miR-1205/DNAJB1 reverses docetaxel chemoresistance in human triple negative breast carcinoma cells via regulation of mutp53/TAp63 signaling.

Chemoresistance is the major cause of therapeutic failure in human triple negative breast carcinoma (TNBC). Docetaxel (DOC), a first-line therapeutic drug in TNBC treatment, is limited for long-term use due to the development of chemoresistance. Thus, overcoming chemoresistance of DOC remains an important challenge to improve patient's outcome of TNBC. In this study, we aimed to investigate the molecular mechanism behind DOC chemoresistance and the possible therapeutic effects of miRNAs. Utilizing qRT-PCR analysis, we discovered that miR-1205 is gradually downregulated in human triple negative breast carcinoma MDA-MB-231 and docetaxel-resistant MDA-MB-231 (MDA-MB-231/DOC) cells compared with Hs 578Bst normal human breast fibroblasts. Cell viability, cell cycle and apoptosis assays in MDA-MB-231/DOC cells indicated that miR-1205 overexpression enhances docetaxel sensitivity by reducing cell viability as well as inducing G2/M cell cycle arrest and cell apoptosis. Western blot analysis, dual-luciferase reporter assay, co-immunoprecipitation assay and chromatin immunoprecipitation assay revealed that miR-1205 overexpression disrupts the stable complex formation of DNAJB1, mutp53 and TAp63 by directly reducing DNAJB1 expression, which abates the sequestrating effect of mutp53 on TAp63, thereby leading to the enhanced DOC sensitivity in MDA-MB-231/DOC cells. Our findings demonstrate the role of the miR-1205/DNAJB1 axis in the docetaxel resistance of TNBC, which may offer a promising therapeutic approach to resolve docetaxel resistance in TNBC.

CO2 conversion by plasma: how to get efficient CO2 conversion and high energy efficiency.

Conversion of CO2 into CO with plasma processing is a potential method to transform intermittent sustainable electricity into storable chemical energy. The main challenges for developing this technology are how to get efficient CO2 conversion with high energy efficiency and how to prove its feasibility on an industrial scale. In this paper we review the mechanisms and performance of different plasma methodologies used in CO2 conversion. Mindful of the goals of obtaining efficient conversion and high energy efficiency, as well as industrial feasibility in mind, we emphasize a promising new approach of CO2 conversion by using a thermal plasma in combination with a carbon co-reactant.

PPARγ provides anti-inflammatory and protective effects in intrahepatic cholestasis of pregnancy through NF-κB pathway.

AIMS: Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific hepatic disorder with potentially deleterious consequences of fetuses. Although the intimate relationship between ICP and peroxisome proliferator-activated receptor γ (PPARγ) has been previously reported in physiological and pathological conditions, the detailed mechanisms in the process of intrahepatic cholestasis of pregnancy has been unclear. The aims of this study are to assess the role of PPARγ regulating the reactive oxygen species (ROS) and inflammation in the process of the ICP. METHODS: Clinical data of the pregnant women were collected. And the serum of cytokines, hepatic function, the expression of PPARγ and NF-κB were measured. The rat and fetal rat ICP model were constructed and detection of the expression of PPARγ and NF-κB, evaluation the level of ROS and inflammation. RESULTS: The clinical data showed that the new-born information in severe ICP group were significantly different as compared to that in control group (P < 0.05), and part of information in mild ICP group were also difference to that in control group (P < 0.05). The expression of PPARγ and NF-κB were significantly higher in clinical pregnant women, rat, fetal rat ICP model groups and taurocholate acid (TCA) treated HTR-8/SVneo cell (P < 0.01). PPARγ inhibited the production of ROS and decreased the level of inflammation. PPARγ down-regulated the NF-κB pathway. CONCLUSIONS: PPARγ provides the anti-inflammatory and protective effects in intrahepatic cholestasis of pregnancy through NF-κB pathway, which might be a probably one of the mechanisms of ICP.

Tubeimoside V sensitizes human triple negative breast cancer MDA-MB-231 cells to anoikis via regulating caveolin-1-related signaling pathways.

Metastatic triple-negative breast cancer (TNBC) has poor outcome with conventional chemotherapy regimens due to its aggressive behavior. The acquisition of anoikis resistance, a programmed cell death process triggered by substratum detachment, is an important mechanism in TNBC metastasis. Therefore, agents that can restore the sensitivity of cancer cells to anoikis may be helpful for the treatment of metastatic TNBC. In this study, we investigated the inhibitory effect of Tubeimosides V (TBMS-V), a cyclic bisdesmoside isolated from the ethanol extracts of tubers of B. paniculatum., on anoikis resistance and the involvement of caveolin-1(CAV-1)-related signaling pathways in such process in MDA-MB-231 cells. The results showed that the treatment of TBMS-V could sensitize cancer cells to anoikis, which was associated with suppression of anchorage-independent culture-induced CAV-1 overexpression, EGFR activation as well as ITGB1-FAK activation. The data from this study might contribute to providing a potential therapeutic target for metastatic TNBC and suggest the possibility of TBMS-V and its derivatives for metastatic TNBC therapy.

Interleukin-6 contributes to chemoresistance in MDA-MB-231 cells via targeting HIF-1α.

Chemoresistance is a critical challenge in the clinical treatment of triple-negative breast cancer (TNBC). It has been well documented that inflammatory mediators from tumor microenvironment are involved in the pathogenesis of TNBC and might be related to chemoresistance of cancer cells. In this study, the contribution of interleukin-6 (IL-6), one of the principal oncogenic molecules, in chemoresistance of a TNBC cell line MDA-MB-231 was first investigated. The results showed that IL-6 treatment could induce upregulation of HIF-1α via the activation of STAT3 in MDA-MB-231 cells, which consequently contributed to its effect against chemotherapeutic drug-induced cytotoxicity and cell apoptosis. However, knockdown of HIF-1α attenuated such effect via affecting the expressions of apoptosis-related molecules as Bax and Bcl-2 and drug transporters as P-gp and MRP1. This study indicated that targeting at IL-6/HIF-1α signaling pathway might be an effective strategy to overcome chemoresistance in TNBC therapy.

Sodium tanshinone IIA sulfonate prevents hypoxic trophoblast-induced endothelial cell dysfunction via targeting HMGB1 release.

Preeclampsia (PE) is a serious blood pressure disorder of pregnancy. Systemic endothelial cell dysfunction, a hallmark of PE, is previously estimated to be induced by hypoxic trophoblast high mobility group box 1 (HMGB1). In the present study, we investigated the protective effect of sodium tanshinone IIA sulfonate (STS), the soluble form of tanshinone IIA isolated from danshen, against hypoxic trophoblast HMGB1-induced human umbilical vein endothelial cell (HUVEC) dysfunction. Our results showed that HMGB1 expression and release were significantly decreased in STS-treated hypoxic JEG-3 cells. A further study revealed hypoxic trophoblast HMGB1-induced cytotoxicity and leukostasis of HUVEC as well as higher expression of cell adhesion molecules (VCAM-1 and ICAM-1) could be reversed by pretreatment with STS. In conclusion, our study suggests that STS is an effective agent against hypoxic trophoblast-induced cell injury of HUVEC via targeting HMGB1 release and forms the basis of the development of such a compound in treating PE.

E-Cadherin, CD44v6, and Insulin-Like Growth Factor-II mRNA-Binding Protein 3 Expressions in Different Stages of Hydatidiform Moles.

E-cadherin, CD44v6, and IMP3 expression in partial, complete, and invasive hydatidiform moles (HMs) was evaluated. High E-cadherin expression with low CD44v6 expression was observed in partial, complete, and invasive HMs, as well as in normal placental tissues; and there was no significant difference in E-cadherin and CD44v6 expression among the four groups. However, IMP3 expression was gradually decreased in the order of normal placental tissues, partial HMs, complete HMs, and invasive HMs; wherein, invasive HMs had the lowest level. Low IMP3 expression may serve as a prognostic biomarker for HMs, and IMP3 may play a certain role in HMs progression.

Galectin-1 knockdown in carcinoma-associated fibroblasts inhibits migration and invasion of human MDA-MB-231 breast cancer cells by modulating MMP-9 expression.

Carcinoma-associated fibroblasts (CAFs) play central roles in facilitating tumor progression and metastasis in breast cancer. Galectin-1 (Gal-1), a marker of CAFs, was previously reported to be associated with tumorigenesis and metastasis of various types of tumors. The aim of this study is to investigate the role of Gal-1 in CAF-mediated breast cancer metastasis and its underlying molecular mechanisms. Our results showed that CAFs isolated from human breast tumor tissues expressed higher level of Gal-1 compared with paired normal fibroblasts, and the conditioned medium (CM) of CAFs significantly induced the migration and invasion of human MDA-MB-231 breast cancer cells. Knockdown of Gal-1 in CAFs dramatically inhibited CAF-CM-induced cell migration and invasion, probably by inhibiting the expression of matrix metalloprotein 9 (MMP-9). Our findings demonstrate that Gal-1-regulated CAFs activation promotes breast cancer cell metastasis by upregulating MMP-9 expression, which indicated that Gal-1 in CAFs might be a potential novel target for breast cancer therapy.

Ziyuglycoside I Inhibits the Proliferation of MDA-MB-231 Breast Carcinoma Cells through Inducing p53-Mediated G2/M Cell Cycle Arrest and Intrinsic/Extrinsic Apoptosis.

BACKGROUND: Due to the aggressive clinical behavior, poor outcome, and lack of effective specific targeted therapies, triple-negative breast cancer (TNBC) has currently been recognized as one of the most malignant types of tumors. In the present study, we investigated the cytotoxic effect of ziyuglycoside I, one of the major components extracted from Chinese anti-tumor herbal Radix Sanguisorbae, on the TNBC cell line MDA-MB-231. METHODS: The underlying molecular mechanism of the cytotoxic effect ziyuglycoside I on MDA-MB-231 cells was investigated with cell viability assay, flow cytometric analysis and Western blot. RESULTS: Compared to normal mammary gland Hs 578Bst cells, treatment of ziyuglycoside I resulted in a significant growth inhibitory effect on MDA-MB-231 cells. Ziyuglycoside I induced the G2/M phase arrest and apoptosis of MDA-MB-231 cells in a dose-dependent manner. These effects were found to be partially mediated through the up-regulation of p53 and p21WAF1, elevated Bax/Bcl-2 ratio, and the activation of both intrinsic (mitochondrial-initiated) and extrinsic (Fas/FasL-initiated) apoptotic pathways. Furthermore, the p53 specific siRNA attenuated these effects. CONCLUSION: Our study suggested that ziyuglycoside I-triggered MDA-MB-231 cell cycle arrest and apoptosis were probably mediated by p53. This suggests that ziyuglycoside I might be a potential drug candidate for treating TNBC.

The role of miR-200a in vasculogenic mimicry and its clinical significance in ovarian cancer.

OBJECTIVE: Vasculogenic mimicry (VM) indicates that aggressive cancer cells can form de novo vascular networks and provide a perfusion pathway for rapidly growing tumors. MiR-200a has been reported significantly deregulated in ovarian cancer. However, miR-200a regulation of VM and its clinical significance in ovarian cancer remain not elucidated. METHODS: In this study, we identified the VM structure by CD34-PAS staining in ovarian cancer tissue. MiR-200a and protein expression was tested by quantitative RT-PCR and western blot. Bioinformatics prediction, luciferase assay and intervention experiments were employed to identify the target of miR-200a. RESULTS: We certified the VM structure in ovarian cancer, and found that the VM positive rate was significantly associated with tumor grade, stage and metastasis. Further study showed that miR-200a expression levels were significantly lower in VM positive ovarian cancer. In addition, our results suggested that miR-200a inhibited VM by negatively regulated EphA2 expression. Consistently, the inverse correlation of miR-200a and EphA2 has also been found in ovarian cancer patients. Moreover, the expression of miR-200a/EphA2 was significantly associated with patient's clinicopathological parameter, such as tumor stage and metastases. Kaplan-Meier curves confirmed that the patients with low miR-200a expression and/or VM positive had a significantly shorter overall survival. CONCLUSIONS: Our research demonstrates that VM, miR-200a and EphA2 play key roles in the progression and prognosis of ovarian cancer, and for the first time suggests that miR-200a inhibits VM by directly regulating EphA2. Therefore, we might have identified a genetic mechanism underlying the involvement of miR-200a in ovarian cancer VM.

Identification of potential biomarkers for idiopathic pulmonary arterial hypertension using single-cell and bulk RNA sequencing analysis.

Idiopathic pulmonary arterial hypertension (IPAH) is a rare and severe cardiopulmonary disease with a challenging prognosis, and its underlying pathogenesis remains elusive. A comprehensive understanding of IPAH is crucial to unveil potential diagnostic markers and therapeutic targets. In this study, we investigated cellular heterogeneity and molecular pathology in IPAH using single-cell RNA sequencing (scRNA-seq) analysis. Our scRNA-seq results revealed significant alterations in three crucial signaling pathways in IPAH: the hypoxia pathway, TGF ß pathway, and ROS pathway, primarily attributed to changes in gene expression within arterial endothelial cells. Moreover, through bulk RNA sequencing analysis, we identified differentially expressed genes (DEGs) enriched in GO and KEGG pathways, implicated in regulating cell adhesion and oxidative phosphorylation in IPAH lungs. Similarly, DEGs-enriched pathways in IPAH arterial endothelial cells were also identified. By integrating DEGs from three IPAH datasets and applying protein-protein interaction (PPI) analysis, we identified 12 candidate biomarkers. Subsequent validation in two additional PAH datasets led us to highlight five potential biomarkers (CTNNB1, MAPK3, ITGB1, HSP90AA1, and DDX5) with promising diagnostic significance for IPAH. Furthermore, real-time quantitative polymerase chain reaction (RT-qPCR) confirmed significant differences in the expression of these five genes in pulmonary arterial endothelial cells from PAH mice. In conclusion, our findings shed light on the pivotal role of arterial endothelial cells in the development of IPAH. Furthermore, the integration of single-cell and bulk RNA sequencing datasets allowed us to pinpoint novel candidate biomarkers for the diagnosis of IPAH. This work opens up new avenues for research and potential therapeutic interventions in IPAH management.

Effect of Nano-selenium on Biological Mechanism of Goblet Cells of the Small Intestine Within Laying Hen.

Dietary selenium intake within the normal physiological range is critical for various supporting biological functions. However, the effect of nano-selenium on biological mechanism of goblet cells associated with autophagy is largely unknown.The purpose of this study was to investigate the effect of nano-selenium on the mucosal immune-defense mechanism of goblet cells (GCs) in the small intestine of laying hens.The autophagy was determined by using specific markers. Nano-selenium-treated group of immunohistochemistry (IHC), immunofluorescence (IF), and western blotting (WB) results indicated the strong positive immune signaling of microtubule-associated light chain (LC3) within the mucosal surface of the small intestine. However, weak expression of LC3 was observed in the 3-methyladenine autophagy inhibitor (3-MA) group. IHC and IF staining results showed the opposite tendency for LC3 of sequestosome 1 (P62/SQSTM1). P62/SQSTM1 showed strong positive immune signaling within the mucosal surface of the small intestine of the 3-MAgroup, and weak immune signaling of P62/SQSTM1 in the nano-selenium-treated group. Moreover, pinpointing autophagy was involved in the mucosal production and enrichment of mucosal immunity of the GCs. The morphology and ultrastructure evidence showed that the mucus secretion of GCs was significantly increased after nano-selenium treatment confirmed by light and transmission electron microscopy. Besides that, immunostaining of IHC, IF and WB showed that autophagy enhanced the secretion of Mucin2 (Muc2) protein in nano-selenium-treated group. This work illustrates that the nano-selenium particle might enhance the mucosal immune-defense mechanism via the protective role of GCs for intestinal homeostasis through autophagy.

HtrA3 is negatively correlated with lymph node metastasis in invasive ductal breast cancer.

Breast cancer is the most common cancer in women worldwide. Studies have shown that the high temperature requirement factor A3 (HtrA3) is involved in important physiological processes including maintenance of mitochondrial homeostasis, cell death, and cell signaling. HtrA3 is reported to be downregulated in several cancers and has been correlated with advancing cancer stage. We performed a retrospective study using our breast cancer tissue bank to investigate whether the expression of HtrA3 correlated with lymphatic metastasis in breast cancer and whether the expression of HtrA3 was correlated with estrogen receptor (ER) and progesterone receptor (PR) expression in breast cancer. Breast cancer tissues from 156 invasive ductal breast cancer patients with or without lymphatic metastasis were collected and the levels of HtrA3 were measured by immunohistochemistry and western blotting. The expression of HtrA3 was lower in breast cancer. In particular, HtrA3 expression in breast cancer with lymphatic metastasis was lower than that in breast cancer without lymphatic metastasis. In breast cancers with no lymphatic metastasis, the expression of HtrA3 was lower in patients with ER- and PR-positive tumors, but when breast cancers with lymphatic metastasis were analyzed, there was no difference in HtrA3 expression between ER- and PR-positive or ER- and PR-negative tumors. These data suggest that the expression of HtrA3 was negatively correlated with lymphatic metastasis in breast cancer but not correlated with ER and PR positivity or negativity. A better understanding of the mechanism of HtrA3 may provide the basis for future development of a novel therapeutic target in breast cancer.

High carrier frequency of pathogenic PATL2 gene mutations predicted in population: a bioinformatics-based approach.

Topoisomerase II homologue 2 (PATL2) has been confirmed to be a key gene that contributes to oocyte maturation. However, the allele distribution and carrier frequency of these mutations remain uncharacterized. So a bioinformatics subcategory analysis of PATL2 mutations from outcome data and Single Nucleotide Polymorphism (SNP) databases was conducted. Altogether, the causative PATL2 mutation number detected in patients with oocyte maturation defects in the clinical studies and pathogenic PATL2 mutation sites predicted by software based on the database was approximately 53. The estimated carrier frequency of pathogenic mutation sites was at least 1.14‰ based on the gnomAD and ExAC database, which was approximately 1/877. The highest frequency of mutations detected in the independent patients was c.223-14_223-2del13. The carrier frequency of this mutation in the population was 0.25‰, which may be a potential threat to fertility. Estimated allele and carrier frequency are relatively higher than those predicted previously based on clinical ascertainment. A review of PATL2 mutation lineage identified in 34 patients showed that 53.81%, 9.22% and 14.72% of the oocytes with PATL2 mutations were arrested at the germinal vesicle (GV) stage, metaphase I (MI) stage and first polar body stage, respectively. Oocytes that could develop to the first polar body stage were extremely rare to fertilise, and their ultimate fate was early embryonic arrest. Phenotypic variability is related to the function of the regions and degree of loss of function of PATL2 protein. A 3D protein structure changes predicted by online tools, AlphaFold, showed aberrations at the mutation sites, which may explain partially the function loss. When the mutated and wild-type proteins are not in the same amino acid category, the protein structure will be considerably unstable. The integration of additional mutation sites with phenotypes is helpful in drawing a complete picture of the disease. Bioinformatics analysis of PATL2 mutations will help reveal molecular epidemiological characteristics and provide an important reference for new mutation assessment, genetic counselling and drug research.

HE4 overexpression in mice leads to leydig cell hyperplasia and spermatogensis impairment: Pathological implications for oligospermia.

Previous studies have shown that HE4 cancer biomarker promoted cancer cell proliferation and tumor growth in mouse xenograft models. Interestingly, HE4 levels are significantly increased in the seminal plasma of oligoasthenospermia patients, raising a question on HE4 role(s) in spermatogenesis. We constructed an HE4 overexpression mouse model (HE4-OE), and observed that HE4-OE male adult mice had small testes, low sperm counts, and elevated serum/testis testosterone levels. These mice exhibited disorganized seminiferous tubules and impaired spermatogenesis. HE4 overexpression concentrated in Leydig cells, and these cells had hyperplasia and increased testosterone biosynthesis. Mechanistic studies indicated that the impaired spermatogenesis was likely caused by a local and direct action of HE4 in the testis rather than by a hypothalamus/pituitary-initiated dysregulation. The new findings reveal a novel HE4 function in male reproductive system, and suggest the existence of a subtype of primary oligoasthenospermia characterized by HE4 overexpression, Leydig cell hyperplasia, and elevated testosterone levels.

Insight of novel biomarkers for papillary thyroid carcinoma through multiomics.

Introduction: The overdiagnosing of papillary thyroid carcinoma (PTC) in China necessitates the development of an evidence-based diagnosis and prognosis strategy in line with precision medicine. A landscape of PTC in Chinese cohorts is needed to provide comprehensiveness. Methods: 6 paired PTC samples were employed for whole-exome sequencing, RNA sequencing, and data-dependent acquisition mass spectrum analysis. Weighted gene co-expression network analysis and protein-protein interactions networks were used to screen for hub genes. Moreover, we verified the hub genes' diagnostic and prognostic potential using online databases. Logistic regression was employed to construct a diagnostic model, and we evaluated its efficacy and specificity based on TCGA-THCA and GEO datasets. Results: The basic multiomics landscape of PTC among local patients were drawn. The similarities and differences were compared between the Chinese cohort and TCGA-THCA cohorts, including the identification of PNPLA5 as a driver gene in addition to BRAF mutation. Besides, we found 572 differentially expressed genes and 79 differentially expressed proteins. Through integrative analysis, we identified 17 hub genes for prognosis and diagnosis of PTC. Four of these genes, ABR, AHNAK2, GPX1, and TPO, were used to construct a diagnostic model with high accuracy, explicitly targeting PTC (AUC=0.969/0.959 in training/test sets). Discussion: Multiomics analysis of the Chinese cohort demonstrated significant distinctions compared to TCGA-THCA cohorts, highlighting the unique genetic characteristics of Chinese individuals with PTC. The novel biomarkers, holding potential for diagnosis and prognosis of PTC, were identified. Furthermore, these biomarkers provide a valuable tool for precise medicine, especially for immunotherapeutic or nanomedicine based cancer therapy.

How Nanotechniques Could Vitalize the O-GlcNAcylation-Targeting Approach for Cancer Therapy.

Accumulated data indicated that many types of cancers have increased protein O-GlcNAcylation at cell surface and inside cells. The aberrant O-GlcNAcylation is considered a potential therapeutic target. Although several types of compounds capable of inhibiting O-GlcNAcylation have been developed, their low solubility, poor permeability and delivery efficiency have impeded the application for in vivo and pre-clinical studies. Nanocarriers have the advantages of controllable drug release and active cancer-targeting capability. Moreover, nanoparticles can improve drug delivery efficiency and reduce the non-specific distribution in normal tissues by the enhanced permeability and retention (EPR) effect in cancer. Taking the advantage of O-GlcNAc-specific antibodies or lectins, nanoparticles could further improve their cancer-targeting capability. Although nanocarriers targeting the canonical N- and O-linked glycosylation have been extensively investigated for cancer detection and therapy, application of nanotechniques for the specific targeting of O-GlcNAcylation has not been actively pursued. This review summarizes the general features of GlcNAcylation and its alterations in cancers. Analyses are focused on the following areas: How the nanocarriers may improve the solubility and/or cell permeability of O-GlcNAc transferase (OGT) inhibitors; The modification of nanocarriers with lectins or antibodies for active targeting of O-GlcNAc; The nanocarriers-mediated co-delivery of OGT inhibitors and conventional drugs, which may lead to synergistic effects. Unsolved issues impeding the research progression on O-GlcNAcylation-targeting scheme are also discussed.

Diagnostic Management of Oncogenic HPV Cervical Infections: The Field Experience in Wuxi, China.

Introduction: A liquid-based cytology test was introduced for cervical cancer screening in the 2000s worldwide. However, the concordance of diagnostic findings between the liquid-based cytology test and cervical biopsy has not been fully investigated, especially the overall failure rate on the diagnosis of cervical cancer and high-grade squamous intraepithelial lesion (HSIL) by cytology testing. The aim of this retrospective study was to investigate the concordance between ThinPrep cytology and histology test in the diagnosis of cervical cancer and HSIL in HPV-positive women. Methods: ThinPrep cytology test was performed in 2,472 HPV-positive women. Out of 2,472 HPV-positive women, the cervical biopsy was concurrently performed in 1,533 women. Data on the HPV type and the diagnostic findings of the ThinPrep cytology test and cervical biopsy were collected from our hospital electronic database. The concordance of diagnostic findings between cytology and histology was compared. Results: The rate of agreement in the diagnosis of the low-grade squamous intraepithelial lesion (LSIL) or HSIL between cervical biopsy and ThinPrep cytology test was 58 or 49%. The overall false negative rate in the diagnosis of cervical cancer and HSIL by ThinPrep cytology test was 6%. However, when considering the total number of HPV-positive women diagnosed with cervical cancer (n = 36) and HSIL (n = 117) by cervical biopsy, we found that a significant number of HPV-positive women with cervical cancer (n = 12, 33%), or women with HSIL (n = 77, 66%) were failed to be diagnosed by the ThinPrep cytology test. These HPV-positive women were either diagnosed with cervical infection or ASCUS, or LSIL. Discussion: Our data demonstrated that in order to ensure an accurate diagnosis, an immediate cervical biopsy in women with cervical infection or ASCUS or LSIL should be strongly recommended in clinical practice.

IGF2BP2 promotes the progression of ovarian endometriosis by regulating m6A-modified MEIS2 and GATA6.

BACKGROUND: m6A-RNA modification mediated by the N6-methyladenosine RNA methylation-related molecule methyltransferase-like 3 has been implicated in the progression of endometriosis. However, the functions of other m6A regulators, especially in ovarian endometriosis, remain unknown. METHODS: Three datasets (GSE7305, GSE7307, and GSE37837) with diagnosed ovarian endometriosis were extracted from the Gene Expression Omnibus database. Using bioinformatics methods such as Weighted Gene Co-expression Network Analysis, Gene Ontology analysis, protein-protein interaction, and correlation, hub genes were identified. Using dot blot and N6-methyladenosine-IP-qPCR, the total and individual N6-methyladenosine gene levels were quantified. On clinical ovarian ectopic and eutopic endometrium tissues, N6-methyladenosine RNA methylation sequencing was performed. To authenticate protein localization and expression level, immunohistochemical staining and western blot were conducted, respectively. The database Connectivity Map was used to predict small molecules with potential therapeutic effects. RESULTS: In ovarian endometriosis, the N6-methyladenosine "reader" molecule IGF2BP2 and related target genes MEIS2 and GATA6 were highly expressed. IGF2BP2 promoted the proliferation, migration, and invasion of ectopic endometrial stromal cells by stabilizing the mRNA of MEIS2 and GATA6. Synergistically, METTL3 and IGF2BP2 increased the N6-methyladenosine methylation of MEIS2 and GATA6. We developed five molecules (Mercaptopurine, MK-886, CP-863187, Canadine, and Securinine) that could be used to treat ovarian endometriosis based on IGF2BP2. CONCLUSION: Our findings provided additional support for a systematized understanding of the role of N6-methyladenosine RNA methylation in endometriosis and confirmed for the first time the mechanism of IGF2BP2 in promoting ovarian endometriosis. This provides the molecular foundation for potential future therapies for ovarian endometriosis. DATA AVAILABILITY: The data used to support the findings of this study are available from the corresponding author upon request.

CMTM7 recognizes an immune-hot tumor microenvironment and predicts therapeutic response of immunotherapy in breast cancer well.

Breast cancer (BRCA) is a complex disease that leads to major mortalities and unsatisfactory clinical outcomes among women worldwide. CKLF-like MARVEL transmembrane domain-containing 7 (CMTM7) is a potential tumor suppressor and regulator of PD-L1, which has been found as a functional signature in considerable oncogenesis, progression, and therapeutic resistance via deletion and downregulation. In this research, triple-negative breast cancer (BRCA), a molecular subtype having a lower response to endocrinotherapy but a higher response to chemotherapy and immunotherapy, showed higher transcriptional levels of CMTM7. Moreover, CMTM7 positively correlated with immunomodulators, tumor-infiltrating immune cells (TIICs), and immune checkpoints in many independent datasets. Furthermore, in an immunotherapy cohort of BRCA, patients with high CMTM7 expression were more sensitive to immunotherapy, and the therapeutic predictive value of CMTM7 is higher than that of PD-1 and PD-L1. To sum up, CMTM7 correlated with an inflamed tumor microenvironment and identified immune-hot tumors, which can be a novel biomarker for the recognition of immunological characteristics and an immunotherapeutic response in BRCA.