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Polo-like kinase 1, a pivotal regulator of mitosis and cytokinesis, is highly expressed in a broad spectrum of tumors and its expression correlates often with poor prognosis, suggesting its potential as a therapeutic target. p53, the guardian of the genome, is the most important tumor suppressor. In this review, we address the intertwined relationship of these two key molecules by fighting each other as eternal rivals in many signaling pathways. p53 represses the promoter of Polo-like kinase 1, whereas Polo-like kinase 1 inhibits p53 and its family members p63 and p73 in cancer cells lacking functional p53. Plk1 inhibitors target all rapidly dividing cells irrespective of tumor cells or non-transformed normal but proliferating cells. Upon treatment with Plk1 inhibitors, p53 in tumor cells is activated and induces strong apoptosis, whereas tumor cells with inactive p53 arrest in mitosis with DNA damage. Thus, inactive p53 is not associated with a susceptible cytotoxicity of Polo-like kinase 1 inhibition and could rather foster the induction of polyploidy/aneuploidy in surviving cells. In addition, compared to the mono-treatment, combination of Polo-like kinase 1 inhibition with anti-mitotic or DNA damaging agents boosts more severe mitotic defects, effectually triggers apoptosis and strongly inhibits proliferation of cancer cells with functional p53. In this regard, restoration of p53 in tumor cells with loss or mutation of p53 will reinforce the cytotoxicity of combined Polo-like kinase 1 therapy and provide a proficient strategy for combating relapse and metastasis of cancer.
Polo-like kinase 1 regulates the stability of the mitotic centromere-associated kinesin in mitosis
(2014)
Proper bi-orientation of chromosomes is critical for the accurate segregation of chromosomes in mitosis. A key regulator of this process is MCAK, the mitotic centromere-associated kinesin. During mitosis the activity and localization of MCAK are regulated by mitotic key kinases including Plk1 and Aurora B. We show here that S621 in the MCAK’s C-terminal domain is the major phosphorylation site for Plk1. This phosphorylation regulates MCAK’s stability and facilitates its recognition by the ubiquitin/proteasome dependent APC/CCdc20 pathway leading to its D-box dependent degradation in mitosis. While phosphorylation of S621 does not directly affect its microtubule depolymerising activity, loss of Plk1 phosphorylation on S621 indirectly enhances its depolymerization activity in vivo by stabilizing MCAK, leading to an increased level of protein. Interfering with phosphorylation at S621 causes spindle formation defects and chromosome misalignments. Therefore, this study suggests a new mechanism by which Plk1 regulates MCAK: by regulating its degradation and hence controlling its turnover in mitosis.
Objective: To compare breech outcomes when mothers delivering vaginally are upright, on their back, or planning cesareans. Methods: A retrospective cohort study was undertaken of all women who presented for singleton breech delivery at a center in Frankfurt, Germany, between January 2004 and June 2011. Results: Of 750 women with term breech delivery, 315 (42.0%) planned and received a cesarean. Of 269 successful vaginal deliveries of neonates, 229 in the upright position were compared with 40 in the dorsal position. Upright deliveries were associated with significantly fewer delivery maneuvers (OR 0.45, 95% CI 0.31–0.68) and neonatal birth injuries (OR 0.08, 95% CI 0.01–0.58), second stages that were on average shorter (1 vs 1.75 hours), and nonsignificantly decreased serious perineal lacerations (OR 0.34, 95% CI 0.05–3.99). When upright position was used almost exclusively, the cesarean rate decreased. Serious fetal and neonatal morbidity potentially related to birth mode was low, and similar for upright vaginal deliveries compared with planned cesareans (OR 1.37, 95% CI 0.10–19.11). Three neonates died; all had lethal birth defects. Forceps were never required. Conclusion: Upright vaginal breech delivery was associated with reductions in duration of the second stage of labor, maneuvers required, maternal/neonatal injuries, and cesarean rate when compared with vaginal delivery in the dorsal position.
The coronavirus disease 2019 COVID-19 pandemic is rapidly spreading worldwide and is becoming a major public health crisis. Increasing evidence demonstrates a strong correlation between obesity and the COVID-19 disease. We have summarized recent studies and addressed the impact of obesity on COVID-19 in terms of hospitalization, severity, mortality, and patient outcome. We discuss the potential molecular mechanisms whereby obesity contributes to the pathogenesis of COVID-19. In addition to obesity-related deregulated immune response, chronic inflammation, endothelium imbalance, metabolic dysfunction, and its associated comorbidities, dysfunctional mesenchymal stem cells/adipose-derived mesenchymal stem cells may also play crucial roles in fueling systemic inflammation contributing to the cytokine storm and promoting pulmonary fibrosis causing lung functional failure, characteristic of severe COVID-19. Moreover, obesity may also compromise motile cilia on airway epithelial cells and impair functioning of the mucociliary escalators, reducing the clearance of severe acute respiratory syndrome coronavirus (SARS-CoV-2). Obese diseased adipose tissues overexpress the receptors and proteases for the SARS-CoV-2 entry, implicating its possible roles as virus reservoir and accelerator reinforcing violent systemic inflammation and immune response. Finally, anti-inflammatory cytokines like anti-interleukin 6 and administration of mesenchymal stromal/stem cells may serve as potential immune modulatory therapies for supportively combating COVID-19. Obesity is conversely related to the development of COVID-19 through numerous molecular mechanisms and individuals with obesity belong to the COVID-19-susceptible population requiring more protective measures.
A message from the human placenta: structural and immunomodulatory defense against SARS-CoV-2
(2020)
The outbreak of the coronavirus disease 2019 (COVID-19) pandemic has caused a global public health crisis. Viral infections may predispose pregnant women to a higher rate of pregnancy complications, including preterm births, miscarriage and stillbirth. Despite reports of neonatal COVID-19, definitive proof of vertical transmission is still lacking. In this review, we summarize studies regarding the potential evidence for transplacental transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), characterize the expression of its receptors and proteases, describe the placental pathology and analyze virus-host interactions at the maternal-fetal interface. We focus on the syncytium, the barrier between mother and fetus, and describe in detail its physical andstructuraldefenseagainstviralinfections. Wefurtherdiscussthepotentialmolecularmechanisms, whereby the placenta serves as a defense front against pathogens by regulating the interferon type III signaling, microRNA-triggered autophagy and the nuclear factor-κB pathway. Based on these data, we conclude that vertical transmission may occur but rare, ascribed to the potent physical barrier, the fine-regulatedplacentalimmunedefenseandmodulationstrategies. Particularly,immunomodulatory mechanismsemployedbytheplacentamaymitigateviolentimmuneresponse,maybesoftencytokine storm tightly associated with severely ill COVID-19 patients, possibly minimizing cell and tissue damages, and potentially reducing SARS-CoV-2 transmission.
The multifaceted p21 (Cip1/Waf1/CDKN1A) in cell differentiation, migration and cancer therapy
(2019)
Loss of cell cycle control is characteristic of tumorigenesis. The protein p21 is the founding member of cyclin-dependent kinase inhibitors and an important versatile cell cycle protein. p21 is transcriptionally controlled by p53 and p53-independent pathways. Its expression is increased in response to various intra- and extracellular stimuli to arrest the cell cycle ensuring genomic stability. Apart from its roles in cell cycle regulation including mitosis, p21 is involved in differentiation, cell migration, cytoskeletal dynamics, apoptosis, transcription, DNA repair, reprogramming of induced pluripotent stem cells, autophagy and the onset of senescence. p21 acts either as a tumor suppressor or as an oncogene depending largely on the cellular context, its subcellular localization and posttranslational modifications. In the present review, we briefly mention the general functions of p21 and summarize its roles in differentiation, migration and invasion in detail. Finally, regarding its dual role as tumor suppressor and oncogene, we highlight the potential, difficulties and risks of using p21 as a biomarker as well as a therapeutic target.
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: Obesity impairs a variety of cell types including adipose-derived mesenchymal stem cells (ASCs). ASCs are indispensable for tissue homeostasis/repair, immunomodulation, and cell renewal. It has been demonstrated that obese ASCs are defective in differentiation, motility, immunomodulation, and replication. We have recently reported that some of these defects are linked to impaired primary cilia, which are unable to properly convey and coordinate a variety of signaling pathways. We hypothesized that the rescue of the primary cilium in obese ASCs would restore their functional properties.
Methods: Obese ASCs derived from subcutaneous and visceral adipose tissues were treated with a specific inhibitor against Aurora A or with an inhibitor against extracellular signal-regulated kinase 1/2 (Erk1/2). Multiple molecular and cellular assays were performed to analyze the altered functionalities and their involved pathways.
Results: The treatment with low doses of these inhibitors extended the length of the primary cilium, restored the invasion and migration potential, and improved the differentiation capacity of obese ASCs. Associated with enhanced differentiation ability, the cells displayed an increased expression of self-renewal/stemness-related genes like SOX2, OCT4, and NANOG, mediated by reduced active glycogen synthase kinase 3 β (GSK3β).
Conclusion: This work describes a novel phenomenon whereby the primary cilium of obese ASCs is rescuable by the low-dose inhibition of Aurora A or Erk1/2, restoring functional ASCs with increased stemness. These cells might be able to improve tissue homeostasis in obese patients and thereby ameliorate obesity-associated diseases. Additionally, these functionally restored obese ASCs could be useful for novel autologous mesenchymal stem cell-based therapies.
Introduction: Vaginal delivery out of a breech presentation in pregnancies at term are being re-implemented into clinical practice. Still, recommendations regarding exclusion criteria leading to caesarean sections are based on expert opinions, not on evidence-based guidelines. The difference in perinatal outcome and course of delivery in births with babies in frank breech position and babies in incomplete or complete breech presentation never has been investigated in a large patient cohort.
Objective: To compare perinatal outcome of vaginally intended breech deliveries between births out of frank breech position and incomplete/complete breech presentation.
Design: Prospective cohort study.
Sample: 884 women at term with a singleton in frank breech presentation (FB) and 284 women with incomplete or complete breech presentation (CB) intending vaginal birth between January 2004 and December 2018.
Methods: Maternal and fetal outcome was compared between groups using Pearson’s Chi Square test. Birth duration parameters were analysed using logistic regression.
Results: There were no differences in cesarean section rates (FB: 25.1%, CB 22.2%, p = 0.317). Short-term fetal morbidity did not differ between groups (FB: 2.5%, CB: 2.8%, p = 0.761). In vaginal deliveries the necessity to perform manual assistance was significantly more frequent in deliveries of infants in CB (FB: 39.9%, CB: 51.6%, p = 0.0013). Cord loops (FB: 10.1%, CB: 18.0%, p = 0.0004) and cesarean sections necessary because of cord prolapses (FB: 1.4%, CB 8.1%, p = 0.005) were significantly more often in deliveries with babies in CB.
Conclusion: This study provides evidence, that perinatal morbidity is not associated with the fetal leg posture in vaginally intended breech deliveries. The higher risk for the need of manual assistance during vaginal birth in deliveries of babies out of complete or incomplete breech presentation suggests that obstetrical departments re-implementing the vaginal breech in their repertoire might start with births of babies out of frank breech presentation.
Aim. To compare the efficacy, safety, and patient’s perception of two prostaglandin E2 application methods for induction of labour.
Method. Above 36th weeks of gestation, all women, who were admitted to hospital for induction of labour, were prospectively randomised to intravaginal 1 mg or intracervical 0.5 mg irrespective of cervical Bishop score. The main outcome variables were induction-to-delivery interval, number of foetal blood samples, PDA rate, rate of oxytocin augmentation, rate of vaginal delivery, and patient’s perception using semantic differential questionnaire.
Results. Thirty-nine patients were enrolled in this study. There was no statistical significant difference between the two groups in regard to perceptions of induction. The median induction delivery time using intravaginal versus intracervical administration was 29.9 versus 12.8 hours, respectively (). No statistically difference between the groups was detected in regard to parity, gestation age, cervical Bishop score, number of foetal blood samples, PDA rate, rate of oxytocin augmentation, and mode of birth.
Summary. Irrespective of the cervical Bishop Score, intracervical gel had a shorter induction delivery time without impingement on the women’s perception of induction.
