in vaginal breech delivery. Methods: We conducted a prospective cohort study with retrospective data acquisition. All women with a singleton fetus in breech presentation presenting after 34 weeks of gestation for counseling between 2013 and 2017 were included. ECV impact factors were analyzed using logistic regression. Results: A total of 1,598 women presented for breech birth planning. ECV was performed on 353 patients. The overall success rate was 22.4%. A later week of gestation (odds ratio [OR] 1.69), an abundant amniotic fluid index (AFI score) (OR 5.74), fundal (OR 3.78) and anterior (OR 0.39) placental location, and an oblique lie (OR 9.08) were significantly associated with successful ECV in our population. No major complications were observed. The overall vaginal delivery rates could be increased to approximately 14% with ECV. Conclusion: The demand for alternative birth modes other than CS for breech birth is high in the area of Frankfurt, Germany. Our study offers evidence of the safety of ECV at 38 weeks. Centers with expertise in vaginal breech delivery and ECV can reduce CS-rates. To further establish vaginal breech delivery and ECV as alternate options, the required knowledge and skill should be implemented in the revised curricula.
Function of p21 (Cip1/Waf1/CDKN1A) in migration and invasion of cancer and trophoblastic cells
(2019)
Tumor progression and pregnancy have several features in common. Tumor cells and placental trophoblasts share many signaling pathways involved in migration and invasion. Preeclampsia, associated with impaired differentiation and migration of trophoblastic cells, is an unpredictable and unpreventable disease leading to maternal and perinatal mortality and morbidity. Like in tumor cells, most pathways, in which p21 is involved, are deregulated in trophoblasts of preeclamptic placentas. The aim of the present study was to enlighten p21’s role in tumorigenic choriocarcinoma and trophoblastic cell lines. We show that knockdown of p21 induces defects in chromosome movement during mitosis, though hardly affecting proliferation and cell cycle distribution. Moreover, suppression of p21 compromises the migration and invasion capability of various trophoblastic and cancer cell lines mediated by, at least partially, a reduction of the extracellular signal-regulated kinase 3, identified using transcriptome-wide profiling, real-time PCR, and Western blot. Further analyses show that downregulation of p21 is associated with reduced matrix metalloproteinase 2 and tissue inhibitor of metalloproteinases 2. This work evinces that p21 is involved in chromosome movement during mitosis as well as in the motility and invasion capacity of trophoblastic and cancer cell lines.
Background: Preeclampsia is one of the leading causes of maternal and perinatal mortality and morbidity worldwide and its pathogenesis is not totally understood. As a member of the chromosomal passenger complex and an inhibitor of apoptosis, survivin is a well-characterized oncoprotein. Its roles in trophoblastic cells remain to be defined.
Methods: The placental samples from 16 preeclampsia patients and 16 well-matched controls were included in this study. Real-time PCR, immunohistochemistry and Western blot analysis were carried out with placental tissues. Primary trophoblastic cells from term placentas were isolated for Western blot analysis. Cell proliferation, cell cycle analysis and immunofluorescence staining were performed in trophoblastic cell lines BeWo, JAR and HTR-8/SVneo.
Results: The survivin gene is reduced but the protein amount is hardly changed in preeclamptic placentas, compared to control placentas. Upon stress, survivin in trophoblastic cells is phosphorylated on its residue serine 20 by protein kinase A and becomes stabilized, accompanied by increased heat shock protein 90. Depletion of survivin induces chromosome misalignment, abnormal centrosome integrity, and reduced localization and activity of Aurora B at the centromeres/kinetochores in trophoblastic metaphase cells.
Conclusions: Our data indicate that survivin plays pivotal roles in cell survival and proliferation of trophoblastic cells. Further investigations are required to define the function of survivin in each cell type of the placenta in the context of proliferation, differentiation, apoptosis, angiogenesis, migration and invasion.
Preeclampsia (PE), a gestational hypertensive disease originating from the placenta, is characterized by an imbalance of various cellular processes. The cell cycle regulator p21Cip1/CDKN1A (p21) and its family members p27 and p57 regulate signaling pathways fundamental to placental development. The aim of the present study was to enlighten the individual roles of these cell cycle regulators in placental development and their molecular involvement in the pathogenesis of PE. The expression and localization of p21, phospho-p21 (Thr-145), p27, and p57 was immunohistochemically analyzed in placental tissues from patients with early-onset PE, early-onset PE complicated by the HELLP (hemolysis, elevated liver enzymes and low platelet count) syndrome as well as late-onset PE compared to their corresponding control tissues from well-matched women undergoing caesarean sections. The gene level was evaluated using real-time quantitative PCR. We demonstrate that the delivery mode strongly influenced placental gene expression, especially for CDKN1A (p21) and CDKN1B (p27), which were significantly upregulated in response to labor. Cell cycle regulators were highly expressed in first trimester placentas and impacted by hypoxic conditions. In support of these observations, p21 protein was abundant in trophoblast organoids and hypoxia reduced its gene expression. Microarray analysis of the trophoblastic BeWo cell line depleted of p21 revealed various interesting candidate genes and signaling pathways for the fusion process. The level of p21 was reduced in fusing cytotrophoblasts in early-onset PE placentas and depletion of p21 led to reduced expression of fusion-related genes such as syncytin-2 and human chorionic gonadotropin (β-hCG), which adversely affected the fusion capability of trophoblastic cells. These data highlight that cell cycle regulators are important for the development of the placenta. Interfering with p21 influences multiple pathways related to the pathogenesis of PE.
Background: The development of the human placenta is tightly coordinated by a multitude of placental cell types, including human chorionic villi mesenchymal stromal cells (hCV-MSCs). Defective hCV-MSCs have been reported in preeclampsia (PE), a gestational hypertensive disease characterized by maternal endothelial dysfunction and systemic inflammation. Our goal was to determine whether hCV-MSCs are ciliated and whether altered ciliation is responsible for defective hCV-MSCs in preeclamptic placentas, as the primary cilium is a hub for signal transduction, which is important for various cellular activities.
Methods: In the present work, we collected placental tissues from different gestational stages and we isolated hCV-MSCs from 1st trimester, term control, and preeclamptic placentas. We studied their ciliation, functionality, and impact on trophoblastic cell lines and organoids formed from human trophoblast stem cells (hTSCs) and from the trophoblastic cell line JEG-3 with various cellular and molecular methods, including immunofluorescence staining, gene analysis, spheroid/organoid formation, motility, and cellular network formation assay. The statistical evaluation was performed using a Student’s t test (two-tailed and paired or homoscedastic) or an unpaired Mann–Whitney U test (two-tailed).
Results: The results show that primary cilia appeared abundantly in normal hCV-MSCs, especially in the early development of the placenta. Compared to control hCV-MSCs, the primary cilia were truncated, and there were fewer ciliated hCV-MSCs derived from preeclamptic placentas with impaired hedgehog signaling. Primary cilia are necessary for hCV-MSCs’ proper signal transduction, motility, homing, and differentiation, which are impaired in preeclamptic hCV-MSCs. Moreover, hCV-MSCs derived from preeclamptic placentas are significantly less capable of promoting growth and differentiation of placental organoids, as well as cellular network formation.
Conclusions: These data suggest that the primary cilium is required for the functionality of hCV-MSCs and primary cilia are impaired in hCV-MSCs from preeclamptic placentas.
Impact of Polo-like kinase 1 inhibitors on human adipose tissue-derived mesenchymal stem cells
(2016)
Polo-like kinase 1 (Plk1) has been established as one of the most promising targets for molecular anticancer intervention. In fact, various Plk1 inhibitors have been identified and characterized. While the data derived from the bench are prospective, the clinical outcomes are less encouraging by showing modest efficacy. One of the explanations for this discrepancy could be unintendedly targeting of non-malignant cells by Plk1 inhibitors. In this work, we have addressed the effect of Plk1 inhibition in adipose tissue-derived mesenchymal stem cells (ASCs). We show that both visceral and subcutaneous ASCs display monopolar spindles, reduced viability and strong apoptosis induction upon treatment with BI 2536 and BI 6727, the Plk1 kinase domain inhibitors, and with Poloxin, the regulatory Polo-box domain inhibitor. While Poloxin triggers quickly apoptosis, BI 2536 and BI 6727 result in mitotic arrest in ASCs. Importantly, survived ASCs exhibit DNA damage and a pronounced senescent phenotype. In addition, Plk1 inhibition impairs ASCs’ motility and homing ability. These results show that Plk1 inhibitors target slowly proliferating ASCs, an important population of anti-inflammation and immune modulation. The toxic effects on primary cells like ASCs could be partially responsible for the reported moderate antitumor activity in patients treated with Plk1 inhibitors.
The oncogene B-cell lymphoma 6 (BCL6) is associated with lymphomagenesis. Intriguingly, its expression is increased in preeclamptic placentas. Preeclampsia is one of the leading causes of maternal and perinatal mortality and morbidity. Preeclamptic placentas are characterized by various defects like deregulated differentiation and impaired fusion of trophoblasts. Its pathogenesis is however not totally understood. We show here that BCL6 is present throughout the cell fusion process in the fusogenic trophoblastic cell line BeWo. Suppression of BCL6 promotes trophoblast fusion, indicated by enhanced levels of fusion-related β-hCG, syncytin 1 and syncytin 2. Increased mRNA levels of these genes could also be observed in primary term cytotrophoblasts depleted of BCL6. Conversely, stable overexpression of BCL6 reduces the fusion capacity of BeWo cells. These data suggest that an accurately regulated expression of BCL6 is important for proper differentiation and successful syncytialization of trophoblasts. While deregulated BCL6 is linked to lymphomagenesis by blocking lymphocyte terminal differentiation, increased BCL6 in the placenta contributes to the development of preeclampsia by impairing trophoblast differentiation and fusion.
Vaginal breech delivery is becoming an extinct art although national guidelines underline its safety and vaginal breech delivery in an upright position has been shown to be a safe birth mode option. In order to spread clinical knowledge and be able to implement vaginal breech delivery into obstetricians’ daily practice, we need to gather knowledge from facilities who teach specialized obstetrical management. Methods: We performed a prospective cohort study on 140 vaginal deliveries out of breech presentation solely-managed by seven newly-trained physicians and compared fetal outcome as well as rates of manual assistance in respect to preexisting experience. Results: Fetal morbidity rate measured with a modified PREMODA score was not significantly different in three sub-cohorts sorted by preexisting expertise levels of managing obstetricians (experience groups EG, EG0: 2, 5%; EG1: 3, 7.5%; EG2: 1, 1.7%; p = 0.357). Manual assistance rate was significantly higher in EG1 (low experience level in breech delivery and only in dorsal position) compared to EG0 and EG2 (EG1 28, 70%; EG0: 14, 25%; EG2: 21, 35%; p = 0.0008). Conclusions: Our study shows that vaginal breech delivery with newly-trained obstetricians is a safe option whether or not they have advanced preexisting expertise in breech delivery. These data should encourage implementing vaginal breech delivery in clinical routine.