H3K4me3 Is a Potential Mediator for Antiproliferative Effects of Calcitriol (1α,25(OH)2D3) in Ovarian Cancer Biology

Abstract Posttranslational histone modification plays an important role in tumorigenesis. Histone modification is a dynamic response of chromatin to various signals, such as the exposure to calcitriol (1α,25(OH)2D3). Recent studies suggested that histone modification levels could be used to predict patient outcomes in various cancers. Our study evaluated the expression level of histone 3 lysine 4 trimethylation (H3K4me3) in a cohort of 156 epithelial ovarian cancer (EOC) cases by immunohistochemical staining and analyzed its correlation to patient prognosis. The influence of 1α,25(OH)2D3 on the proliferation of ovarian cancer cells was measured by BrdU proliferation assay in vitro. We could show that higher levels of H3K4me3 were correlated with improved overall survival (median overall survival (OS) not reached vs. 37.0 months, p = 0.047) and identified H3K4me3 as a potential prognostic factor for the present cohort. Ovarian cancer cell 1α,25(OH)2D3 treatment induced H3K4me3 protein expression and exhibited antiproliferative effects. By this, the study suggests a possible impact of H3K4me3 expression on EOC progression as well as its relation to calcitriol (1α,25(OH)2D3) treatment. These results may serve as an explanation on how 1α,25(OH)2D3 mediates its known antiproliferative effects. In addition, they further underline the potential benefit of 1α,25(OH)2D3 supplementation in context of ovarian cancer care

Influences on patient safety in intrapartum electronic fetal heart rate monitoring with cardiotocography (iSafe): protocol for a systematic scoping review

Intrapartum electronic fetal monitoring (EFM) using cardiotocography (CTG) is the recommended method for monitoring the fetal heart rate during labour for high-risk births in England. An abnormal CTG indicates the need for further review and management including potential urgent intervention (e.g. expediting birth) to minimise risk of serious long-term harm to the baby or stillbirth. In the UK, as other European countries, sub-optimal intrapartum EFM management is implicated in a large share of cerebral palsy, birth asphyxia, peripartum hypoxic brain injuries and obstetric malpractice claims. In addition to the psychosocial and social impact of stillbirth or life-long disability on parents and babies, obstetric brain injury is costly, potentially resulting in settlements for millions of pounds to support families over a lifetime of care. Every baby born in the NHS in England now incurs indemnity costs of £1,100. Of the total Clinical Negligence Scheme for Trusts provision of £78bn, 70% relates to maternity. Though maternity claims made up just 10% of the number of clinical negligence claims received by NHS Resolution in 2018-19, they accounted for 50% of the total value of claims. The need for action to improve safety of intrapartum EFM is now urgent, but questions remain about how it can best be achieved. We propose that reducing avoidable harm linked to intrapartum EFM requires sound understanding of the influences on sub-optimal practice. A perhaps more fruitful approach than one that focuses solely on CTG interpretation, more technology and/or solely on training, is to look more broadly at influences on safety. Such an approach would be consistent with the literature in patient safety that has advocated a systems approach to understanding and addressing the effects and interactions of real-world contexts such as teamwork, tasks, equipment, workspace, culture and organisation on clinical performance. It is also consistent with a well-established definition of safety as an attribute of health systems. This systematic scoping review aims to identify what is known in the published literature about such influences on patient safety in intrapartum electronic fetal heart rate monitoring with cardiotocography.This work is part of THIS Institute’s research programme and is funded by the Health Foundation’s grant for THIS Institute to the University of Cambridge. The Health Foundation is an independent charity committed to bringing about better health and health care for people in the UK. The Health Foundation have had no involvement in the development of this protocol

CCL22-polarized TAMs to M2a macrophages in cervical cancer in vitro model

Macrophages are dynamic cells susceptible to the local microenvironment which includes tumor-associated macrophages (TAMs) in cancers. TAMs are a collection of heterogeneous macrophages, including M1 and M2 subtypes, shaped by various activation modes and labeled with various markers in different tumors. CCL22+-infiltrating cells are thought to be significantly associated with the prognosis of cervical cancer patients. Moreover, CCL22 is an established marker of M2a macrophages. Although the phenotypic identification of M1 and M2 macrophages is well established in mice and human macrophages cultured in a medium with fetal calf serum (FCS), fewer studies have focused on M2 subtypes. In addition, the question of whether CCL22 affects polarization of M2a macrophages remains unanswered. This study constructed a co-culture system to shape TAMs in vitro. We found that CCL22 was mainly secreted by TAMs but not cervical cancer cell lines. Human peripheral blood monocytes were differentiated into uncommitted macrophages (M0) and then polarized to M1, M2a, M2b, and M2c macrophages using LPS plus IFNr, IL-4, LPS plus IL1β, and IL-10, respectively. Using flowcytometry, we found CD80++ was the marker of M1 and M2b, CD206++ was the marker of M2a, and CD163++ was the marker of M2c, compared with M0 macrophages. By regulating CCL22, we found that the mean fluorescence intensity (MFI) of CD206 in TAMs was significantly affected compared to the control group. Therefore, CCL22 could polarize TAMs of cervical cancer toward M2a macrophages. In conclusion, our study revealed that CCL22 could be a therapeutic target for cervical cancer, which might be because of its role in regulating macrophage polarization

The G-Protein-Coupled Estrogen Receptor (GPER) Regulates Trimethylation of Histone H3 at Lysine 4 and Represses Migration and Proliferation of Ovarian Cancer Cells In Vitro

Histone H3 lysine 4 trimethylation (H3K4me3) is one of the most recognized epigenetic regulators of transcriptional activity representing, an epigenetic modification of Histone H3. Previous reports have suggested that the broad H3K4me3 domain can be considered as an epigenetic signature for tumor-suppressor genes in human cells. G-protein-coupled estrogen receptor (GPER), a new membrane-bound estrogen receptor, acts as an inhibitor on cell growth via epigenetic regulation in breast and ovarian cancer cells. This study was conducted to evaluate the relationship of GPER and H3K4me3 in ovarian cancer tissue samples as well as in two different cell lines (Caov3 and Caov4). Silencing of GPER by a specific siRNA and two selective regulators with agonistic (G1) and antagonistic (G15) activity were applied for consecutive in vitro studies to investigate their impacts on tumor cell growth and the changes in phosphorylated ERK1/2 (p-ERK1/2) and H3K4me3. We found a positive correlation between GPER and H3K4me3 expression in ovarian cancer patients. Patients overexpressing GPER as well as H3K4me3 had significantly improved overall survival. Increased H3K4me3 and p-ERK1/2 levels and attenuated cell proliferation and migration were observed in Caov3 and Caov4 cells via activation of GPER by G1. Conversely, antagonizing GPER activity by G15 resulted in opposite effects in the Caov4 cell line. In conclusion, interaction of GPER and H3K4me3 appears to be of prognostic significance for ovarian cancer patients. The results of the in vitro analyses confirm the biological rationale for their interplay and identify GPER agonists, such as G1, as a potential therapeutic approach for future investigations

Lysine-specific histone demethylase 1A (LSD1) in cervical cancer

PURPOSE Demethylation of DNA through enzymes like LSD1 showed a crucial impact on different kind of cancers. Epigenetic modifications in cervical cancer are still not fully investigated nevertheless of high interest for a therapeutic use. METHODS Tumor samples of 250 cervical cancer patients were immunochemically stained and evaluated based on Immunoreactive Score. Results were statistically analyzed for clinical and pathological parameters. RESULTS Our patient collective showed a disadvantage for 10-year survival for patients with a strong expression of LSD1 in the cytoplasm of cervical cancer cells. The results of the correlational analysis further revealed a negative correlation of LSD1 to G-protein coupled estrogen receptor (GPER). CONCLUSIONS Epigenetic changes through enzymes like LSD1 may also be of interest for patients with cervical cancer. A combined therapy with other proteins relayed to cervical cancer like GPER might be of interest for future investigations

Subcellular distribution of thyroid hormone receptor beta in ovarian cancer

Background: Since the most well-known function of thyroid hormone receptors (TRs) relies on their ability to act as ligand-activated transcription factors, their subcellular localization has been recognized to be relevant for their biological meaning. The current study aimed to determine the prevalence and subcellular distribution of TR beta and TR beta-1 in ovarian cancer (OC). Methods: Tissue was collected from 153 patients that had undergone surgery due to OC at the Department of Obstetrics and Gynaecology of the Ludwig-Maximilians-University Munich. Immunohistochemistry detecting TR beta and TR beta-1 was performed. Staining signals were quantified and tested for association with clinico-pathological parameters including overall survival (OS). Results: The subcellular distribution of TR beta and TR beta-1 differed among histologic subtypes, grade and FIGO stage. TR beta positivity was strongly linked to shortened overall survival (p < 0.001). Strikingly, this shortened OS was mainly attributed to those cases showing complete (p = 0.005) or incomplete shift of TR beta to the cytoplasm (p < 0.001). Significance was lost in multivariate testing. Conclusions: Cytoplasmatic localization of TR beta was associated with reduced OS, at least in univariate analysis. Since TRs have long been supposed to mainly function via the regulation of gene transcription in the nucleus, cytoplasmatic shifting might be interpreted as a regulator of their activity

Local Optical Spectroscopy in Quantum Confined Systems: A Theoretical Description

A theoretical description of local absorption is proposed in order to investigate spectral variations on a length scale comparable with the extension of the relevant quantum states. A general formulation is derived within the density-matrix formalism including Coulomb correlation, and applied to the prototypical case of coupled quantum wires. The results show that excitonic effects may have a crucial impact on the local absorption with implications for the spatial resolution and the interpretation of near-field optical spectra.Comment: To appear in Phys. Rev. Lett. - 11 pages, 3 PostScript figures (1 figure in colors) embedded. Uses RevTex, and psfig style