Downregulation of KLF5 by EBER1 via the ERK signaling pathway in EBV-positive nasopharyngeal carcinoma cells: implications for latent EBV infection.

Nasopharyngeal carcinoma (NPC) carcinogenesis and malignant transformation are intimately associated with Epstein-Barr virus (EBV) infection. A zinc-fingered transcription factor known as Krüppel-like factor 5 (KLF5) has been shown to be aberrantly expressed in a number of cancer types. However, little is known about the regulatory pathways and roles of KLF5 in EBV-positive NPC. Our study found that KLF5 expression was significantly lower in EBV-positive NPC than in EBV-negative NPC. Further investigation revealed that EBER1, which is encoded by EBV, down-regulates KLF5 via the extracellular signal-regulated kinase (ERK) signalling pathway. This down-regulation of KLF5 by EBER1 contributes to maintaining latent EBV infection in NPC. Furthermore, we uncovered the biological roles of KLF5 in NPC cells. Specifically, KLF5 may influence the cell cycle, prevent apoptosis, and encourage cell migration and proliferation - all of which have a generally pro-cancer impact. In conclusion, these findings offer novel strategies for EBV-positive NPC patients' antitumour treatment.

Antagonizing roles of SHP1 in the pathogenesis of Helicobacter pylori infection.

BACKGROUND: SHP1 has been documented as a tumor suppressor and it was thought to play an antagonistic role in the pathogenesis of Helicobacter pylori infection. In this study, the exact mechanism of this antagonistic action was studied. MATERIALS AND METHODS: AGS, MGC803, and GES-1 cells were infected with H. pylori, intracellular distribution changes of SHP1 were first detected by immunofluorescence. SHP1 overexpression and knockdown were then constructed in these cells to investigate its antagonistic roles in H. pylori infection. Migration and invasion of infected cells were detected by transwell assay, secretion of IL-8 was examined via ELISA, the cells with hummingbird-like alteration were determined by microexamination, and activation of JAK2/STAT3, PI3K/Akt, and ERK pathways were detected by immunoblotting. Mice infection model was established and gastric pathological changes were evaluated. Finally, the SHP1 activator sorafenib was used to analyze the attenuating effect of SHP1 activation on H. pylori pathogenesis in vitro and in vivo. RESULTS: The sub-localization of SHP1 changed after H. pylori infection, specifically that the majority of the cytoplasmic SHP1 was transferred to the cell membrane. SHP1 inhibited H. pylori-induced activation of JAK2/STAT3 pathway, PI3K/Akt pathway, nuclear translocation of NF-κB, and then reduced EMT, migration, invasion, and IL-8 secretion. In addition, SHP1 inhibited the formation of CagA-SHP2 complex by dephosphorylating phosphorylated CagA, reduced ERK phosphorylation and the formation of CagA-dependent hummingbird-like cells. In the mice infection model, gastric pathological changes were observed and increased IL-8 secretion, indicators of cell proliferation and EMT progression were also detected. By activating SHP1 with sorafenib, a significant curative effect against H. pylori infection was obtained in vitro and in vivo. CONCLUSIONS: SHP1 plays an antagonistic role in H. pylori pathogenesis by inhibiting JAK2/STAT3 and PI3K/Akt pathways, NF-κB nuclear translocation, and CagA phosphorylation, thereby reducing cell EMT, migration, invasion, IL-8 secretion, and hummingbird-like changes.

Zishen Qingre Lishi Huayu recipe promotes proliferation and inhibits apoptosis of GCs of PCOS via KLF4-C/EBPß pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Zishen Qingre Lishi Huayu recipe (ZQLHR) is a herbal recipe created on the basis on the theory of traditional Chinese medicine and clinical practice, and is mainly used in the treatment of polycystic ovary syndrome (PCOS). However, the underlying mechanism for this fact has not been clearly elucidated. AIM OF THE STUDY: To verify whether ZQLHR regulates granulosa cells (GCs) proliferation and apoptosis through the Krüppel-like factor 4 (KLF4) - CCATT enhancer-binding proteinß (C/EBPß) pathway, and to provide in vitro molecular mechanism supporting for the effects of ZQLHR to enhance follicular development and treat patients with PCOS. MATERIALS AND METHODS: Based on previous experiments, we performed the following experiments. Firstly, we treated KGN cells (a steroidogenic human granulosa-like tumor cell line) for 48 h using different concentrations of ZQLHR in order to observe apoptosis in each group. Secondly, the mRNA and protein expression levels of KLF4 and C/EBPß in KGN cells after administrated with ZQLHR were examined by quantitative real-time PCR(q-PCR) and Western blot assay. Thirdly, after knocking down KLF4 and C/EBPß using siRNAs, the relationship between KLF4 and C/EBPß in KGN cells was detected. Further, cell counting kit-8 assay, colony formation assay and flow cytometry were used to verify whether ZQLHR promotes proliferation and facilitates apoptosis in KGN cells through the KLF4-C/EBPß pathway. Finally, q-PCR and Western blot were used to test whether ZQLHR mediated proliferation and apoptosis-related factors such as B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X (BAX), proliferating cell nuclear antigen (PCNA) and cleaved caspase-3 to affect the proliferation and apoptosis of KGN cells through the KLF4-C/EBPß pathway. CONCLUSIONS: ZQLHR, containing 0.2% by volume, administered to KGN cells resulted in the lowest rate of apoptosis. The expression levels of KLF4 and C/EBPß were increased in KGN cells following ZQLHR treatment. Additionally, ZQLHR promoted proliferation and inhibited apoptosis of KGN cells by modulating proliferation and apoptosis-related factors via the KLF4-C/EBPß pathway. Furthermore, we confirmed that KLF4 and C/EBPß regulate each other in KGN cells. These findings indicate that ZQLHR enhances the proliferation of GCs and suppresses their apoptosis, which constitutes a therapeutic mechanism for treating patients with PCOS.

Effects of Benzo (a) Pyrene and 2,2',4,4'-Tetrabromodiphenyl Ether Exposure on the Thyroid Gland in Rats by Attenuated Total Reflection Fourier-Transform Infrared Spectroscopy.

Benzo[a]pyrene (B[a]P) and 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) are widespread environmental pollutants and can destroy thyroid function. We assessed the biochemical changes in the thyroid tissue of rats exposed to B[a]P and BDE-47 using attenuated total reflection Fourier-transform infrared spectroscopy combined with support vector machine(SVM). After B[a]P and BDE-47 treatment in rats, the structure of thyroid follicles was destroyed and epithelial cells were necrotic, indicating that B[a]P and BDE-47 may lead to changes of the thyroid morphology of the rats. These damages are mainly related to C=O stretch vibrations of lipids (1743 cm-1), as well as the secondary structure of proteins [amide I (1645 cm-1) and amide II (1550 cm-1)], and carbohydrates [C-OH (1138 cm-1), C-O (1106 cm-1, 1049 cm-1, 991 cm-1), C-C (1106 cm-1) stretching] and collagen (phosphodiester stretching at 922 cm-1) vibration modes. When SVM was used for classification, there was a substantial separation between the control and the exposure groups (accuracy = 96%; sensitivity = 98%; specificity = 87%), and there was also a major separation between the exposed groups (accuracy = 93%; sensitivity = 94%; and specificity = 92%).

Thyroid Metastases from Triple-Negative Breast Cancer with High PD-L1 Expression - A Rare Presentation.

Thyroid metastases secondary to triple-negative breast cancer are sporadic. Diagnosis usually requires fine needle aspiration biopsy (FNAB) and immunohistochemistry. There are no treatment guidelines for this type of cancer, and to date, reports of chemotherapy combined with immunotherapy in thyroid metastases are very rare. Here, we first report the effectiveness of anti-PD-1 inhibitor in combination with chemotherapy for the treatment of metastatic thyroid cancer secondary to advanced triple-negative breast cancer with high expression of programmed cell death ligand 1 (PD-L1). Following six cycles of albumin paclitaxel (400mg d1/21 days) plus PD-1 antibody inhibitor (Sindilizumab 200mg d1/21 days), the patient experienced significant relief of neck swelling and obstructive feeding, both the thyroid metastases and the right breast lesion regressed completely following six cycles of treatment. Chemotherapy combined with immunotherapy may provide a new direction for unresectable advanced thyroid metastases.

Mesenchymal stem cell-derived extracellular vesicles: A novel promising neuroprotective agent for Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive loss of neurons in the brain. However, there are no effective drugs for AD. Mesenchymal stem cell-derived extracellular vesicles (MSCs-EVs), as a new mediator of intercellular communication, are associated with low immunogenicity, low risk of tumor formation, and good safety profile. Therefore, MSCs-EVs may be a safe and attractive cell-free nanotherapeutics, offering a new perspective for AD treatment. Although preclinical studies have demonstrated that MSCs-EVs have significant neuroprotective effects, the underlying mechanism is unclear. This study aimed to: outline the diagnostic and delivery roles of MSCs-EVs for AD treatment; summarize the optimal sources and delivery methods of MSCs-EVs; provide a comprehensive review on the neuroprotective mechanisms of MSCs-EVs; explore how to enhance the neuroprotective effects of MSCs-EVs; and discuss the limitations and potential of their translation to the clinic. Therefore, this study may provide a more precise theoretical reference and practical basis for clinical research of MSCs-EVs.

Enhancing immune responses of ESC-based TAA cancer vaccines with a novel OMV delivery system.

Embryonic stem cell (ESC)-derived epitopes can act as therapeutic tumor vaccines against different types of tumors Jin (Adv Healthc Mater 2023). However, these epitopes have poor immunogenicity and stimulate insufficient CD8+ T cell responses, which motivated us to develop a new method to deliver and enhance their effectiveness. Bacterial outer membrane vesicles (OMVs) can serve as immunoadjuvants and act as a delivery vector for tumor antigens. In the current study, we engineered a new OMV platform for the co-delivery of ESC-derived tumor antigens and immune checkpoint inhibitors (PD-L1 antibody). An engineered Staphylococcal Protein A (SpA) was created to non-specifically bind to anti-PD-L1 antibody. SpyCatcher (SpC) and SpA were fused into the cell outer membrane protein OmpA to capture SpyTag-attached peptides and PD-L1 antibody, respectively. The modified OMV was able to efficiently conjugate with ESC-derived TAAs and PD-L1 antibody (SpC-OMVs + SpT-peptides + anti-PD-L1), increasing the residence time of TAAs in the body. The results showed that the combination therapy of ESC-based TAAs and PD-L1 antibody delivered by OMV had significant inhibitory effects in mouse tumor model. Specifically, it was effective in reducing tumor growth by enhancing IFN-γ-CD8+ T cell responses and increasing the number of CD8+ memory cells and antigen-specific T cells. Overall, the new OMV delivery system is a versatile platform that can enhance the immune responses of ESC-based TAA cancer vaccines.

Anti-tumor therapy of glycyrrhetinic acid targeted liposome co-delivery of doxorubicin and berberine for hepatocellular carcinoma.

During the development of hepatocellular carcinoma (HCC), hepatic stellate cells undergo activation and transform into cancer-associated fibroblasts (CAFs) due to the influence of tumor cells. The interaction between CAFs and tumor cells can compromise the effectiveness of chemotherapy drugs and promote tumor proliferation, invasion, and metastasis. This study explores the potential of glycyrrhetinic acid (GA)-modified liposomes (lip-GA) as a strategy for co-delivery of berberine (Ber) and doxorubicin (Dox) to treat HCC. The characterizations of liposomes, including particle size, zeta potential, polydispersity index, stability and in vitro drug release, were investigated. The study evaluated the anti-proliferation and anti-migration effects of Dox&Ber@lip-GA on the Huh-7 + LX-2 cell model were through MTT and wound-healing assays. Additionally, the in vivo drug distribution and anti-tumor efficacy were investigated using the H22 + NIH-3T3-bearing mouse model. The results indicated that Dox&Ber@lip-GA exhibited a nanoscale particle size, accumulated specifically in the tumor region, and was efficiently taken up by tumor cells. Compared to other groups, Dox&Ber@lip-GA demonstrated higher cytotoxicity and lower migration rates. Additionally, it significantly reduced the deposition of extracellular matrix (ECM) and inhibited tumor angiogenesis, thereby suppressing tumor growth. In conclusion, Dox&Ber@lip-GA exhibited superior anti-tumor effects both in vitro and in vivo, highlighting its potential as an effective therapeutic strategy for combating HCC.

Targeting EBV-encoded products: Implications for drug development in EBV-associated diseases.

Epstein-Barr virus, a human gamma-herpesvirus, has a close connection to the pathogenesis of cancers and other diseases, which are a burden for public health worldwide. So far, several drugs or biomolecules have been discovered that can target EBV-encoded products for treatment, such as Silvestrol, affinity toxin, roscovitine, H20, H31, curcumin, thymoquinone, and ribosomal protein L22. These drugs activate or inhibit the function of some biomolecules, affecting subsequent signalling pathways by acting on the products of EBV. These drugs usually target LMP1, LMP2; EBNA1, EBNA2, EBNA3; EBER1, EBER2; Bam-HI A rightward transcript and BHRF1. Additionally, some promising findings in the fields of vaccines, immunological, and cellular therapies have been established. In this review, we mainly summarise the function of drugs mentioned above and unique mechanisms, hoping that we can help giving insight to the design of drugs for the treatment of EBV-associated diseases.

Lung metastasis from thyroid cancer: A case report of unusual imaging presentation of lung metastases.

RATIONALE: Thyroid cancer (TC) is the most common malignancy of the head and neck and endocrine system. Distant metastases from TC are rare and are diagnosed in only 1% to 4% of patients, and these patients have a poor prognosis, which is the leading cause of TC-related deaths. There are few reports on metastatic TC in China and abroad, and even fewer reports on lung metastases from TC. We report a special patient with lung metastases of TC. PATIENT CONCERNS: The patient is a 31-year-old female who was found to have both lung nodules during physical examination. Chest computed tomography (CT) showed that the density of both lung nodules was the same as the vascular density, considering that the possibility of vascular origin was not excluded. DIAGNOSIS: After consultation with the whole hospital, it was considered that vascular malformations, hemangiomas, and malignant metastases were not excluded, the patient percutaneous lung biopsy had a high risk of bleeding, and thoracoscopic lobectomy could be performed in thoracic surgery to further clarify the pathology and diagnosis. OUTCOMES: The patient underwent thoracoscopic left lower lobe wedge resection on February 24, 2021. Postoperative pathology: (left lower lung mass) metastatic carcinoma, combined with morphology and immunohistochemistry, leaning toward thyroid follicular carcinoma lung metastasis. On May 27, 2021, the patient underwent "total thyroidectomy + lymph node dissection in the right cervical VI region." Pathological examination: (right lobe and isthmus of the thyroid gland) papillary TC, follicular subtype, and classic type, with interstitial fibrosis. The patient was diagnosed with lung metastasis of TC. LESSONS: This patient had the same CT value of lung metastases as the vascular CT value, which is relatively rare in our clinical practice and worthy of our study. The special CT imaging presentation of this TC patient with lung metastases further broadened our horizon. In clinical practice, when we encounter similar cases, we should combine more with other tests and examinations of patients to avoid misdiagnosis and missed diagnosis.

Ferroptosis: Underlying mechanism and the crosstalk with other modes of neuronal death after intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is a serious cerebrovascular disease with high rates of morbidity, mortality, and disability. Optimal treatment of ICH is a major clinical challenge, as the underlying mechanisms remain unclear. Ferroptosis, a newly identified form of non-apoptotic programmed cell death, is characterized by the iron-induced accumulation of lipid reactive oxygen species (ROS), leading to intracellular oxidative stress. Lipid ROS causes damage to nucleic acids, proteins, and cell membranes, eventually resulting in ferroptosis. In the past 10 years, ferroptosis has resulted in plenty of discoveries and breakthroughs in cancer, neurodegeneration, and other diseases. Some studies have also reported that ferroptosis does occur after ICH in vitro and in vivo and contribute to neuronal death. However, the studies on ferroptosis following ICH are still in the preliminary stage. In this review, we will summarize the current evidence on the mechanism underlying ferroptosis after ICH. And review the traditional modes of neuronal death to identify the crosstalk with ferroptosis in ICH, including apoptosis, necroptosis, and autophagy. Additionally, we also aim to explore the promising therapeutic application of ferroptosis in cell death-based ICH.

When AHR signaling pathways meet viral infections.

Aryl hydrocarbon receptor (AHR) is a ligand-dependent transcriptional factor widely expressed among immune, epithelial, endothelial and stromal cells in barrier tissues. It can be activated by small molecules provided by pollutants, microorganisms, food, and metabolism. It has been demonstrated that AHR plays an important role in modulating the response to many microbial pathogens, and the abnormal expression of AHR signaling pathways may disrupt endocrine, cause immunotoxicity, and even lead to the occurrence of cancer. Most humans are infected with at least one known human cancer virus. While the initial infection with these viruses does not cause major disease, the metabolic activity of infected cells changes, thus affecting the activation of oncogenic signaling pathways. In the past few years, lots of studies have shown that viral infections can affect disease progression by regulating the transmission of multiple signaling pathways. This review aims to discuss the potential effects of virus infections on AHR signaling pathways so that we may find a new strategy to minimize the adverse effects of the AHR pathway on diseases. Video Abstract.

JAK2/STAT3 Signaling Pathway and Klotho Gene in Cadmium-induced Neurotoxicity In Vitro and In Vivo.

Cadmium (Cd), a common heavy metal in the environment, is associated with cognitive impairment. In the present study, we carried out a preliminary inquiry to explore whether Cd causes neurotoxicity by regulating the JAK2/STAT3 signaling pathway and affecting the expression of klotho genes in vivo and in vitro, providing clues for the mechanism of Cd-induced cognitive dysfunction. The rat samples were injected with Cd chloride solution for 14 weeks, and the memory function of the rats was detected. Different concentrations of Cd and JAK2/STAT3 signaling pathway inhibitors were used to treat PC12 cells and thus detect the apoptosis rate. The protein expression levels of JAK2, p-JAK2, STAT3, p-STAT3, and klotho in rat and PC12 cell were detected by ELISA and Western blot, respectively. With the increase in exposure dose, the memory function of rats was severely impaired. The expression of p-JAK2 and p-STAT3 proteins was significantly up-regulated, whereas that of klotho was significantly down-regulated both in vivo and in vitro (p < 0.05). In comparison with the high-dose Cd exposure group, after adding tyrphostin AG490 (AG490), the apoptosis rate of PC12 cells increased, whereas the phosphorylation levels of JAK2 and STAT3 in the cells decreased significantly (p < 0.05). Cd exposure may cause neurotoxicity by regulating the JAK2/STAT3 signaling pathway and down-regulating klotho protein expression, leading to cognitive dysfunction.

Targeting H3K27me3 demethylase to inhibit Shh signaling and cholesterol metabolism in medulloblastoma growth.

Previously we uncovered the epigenetic regulation of medulloblastoma that low levels of H3K27me3 are required for Shh target gene expression and medulloblastoma growth. Since Jmjd3, an H3K27me3 demethylase, is responsible for maintaining low H3K27me3 at Shh target genes, targeting Jmjd3 could be an efficient way to inhibit Shh signaling and medulloblastoma growth. Here we show that the small molecule GSK-J4, an inhibitor of Jmjd3, significantly inhibited the expression of Shh target genes in Shh responsive cell models and primary cerebellar granule neuron precursors. GSK-J4 also significantly reduced the growth of primary Shh medulloblastoma cultures. Treating human medulloblastoma cell line DaoY by GSK-J4 led to cell cycle arrest at G0/G1 phase with decreased cells in S-phase. Tumor cell proliferation was significantly inhibited by GSK-J4 treatment. Gene expression analyses showed that GSK-J4 additionally constrained the expression of key genes in cholesterol biosynthesis. Our results highlight the possibility that targeting H3K27me3 demethylase Jmjd3 with GSK-J4 to inhibit Shh signaling and cholesterol metabolism is a potential application to treat Shh medulloblastoma.

Comparative efficacy and safety of Chinese medicine injections combined with capecitabine and oxaliplatin chemotherapies in treatment of colorectal cancer: A bayesian network meta-analysis.

Objective: The aim of the present Bayesian network meta-analysis (NMA) was to explore the comparative effectiveness and safeaty of different Chinese Medicine injections (CMIs) combined with the XELOX regimen versus XELOX alone for colorectal cancer (CRC). Methods: A comprehensive search for randomized controlled trials (RCTs) was performed with regard to different CMIs for the treatment of CRC in several electronic databases up to April 2022. The quality assessment of the included RCTs was conducted according to the Cochrane risk of bias tool. Standard pair-wise and Bayesian NMA were designed to comparethe effectiveness and safety of different CMIs combined with the XELOX regimen by utilizing R 4.0.3 software and Stata 15.1 software simultaneously. Results: Initially, a total of 4296 citations were retrieved through comprehensive searching, and 32 eligible articles involving 2847 participants and 11 CMIs were ultimately included. CMIs combined with XELOX were superior to the XELOX regimen alone, and a total of ten Observation Indicators were included in the study, with the following results. Among all the injections, Shengmaiyin, Shenmai, and Kanglaite combined with the XELOX regimen were the three CMIs with the highest clinical efficiency. The top three in terms of improving CD3+ values were Shengmaiyin, Shenqifuzheng, and Cinobufacini injections. Shenqifuzheng, Shengmaiyin, and BruceaJavanica oil injections combined with the XELOX regimen performed best at raising CD4+ values. Kanglaite, Cinobufacini, and Matrine injections combined with the XELOX regimen performed best in improving CD4+/CD8+ rates. The top three in terms of improving performance status were Xiaoaiping, Shenmai, and Kanglaite injections. Cinobufacini and Brucea Javanica oil injections combined with the XELOX regimen performed best at raising CD8+ values. Shenqifuzheng, Kangai, and Matrine injections combined with the XELOX regimen performed best in improving Gastrointestinal reactions.The top threein terms of improving Leukopenia were Shenqifuzheng, Compound Kushen and Kanglaite injections. The top three in terms of improving Platelet decline were Compound Kushen, Cinobufacini and Shenqifuzheng injections. Additionally, those that were best at improving nausea and vomitting were Cinobufacini, Compound Kushen and Aidi injections. Conclusion: The results of the analysis demonstrated thatShengmaiyin, Kanglaite, and Cinobufacini injections and the XELOX regimen were associated with morepreferable and beneficial outcomes than other CMI groups. Nevertheless, additional results from multicenter trials and high-quality studies will bevital to support our findings. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=326097, CRD42022326097.

The prognostic value of miR-487a in clear cell renal cell carcinoma and its influence on cell biological behavior.

OBJECTIVES: Clear cell renal cell carcinoma (ccRCC) is a type of kidney cancer that has a poor prognosis. microRNA-487a (miR-487a) plays a role in the prognosis of gastric cancer, liver cancer, and other cancers. The purpose of this study is to explore the role of miR-487a in the generation and progression of ccRCC. MATERIALS AND METHODS: The RT-qPCR technology was used to detect the expression levels of miR-487a in ccRCC tissues and cell lines. The association between miR-487a and clinical-pathological characteristics of patients was analyzed using the chi-square test. Kaplan-Meier survival analysis and Cox regression analysis were used to analyze the prognostic significance of miR-487a in ccRCC. CCK-8 and Transwell assays were used to analyze the influences of miR-487a on cell proliferation, migration, and invasion. RESULTS: miR-487a was significantly up-regulated in ccRCC tissues and cell lines. The high expression of miR-487a is related to lymph node metastasis and TNM staging and may be used as an independent prognostic factor related to lower overall survival and disease-free survival rate. Increased expression of miR-487a accelerated the proliferation, migration, and invasion of ccRCC cells. CONCLUSION: The enhanced expression of miR-487a was related to the prognosis of ccRCC, and it also facilitated cell proliferation, migration, and invasion.

pH-responsive Sulfated Hyaluronic Acid Nanoparticles Targeting Tumor Cells and CAFs for the Treatment of Breast Cancer.

BACKGROUND: Tumor metastasis is a main cause of death in patients with breast cancer. The cross-talk between cancer-associated fibroblasts (CAFs) and tumor cells plays an important role in promoting tumor invasion and metastasis. It is important to develop a novel delivery system to inhibit tumor development by simultaneously targeting both CAFs and tumor cells. OBJECTIVES: The main objective of this research was to prepare nanoparticles to inhibit tumor proliferation and migration by blocking the cross-talk of tumor-CAFs. Additionally, a novel "MCF- 7+NIH/3T3" mixed cell model was established to mimic the tumor microenvironment (TME). METHODS: In this study, the pH-responsive nanoparticles (MIF/DOX-sul-HA NPs) based on sulfated hyaluronic acid (sul-HA) polymers were prepared for co-delivery of doxorubicin (DOX) and mifepristone (MIF). The effects of anti-proliferation and anti-metastasis of MIF/DOX-sul-HA NPs were investigated both in vitro and in vivo. RESULTS: The results showed that MIF/DOX-sul-HA NPs were nearly spherical in shape with narrow particle size distribution and pH-responsive drug release, and could be taken up by both MCF-7 and NIH/3T3 cells. Compared with MCF-7 cells alone, the anti-tumor effect of single DOX was weak in the "MCF-7+NIH/3T3" mixed cell model. MIF/DOX-sul-HA NPs exhibited strong effects of anti-proliferation and anti-metastasis than the free single drug. CONCLUSION: The sul-HA nanoparticles for co-delivery of DOX and MIF could be a promising combined therapy strategy for the treatment of breast cancer.

LMP2A inhibits the expression of KLF5 through the mTORC1 pathway in EBV-associated gastric carcinoma.

OBJECTIVE: To investigate the expression and biological role of KLF5 in EBV-associated gastric carcinoma (EBVaGC) and EBV-negative gastric carcinoma (EBVnGC), and to clarify the relationship between EBV and KLF5. METHODS: The expression of KLF5 in GC tissues was detected by immunohistochemistry. Western blot and immunofluorescence assay were used to examine the expression and localization of KLF5 in EBV positive and negative GC cell lines. The effect of LMP2A on KLF5 was analyzed by transfection of LMP2A plasmid or siRNA. The function of KLF5 in GC was elucidated by molecular biology experiments. RESULTS: The expression of KLF5 was significantly reduced in EBVaGC tissues and cell lines. LMP2A inhibited KLF5 expression through inactivating mTORC1 pathway in EBV positive GC cell lines. Meanwhile, KLF5 could enhance the migration ability of GC cells and induce autophagy. CONCLUSION: LMP2A downregulated KLF5 expression by inhibiting the mTORC1 pathway in EBV positive GC cells. KLF5 might play an oncogene-like role by promoting the migration of GC cells and inducing autophagy.

Populations at high risk of cervical cancer in Guangxi Province: Findings from two screening projects in a minority area of South China.

OBJECTIVE: To analyse the positive rates of low-grade (LSIL) and high-grade (HSIL) squamous intraepithelial lesions, and cervical cancer (CC), and identify groups at high risk for CC in Guangxi. SETTING: CC screening options in Guangxi, which is the only minority autonomous area in South China, include the National Cervical Cancer Screening Project (NCCSP) and physical examination (PE). METHODS: This study was based on PE and NCCSP sample data obtained from 2012 to 2019. We calculated the positive rates of LSIL, HSIL, and CC; analysed the adjusted odds ratio (aOR) and 95% confidence intervals (CI) of the variables in multivariate logistic regression; and subsequently identified groups at high risk for CC. RESULTS: The positive rates of LSIL, HSIL, and CC for the total of 873,880 samples were 1.89%, 0.60%, and 0.03%, respectively. Females over 64 years of age (vs. 50-64; aOR = 2.05; 95% CI, 1.71-2.46; P < 0.001) and those from urban (vs. rural; aOR = 1.66; 95% CI, 1.57-1.76; P < 0.001), minority (vs. non-minority; aOR = 1.24; 95% CI, 1.13-1.35; P < 0.001), and coastal (vs. inland; aOR = 1.15; 95% CI, 1.06-1.25; P = 0.001) areas were associated with a high risk of HSIL. Females over 64 (vs. 50-64; aOR = 4.37; 95% CI, 2.88-6.63; P < 0.001) and those from urban (vs. rural; aOR = 3.05; 95% CI, 2.36-3.95; P < 0.001) areas were significantly associated with a high risk of CC. CONCLUSION: Females from urban areas in Guangxi are at high risk for CC. Public health strategies should focus on high-risk populations.