Prognostic and therapeutic roles of SETD2 in cutaneous melanoma.

BACKGROUND: Cutaneous melanoma (CM) is an aggressive form of skin cancer with limited treatment options for advanced stages. Prognostic markers that accurately predict patients' outcomes and guide therapeutic strategies are crucial for improving melanoma management. SETD2 (SET Domain-Containing Protein 2), a histone methyltransferase involved in chromatin remodeling and gene regulation, has recently emerged as a tumor suppressor. Its dysfunction is involved in oncogenesis in some cancers, but little is known about its functions in progression and therapeutic response of melanoma. METHODS: RNA-seq and clinical data from public database were used to evaluate the survival analysis, gene set enrichment, IC50 of therapeutics and immunotherapy response. SETD2 knock-out A375 cell line (A375SETD2ko) was developed by Crispr/cas9 and CCK-8 analysis and nude mice used to evaluate the proliferation and invasion of melanoma cells in vitro and in vivo, while Western blotting tested the MMR-related protein. RESULTS: SETD2 was commonly down-regulated in melanoma samples which demonstrated an unfavorable survival. Cells without SETD2 expression tend to have a more progressive and invasive behavior, with resistance to chemotherapy. However, they are more sensitive to tyrosine kinase inhibitors (TKIs). They also exhibit inflamed features with lower TIDE (Tumor Immune Dysfunction and Exclusion) score and higher tumor mutation burden (TMB), showing that these patients may benefit from immunotherapy. CONCLUSIONS: This study revealed that SETD2 dysfunction in melanoma implied a poor prognosis and chemotherapy resistance, but highly sensitive to TKIs and immunotherapy, highlighting the prognostic and therapeutic value of SETD2 in cutaneous melanoma.

Deciphering the Epigenetic Landscape: Placental Development and Its Role in Pregnancy Outcomes.

The placenta stands out as a unique, transitory, and multifaceted organ, essential to the optimal growth and maturation of the fetus. Functioning as a vital nexus between the maternal and fetal circulatory systems, it oversees the critical exchange of nutrients and waste. This exchange is facilitated by placental cells, known as trophoblasts, which adeptly invade and remodel uterine blood vessels. Deviations in placental development underpin a slew of pregnancy complications, notably fetal growth restriction (FGR), preeclampsia (PE), recurrent spontaneous abortions (RSA), and preterm birth. Central to placental function and development is epigenetic regulation. Despite its importance, the intricate mechanisms by which epigenetics influence the placenta are not entirely elucidated. Recently, the scientific community has turned its focus to parsing out the epigenetic alterations during placental development, such as variations in promoter DNA methylation, genomic imprints, and shifts in non-coding RNA expression. By establishing correlations between epigenetic shifts in the placenta and pregnancy complications, researchers are unearthing invaluable insights into the biology and pathophysiology of these conditions. This review seeks to synthesize the latest findings on placental epigenetic regulation, spotlighting its crucial role in shaping fetal growth trajectories and development. Through this lens, we underscore the overarching significance of the placenta in the larger narrative of gestational health.

Synthesis of carbon dot based Schiff bases and selective anticancer activity in glioma cells.

Schiff bases have remarkable anticancer activity and are used for glioma therapy. However, the poor water solubility/dispersibility limits their therapeutic potential in biological systems. To address this issue, carbon dots (CDs) have been utilized to enhance the dispersibility in water and biological efficacy of Schiff bases. The amino groups on the surface of CDs were conjugated effectively with the aldehyde group of terephthalaldehyde to form novel CD-based Schiff bases (CDSBs). The results of the MTT assays demonstrate that CDSBs have significant anticancer activity in glioma GL261 cells and U251 cells, with IC50 values of 17.9 µg mL-1 and 14.9 µg mL-1, respectively. CDSBs have also been found to have good biocompatibility with normal glial cells. The production of reactive oxygen species (ROS) in GL261 glioma cells showed that CDSBs, at a concentration of 44 µg mL-1, resulted in approximately 13 times higher intracellular ROS production than in the control group. These experiments offer evidence that CDSBs induce mitochondrial damage, leading to a reduction in mitochondrial membrane potential in GL261 cells. In particular, in this work, CDs serve not as carriers, but as an integral part of the anticancer drugs, which can expand the role of CDs in cancer treatment.

GAS-STING: a classical DNA recognition pathways to tumor therapy.

Cyclic GMP-AMP synthetase (cGAS), recognized as the primary DNA sensor within cells, possesses the capability to identify foreign DNA molecules along with free DNA fragments. This identification process facilitates the production of type I IFNs through the activator of the interferon gene (STING) which induces the phosphorylation of downstream transcription factors. This action characterizes the most archetypal biological functionality of the cGAS-STING pathway. When treated with anti-tumor agents, cells experience DNA damage that triggers activation of the cGAS-STING pathway, culminating in the expression of type I IFNs and associated downstream interferon-stimulated genes. cGAS-STING is one of the important innate immune pathways,the role of type I IFNs in the articulation between innate immunity and T-cell antitumour immunity.type I IFNs promote the recruitment and activation of inflammatory cells (including NK cells) at the tumor site.Type I IFNs also can promote the activation and maturation of dendritic cel(DC), improve the antigen presentation of CD4+T lymphocytes, and enhance the cross-presentation of CD8+T lymphocytes to upregulating anti-tumor responses. This review discussed the cGAS-STING signaling and its mechanism and biological function in traditional tumor therapy and immunotherapy.

Nono deficiency impedes the proliferation and adhesion of H9c2 cardiomyocytes through Pi3k/Akt signaling pathway.

Congenital heart disease (CHD) is the most common type of birth defect and the main noninfectious cause of death during the neonatal stage. The non-POU domain containing, octamer-binding gene, NONO, performs a variety of roles involved in DNA repair, RNA synthesis, transcriptional and post-transcriptional regulation. Currently, hemizygous loss-of-function mutation of NONO have been described as the genetic origin of CHD. However, essential effects of NONO during cardiac development have not been fully elucidated. In this study, we aim to understand role of Nono in cardiomyocytes during development by utilizing the CRISPR/Cas9 gene editing system to deplete Nono in the rat cardiomyocytes H9c2. Functional comparison of H9c2 control and knockout cells showed that Nono deficiency suppressed cell proliferation and adhesion. Furthermore, Nono depletion significantly affected the mitochondrial oxidative phosphorylation (OXPHOS) and glycolysis, resulting in H9c2 overall metabolic deficits. Mechanistically we demonstrated that the Nono knockout impeded the cardiomyocyte function by attenuating phosphatidyl inositol 3 kinase-serine/threonine kinase (Pi3k/Akt) signaling via the assay for transposase-accessible chromatin using sequencing in combination with RNA sequencing. From these results we propose a novel molecular mechanism of Nono to influence cardiomyocytes differentiation and proliferation during the development of embryonic heart. We conclude that NONO may represent an emerging possible biomarkers and targets for the diagnosis and treatment of human cardiac development defects.

GOLPH3 modulates expression and alternative splicing of transcription factors associated with endometrial decidualization in human endometrial stromal cells.

Endometrial decidualization is a decidual tissue formed by the proliferation and re-differentiation of endometrial stroma stimulated by decidualization inducing factors. It is very important for the proper maintenance of pregnancy. Previous studies speculated that Golgi phosphoprotein 3 (GOLPH3) may have a regulatory role in the process of endometrial decidualization, while the specific molecular mechanisms of GOLPH3 is unclear. In this part, GOLPH3 was silenced in human endometrial stromal cells (hESCs), and the transcriptome data (RNA-seq) by GOLPH3 knockdown (siGOLPH3) was obtained by high-throughput sequencing technology so as to analyze the potential targets of GOLPH3 at expression and alternative splicing levels in hESCs. Through bioinformatics analysis, we found that siGOLPH3 can significantly affect the overall transcriptional level of hESCs. A total of 6,025 differentially expressed genes (DEGs) and 4,131 differentially alternative splicing events (DASEs) were identified. Through functional cluster analysis of these DEGs and genes where differential alternative splicing events are located, it is found that they are enriched in the PI3K/Akt signaling pathway, RNA splicing and processing, transcription factors and other pathways related to endometrial decidualization and important biological processes, indicating the important biological function of GOLPH3. At the same time, we focused on the analysis of the transcription factors regulated by GOLPH3, including gene expression regulation and the regulation of variable splicing. We found that GOLPH3can regulate the expression of transcription factors such as LD1, FOSL2, GATA2, CSDC2 and CREB3L1. At the same time, it affects the variable splicing mode of FOXM1 and TCF3. The function of these transcription factors is directly related to decidualization of endometrium. Therefore, we infer that GOLPH3 may participate in endometrial de membrane by regulating expression and alternative splicing levels of transcription factors. We further identified the role of GOLPH3 in the transcriptional mechanism. At the same time, it also expands the function mode of GOLPH3 protein molecule, and provides a theoretical basis for downstream targeted drug research and development and clinical application.

CRISPR/Cas12a-based assay for the rapid and high-sensitivity detection of Streptococcus agalactiae colonization in pregnant women with premature rupture of membrane.

BACKGROUND: Streptococcus agalactiae or group B Streptococcus (GBS) is a leading infectious cause of neonatal morbidity and mortality. It is essential to establish a robust method for the rapid and ultra-sensitive detection of GBS in pregnant women with premature rupture of membrane (PROM). METHODS: This study developed a CRISPR-GBS assay that combined the advantages of the recombinase polymerase amplification (RPA) and CRISPR/Cas12a system for GBS detection. The clinical performance of the CRISPR-GBS assay was assessed using vaginal or cervical swabs that were collected from 179 pregnant women with PROM, compared in parallel to culture-based matrix-assisted laser desorption ionization time-of-flight mass spectrometry (culture-MS) method and real-time quantitative polymerase chain reaction (qPCR) assay. RESULTS: The CRISPR-GBS assay can be completed within 35 min and the limit of detection was as low as 5 copies µL-1. Compared with the culture-MS, the CRISPR-GBS assay demonstrated a sensitivity of 96.64% (144/149, 95% confidence interval [CI] 92.39-98.56%) and a specificity of 100% (30/30, 95% CI 88.65-100%). It also had a high concordance rate of 98.88% with the qPCR assay. CONCLUSIONS: The established CRISPR-GBS platform can detect GBS in a rapid, accurate, easy-to-operate, and cost-efficient manner. It offered a promising tool for the intrapartum screening of GBS colonization.

Effects of bepridil on early cardiac development of zebrafish.

Bepridil is a commonly used medication for arrhythmia and heart failure. It primarily exerts hemodynamic effects by inhibiting Na+/K+ movement and regulating the Na+/Ca2+ exchange. In comparison to other Ca2+ inhibitors, bepridil has a long half-life and a complex pharmacology. Additionally, it is widely used in antiviral research and the treatment of various diseases. However, the toxicity of this compound and its other possible effects on embryonic development are unknown. In this study, we investigated the toxicity of bepridil on rat myocardial H9c2 cells. After treatment with bepridil, the cells became overloaded with Ca2+ and entered a state of cytoplasmic vacuolization and nuclear abnormality. Bepridil treatment resulted in several morphological abnormalities in zebrafish embryo models, including pericardium enlargement, yolk sac swelling, and growth stunting. The hemodynamic effects on fetal development resulted in abnormal cardiovascular circulation and myocardial weakness. After inhibiting the Ca2+ transmembrane, the liver of zebrafish larvae also displayed an ectopic and deficient spatial location. Additionally, the results of the RNA-seq analysis revealed the detailed gene expression profiles and metabolic responses to bepridil treatment in zebrafish embryonic development. Taken together, our study provides an important evaluation of antiarrhythmic agents for clinical use in prenatal heart patients.

High expression level of MMP9 is associated with poor prognosis in patients with clear cell renal carcinoma.

Matrix metallopeptidase 9 (MMP9) was found to be associated with tumor aggressiveness. In this study, we focused on the correlation between MMP9 expression and clear cell renal carcinoma (ccRCC). Through the Gene Expression Omnibus (GEO) database, the Cancer Genome Atlas (TCGA) database and immunohistochemical (IHC) staining, we observed that compared with adjacent normal renal tissues, in ccRCC tissues the mRNA and protein levels of MMP9 were enhanced, and the mRNA levels of GTP-binding protein smg p21B(RAP1B), B rapidly accelerated fibrosarcoma (RAF), methyl ethyl ketone2 (MEK2), extracellular regulated protein kinases1 (ERK1), ERK2, v-ets avian erythroblastosis virus E26 oncogene homolog1 (ETS1) and ETS2 also increased. The Kaplan-Meier survival analysis suggested that high MMP9 expression was an unfavorable prognostic biomarker for ccRCC patients. Our results indicated that the increased expression level of MMP9 in ccRCC may be due to the activation of the Mitogen-activated protein kinases (MAPK)/ERK signaling pathway, and MMP9 may be an attractive target for ccRCC therapy.