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Metastasis is the leading cause of death in breast cancer patients. Osthole, as an active compound detected in the traditional Chinese medicine Wenshen Zhuanggu Formula, has shown a promising anti-metastatic activity in human breast cancer cells, but the underlying mechanisms remain ambiguous. In this study we elucidated the anti-metastatic mechanisms of osthole in highly metastatic breast cancer cells and a zebrafish xenograft model. We showed that the expression of integrin α3 (ITGα3) and integrin β5 (ITGβ5) was upregulated in highly metastatic MDA-MB-231, MDA-MB-231BO breast cancer cell lines but was downregulated in poorly metastatic MCF-7 breast cancer cell line, which might be the key targets of osthole's anti-metastatic action. Furthermore, we showed that knockdown of ITGα3 and ITGβ5 attenuated breast cancer cell migration and invasion possibly via suppression of FAK/Src/Rac1 pathway, whereas overexpression of ITGα3 and ITGβ5 caused the opposite effects. Consistently, osthole significantly inhibited breast cancer metastasis by downregulating ITGα3/ITGβ5 signaling in vitro and in vivo. These results provide new evidence that osthole may be developed as a candidate therapeutic drug for metastatic breast cancer.

Rougan Formula (RG) has long been clinically applied to treat hepatic fibrosis in patients with different chronic liver diseases. However, the core active substances and the potential pharmacological mechanisms of RG remain unclear.The purpose of this study is to explore bioactive components, key targets, and potential mechanisms of RG by performing network pharmacological analyses and experimental model validation.All chemical components in RG extract were identified using ultraperformance liquid chromatography-quadrupole/time-of-flight tandem mass technology. The candidate components and drug targets of RG, as well as disease-related genes, were extracted from TCMSP and GeneCards databases. The potential pathways related to genes were predicted by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. The core bioactive components, key targets, and signaling pathways were ultimately obtained by analyzing protein-protein interaction (PPI) and component-target-pathway (C-T-P) networks. Subsequently, the efficacy and underlying mechanisms of RG on hepatic fibrosis were experimentally validated in transforming growth factor-beta 1 (TGF-β1)-induced hepatic stellate cell activation model and CCLA total of 52 components in RG extract were obtained, and 22 of them were selected as the core bioactive components. Five hundred and thirty-nine overlapped targets were determined by matching drug targets with disease-related targets. The results of PPI and C-T-P network analyses revealed 100 key targets and 19 signaling pathways associated with RG efficacy. In vitro and in vivo studies further verified that RG exerted a significant anti-hepatic fibrotic effect by suppressing the activation of hepatic stellate cells by downregulating the TGF-β1/Smads signaling pathway.These results may provide some evidence for further clinical research and development of RG formula as an effective and safe drug for hepatic fibrosis treatment.

Background: Triple-negative breast cancer (TNBC), the most common type of breast cancer, is associated with poor patient prognosis. Platinum-containing chemotherapies are commonly used in the treatment and prevention of advanced TNBC. Objectives and Methods: To systematically evaluate the effectiveness and safety of platinum-containing chemotherapies in patients with advanced TNBC, we searched several databases, including PubMed, Medline, Embase, ClinicalTrials.gov, Cochrane Library, CNKI, CBM, and the Chinese Cochrane Center, to collect published randomized controlled clinical studies of platinum-containing chemotherapies for advanced TNBC before November 2020. The meta-analysis was performed using Review Manager version 5.3. To assess effectiveness and safety, dichotomous and continuous variables were assessed using odds ratio (OR) and mean difference (MD), respectively, with 95% CI. Results: A total of 1,222 patients with advanced TNBC were enrolled in 11 eligible trials, including 489 patients in the treatment group (platinum-containing) and 447 patients in the control group (non-platinum-containing). We also retrieved information whether a PARP inhibitor was combined with platinum-containing chemotherapy for patients with metastatic TNBC and identified 224 patients who received a PARP inhibitor combined with platinum-containing chemotherapy and 62 patients in the platinum-containing group who did not. The platinum-containing chemotherapy group had a significantly better objective response rate (OR 1.43, 95% CI 1.20–1.71, p < 0.001) and longer progression-free survival (PFS; MD 1.15, 95% CI 0.03–2.28, p < 0.05) than the non-platinum-containing chemotherapy group. However, there was no significant difference in overall survival (OS) of patients with advanced TNBC between the two groups (MD 2.04, 95% CI –0.83 to 4.91, p > 0.05). Related adverse effects of platinum-containing chemotherapies involved gastrointestinal reaction, myelosuppression and liver function damage. Platinum-containing chemotherapies were not associated with an increased incidence of adverse side effects compared with non-platinum-containing chemotherapies, with the exception of nausea and vomiting (OR 2.22, 95% CI 1.10–4.46, p < 0.05). Furthermore, the addition of the PARP inhibitor iniparib to gemcitabine and carboplatin treatment improved the rate of clinical benefit, OS and PFS. Conclusions: Platinum-containing chemotherapy remains a highly recommended therapeutic regimen due to greater effectiveness and tolerance for patients with advanced TNBC.

Background: Doxorubicin (Dox) is one of the most effective chemotherapy agents used in the treatment of solid tumors and hematological malignancies. However, it causes dose-related cardiotoxicity that may lead to heart failure in patients. Luteolin (Lut) is a common flavonoid that exists in many types of plants. It has been studied for treating various diseases such as hypertension, inflammatory disorders, and cancer. In this study, we evaluated the cardioprotective and anticancer effects of Lut on Dox-induced cardiomyopathy in vitro and in vivo to explore related mechanisms in alleviating dynamin-related protein (Drp1)-mediated mitochondrial apoptosis.Methods: MTT and LDH assay were used to determine the viability and toxicity of cardiomyocytes treated with Dox and Lut. Flow cytometry was used to examine ROS levels, and electron and confocal microscopy was employed to assess the mitochondrial morphology. The level of apoptosis was examined by Hoechst 33258 staining. The protein levels of myocardial fission protein and apoptosis-related protein were examined using Western blot. Transcriptome analysis of the protective effect of Lut against Dox-induced cardiac toxicity in myocardial cells was performed using RNA sequencing technology. The protective effects of Lut against cardiotoxicity mediated by Dox in zebrafish were quantified. The effect of Lut increase the antitumor activity of Dox in breast cancer both in vitro and in vivo were further employed.Results: Lut ameliorated Dox-induced toxicity in H9c2 and AC16 cells. The level of oxidative stress was downregulated by Lut after Dox treatment of myocardial cells. Lut effectively reduced the increased mitochondrial fission post Dox stimulation in cardiomyocytes. Apoptosis, fission protein Drp1, and Ser616 phosphorylation were also increased post Dox and reduced by Lut. In the zebrafish model, Lut significantly preserved the ventricular function of zebrafish after Dox treatment. Moreover, in the mouse model, Lut prevented Dox-induced cardiotoxicity and enhanced the cytotoxicity in triple-negative breast cancer by inhibiting proliferation and metastasis and inducing apoptosis.

Capsid assembly modulators (CAMs) have recently been revealed to be effective in blocking HBV replication. HBV capsid protein inhibitors reduce and ultimately eliminate HBV by inhibiting virus replication and blocking hepatocyte infection. Sulfonamides are synthetic functional groups in development of different kinds of drugs. Sulfonyl benzamide clinical drugs NVR 3-778 and BA-38017 are lead compounds in discovery of antiviral compounds with increased activity and reduced cytotoxicity by drug design strategies including pharmacophore hybrid, bioisosterism and scaffold hopping. In current study, three series of target compounds were synthesized, and their anti-HBV activity was evaluated against HepAD38 cells. Compound 5a (EC

Background: Olaparib, a potent oral poly (ADP-ribose) polymerase inhibitor, exhibits antitumor activity and prevents the recurrence in advanced ovarian cancer. In this article, we assessed the efficacy and safety of olaparib maintenance therapy on platinum-sensitive ovarian cancer patients with BRCA mutations through a meta-analysis of available randomized controlled trials (RCTs) to provide more evidence for its clinical applications. Methods: We searched PubMed, Embase, Wanfang, CNKI, Web of Science, Cochrane Library, and VIP databases from 1 August 2018 to identify RCTs and finally included four RCTs (seven articles) with 567 eligible participants beyond the participants, interventions, comparisons, outcomes, and study design regulation. The outcomes of olaparib efficacy including progression-free survival (PFS) and overall survival (OS) were measured by HR and 95% CI, while the quality of life was evaluated by calculating the combination of P-value. Seven common adverse events were tested by risk ratio and 95% CI as the outcomes of olaparib safety. These data were analyzed, and the forest figures were produced using Review Manager 5.3. Results: Compared with other interventions (ie, placebo or chemotherapy drugs), olaparib significantly prolonged PFS (HR=0.31, 95% CI=0.15-0.62) and slightly improved OS (HR=0.75, 95% CI=0.56-0.99), but did not influence the quality of life (P=0.058) in the patients with platinum-sensitive BRCA-mutated ovarian cancer. Additionally, the toxicity profile of olaparib involved anemia, fatigue, vomiting, diarrhea, and nausea with grade 1-2. Conclusion: This meta-analysis suggests that olaparib maintenance therapy is effective and well-tolerated for the patients with platinum-sensitive BRCA-mutated ovarian cancer. More updated RCTs and long-term follow-up should be conducted to compare and analyze the efficacy and toxicity of olaparib at different doses in ovarian cancer patients.

Ethnopharmacological relevance Wenshen Zhuanggu Formula (WSZG) is a traditional Chinese medicine (TCM) prescription used in clinics for adjuvant treatment of breast cancer bone metastases in Longhua Hospital in China. WSZG has been reported to decrease the risk of bone metastases and alleviate the severity of bone lesions in a breast cancer xenograft model. Aim of the study The present study aimed at investigating the pharmacokinetic behaviors of six coumarins in normal and breast cancer bone-metastatic mice following oral administration of WSZG extract. Materials and methods A bone-metastatic mouse model was established by intracardiac injection of MDA-MB-231BO breast cancer cells, and WSZG extract (1.60 g/kg) was given orally to the model and normal mice for 4 weeks. Then, the blood pharmacokinetic parameters of six bioactive components from WSZG (psoralen, isopsoralen, bergapten, xanthotoxin, osthole, and imperatorin) were analyzed by liquid chromatography tandem mass spectrometry. Results There were significant differences in pharmacokinetic behaviors between normal and pathological states. Compared with normal mice, the model mice showed significantly increased AUC0–t and AUC0–∞ of the bioactive compounds (P Conclusions The different pharmacokinetic behaviors might be partly ascribed to intestinal functional disorders and imbalance of gastrointestinal microbiota under the morbid state. The findings provide some valuable information to evaluate the clinical efficacy and safety of this TCM formula.

Ethnopharmacological relevance Jinfukang has long been used for the clinical treatment of lung cancer. Previous studies have shown that Jinfukang can induce the apoptosis of circulating tumor cells by intervening ROS-mediated DNA damage pathway. However, whether Jinfukang can inhibit the metastasis of circulating tumor cells and its mechanism are still unclear. Aim of the study To further investigate the mechanism of Jinfukang in anti-metastasis of lung cancer from the perspective of intervention of tumor exosomes. Materials and methods The invadopodia formation was determined with immunofluorescence. Invasion and migration were detected using the Transwell assay. Ultracentrifugation was used to isolate exosomes. Exosomes were characterized by electron microscopy, nanoparticle tracking analysis and immunoblotting, and the protein profile was evaluated by proteomic analysis. The molecular functions, biological processes and signaling pathway enrichment analysis were performed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Key differentially expressed proteins were verified by Western blot. Results Jinfukang can inhibit the expression of MMP14, cortactin, Tks5 and the formation of invadopodia of CTC-TJH-01 cells. Furthermore, Jinfukang can significantly inhibit the invasion and migration of CTC-TJH-01 cells. The diameter of exosomes extracted from the CTC-TJH-01 cells treated by Jinfukang was 30–100 nm, and the exosomal markers CD63, CD81 and TSG101 were expressed. We identified 680 deferentially expressed proteins. Gene oncology analysis indicated that exosomes were mostly derived from plasma membrane and mainly involved in protein localization and intracellular signaling. The ingenuity pathway analysis showed that the EGF pathway was significantly inhibited, whereas the GP6 signaling pathway was significantly activated. We also confirmed that Jinfukang inhibited the expression of EGF pathway-related proteins in CTC-TJH-01 cells. Besides, when EGF was used to activate EGF signaling pathway, the inhibition of Jinfukang on CTC cell metastasis was reversed. Conclusion Jinfukang inhibits the metastasis of CTC-TJH-01 cells through the EGF pathway.

In this paper, BaTiO3 platelets are utilized for the first time to incorporate into polymer matrix for energy storage. To improve the dispersibility and compatibility of the BaTiO3 platelets in the composites, a new type of fluoro-polymer poly{2,5-bis[(2,3,5,6-tetrafluoro-4-trifluoromethyl)oxycarbonyl]styrene} (PM7F) was designed for the first time to engineer the surface of BaTiO3 platelets by surface-initiated reversible-addition-fragmentation chain transfer polymerization method. Each structural unit in the molecular chain of this novel modifier contained 14 fluorine atoms, resulting in effectively decreasing the surface energy of BaTiO3 platelets. As a result, the BaTiO3 platelets modified by PM7F were homogeneously dispersed in the polymer poly(vinylidene fluoride-trifluoroethylene-chlorofluoroethylene) (P(VDF-TrFE-CTFE)) matrix. The permittivities of the nanocomposites were significantly improved compared with the pure polymer matrix. The energy storage density of the nanocomposites was largely enhanced by adding the BaTiO3 platelets. The discharged energy density of the nanocomposite with 15 vol% BaTiO3 platelets was 1.26 J/cm3, which was nearly double to that of pure P(VDF-TrFE-CTFE) (0.64 J/cm3) at the same electric field (60 kV/mm). The findings provide an effective modifier and a new routine for high performance capacitors.

Long-alkyl tail triphenylene (TP) side-chain liquid crystalline polymers (SCLCPs) with different spacer length (P-m-TP, m = 2, 3, 4, 6, 8, which is the number of carbon atom in the flexible alkyl spacers) have been successfully synthesized via free radical polymerization. The differential scanning calorimetry (DSC), polarized light microscopy (POM), ultraviolet-visible spectroscopy (UV-Vis), wide-angle X-ray diffraction (WAXD) and small-angle X-ray scattering (SAXS) measurements were performed to investigate the influence of multiple effects on the self-organization behaviors of P-m-TP, including steric effect, decoupling effect and π-π stacking effect. The experimental results revealed that P-m-TP (m = 2, 3, 4) formed the columnar phase which was developed by the TP moieties and the main chain as a whole, suggesting that the side-chains had strong steric effect even though the number of spacer length (m) exceeded 4. In addition, the clearing points (Tis) of the polymers were above 300 °C. When m = 6 and 8, the polymers displayed hexagonal columnar phase and exhibited the low Tis (91 and 80 °C respectively), originating from the self-assembly of triphenylene due to the decoupling effect and π-π stacking effect. This work offers a viable and inspiring pathway to control the phase transition temperature and phase structure of TP SCLCPs via simply tailoring the spacer length and increasing the alkyl tail length of TP.

A substantial number of studies have revealed that a growing list of cancers might be influenced by obesity. In this regard, one of the most prominent and well-characterized cancers is breast cancer, the leading cause of cancer death among women. Obesity is associated with an increased risk for the occurrence and development of breast cancer particular in postmenopausal women. Moreover, the relationship between adiposity and breast cancer risk is complex, with associations that differ depending on when body size is assessed (eg, premenopausal vs postmenopausal obesity) and when breast cancer is diagnosed (ie, premenopausal vs postmenopausal disease). Obesity is mainly due to excessive fat accumulation in the regional tissue. Adipocytes in obese individuals produce endocrine, inflammatory, and angiogenic factors to affect adjacent breast cancer cells. Adipocytokines, are biologically active polypeptides that are produced either exclusively or substantially by adipocytes, play a critical and complex role, and act by endocrine, paracrine, and autocrine pathways in the malignant progression of breast cancer. Furthermore, the increased levels of leptin, resistin, and decreased adiponectin secretion are directly associated with breast cancer development. And there are also many studies indicating that adipocytokines could mediate the survival, growth, invasion, and metastasis of breast cancer cells by different cellular and molecular mechanisms to reduce the survival time and prompt the malignancy. In present review, we discuss the correlations between several adipocytokines and breast cancer cells in obesity as well as the underlying signaling pathways to provide the novel ideas for the prevention and treatment of breast cancer.

Polymer nanocomposites based on conductive fillers for high performance dielectrics have attracted increasing attention in recent years. However, a number of physical issues are unclear, such as the effect of interfacial thickness on the dielectric properties of the polymer nanocomposites, which limits the enhancement of permittivity. In this research, two core-shell structured reduced graphene oxide (rGO)@rigid-fluoro-polymer conducting fillers with different shell thicknesses are prepared using a surface-initiated reversible-addition-fragmentation chain transfer polymerization method, which are denoted as rGO@PTFMS-1 with a thin shell and rGO@PTFMS-2 with a thick shell. A rigid liquid crystalline fluoride-polymer poly{5-bis[(4-trifluoro-methoxyphenyl)oxycarbonyl]styrene} (PTFMS) is chosen for the first time to tailor the shell thicknesses of rGO via tailoring the degree of polymerization. The effect of interfacial thickness on the dielectric behavior of the P(VDF-TrFE-CTFE) nanocomposites with rGO and modified rGO is studied in detail. The results demonstrate that the percolation threshold of the nanocomposites increased from 0.68 vol% to 1.69 vol% with an increase in shell thickness. Compared to the rGO@PTFMS-1/P(VDF-TrFE-CTFE) composites, the rGO@PTFMS-2/P(VDF-TrFE-CTFE) composites exhibited a higher breakdown strength and a lower dielectric constant, which can be interpreted by interfacial polarization and the micro-capacitor model, resulting from the insulating nature of the rigid-polymer shell and the change of rGO's morphology. The findings provide an innovative approach to tailor dielectric composites, and promote a deeper understanding of the influence of interfacial region thickness on the dielectric performance.

Dielectric nanocomposites incorporating core–shell structured nanoparticles have drawn increasing attention in recent years for energy storage applications. Among the many key factors, the thickness and the chemical structure of the interfacial layer are rarely investigated. This work presents a novel approach to precisely tailor the interfacial layer thicknesses by modulating the polymerization degree of a rigid liquid-crystalline fluoro-polymer. BaTiO3@rigid-fluoro-polymer nanoparticles with a range of interfacial thicknesses were prepared by a surface-initiated reversible-addition–fragmentation chain transfer polymerization method. The frequency dependent dielectric properties and energy storage capability of dielectric nanocomposites based on a poly(vinylidene fluoride-trifluoroethylene-chlorotrifluoroethylene) P(VDF-TrFE-CTFE) matrix and the modified BaTiO3 nanofiller were investigated. The results demonstrated that the permittivity, breakdown strength and energy density of the polymer nanocomposites were significantly affected by the thickness of the rigid-fluoro-polymer shell around BaTiO3. Moreover, a high discharged energy density of 16.18 J cm−3 was achieved in nanocomposites containing 5 vol% BaTiO3, when the shell thickness was approximately 11 nm. The findings provide a new and innovative approach to prepare dielectric composites with high energy density, and enable a deeper understanding of the influence of the interfacial layer thickness on the dielectric performance.

Lung metastasis of Triple-negative breast cancer (TNBC) causes severe breath-related events and poor prognosis. Ruyiping (RYP), a traditional Chinese medicine prescription, is used to treat breast cancer lung metastasis in clinical practice. This study was to explore the anti-lung-metastatic activities and mechanism of RYP extract by regulating macrophage polarization. The results showed that RYP can inhibit the viability and induce the apoptosis of TNBC cells. In in vitro experiments, RYP significantly inhibited the invasion and migration ability of TNBC cells promoted by M2, the subtype of macrophage which increased TNBC metastasis related genes. In in vivo experiments, RYP reduced the TNBC progression and lung metastasis. M2/M1 ration in the lung and M2 in the tumor was reduced by RYP, as well as M2 master regulator Stat6. Therefore, RYP extract may exhibit anti-lung metastasis function by reducing M2 in both tumor and lung through reducing Stat6.

Ceramic/polymer nanocomposites are attractive for energy storage applications due to their ability to exploit the high permittivity of ceramic fillers and high breakdown strength of the polymer matrix. One challenge for the development of high performance nanocomposites based on ceramic particulates or fibers in a polymer matrix is that they often require a high volume fraction (>50%) to achieve a high permittivity, which is often at the expense of a reduction in dielectric strength and mechanical flexibility. In this paper we demonstrate by both experiment and finite element simulation that high aspect ratio nanofiber fillers offer an effective approach to achieve high energy density and dielectric strength. Lead-free ferroelectric Na0.5Bi0.5TiO3 (BNT) nanofibers with a high aspect ratio (>200) are synthesized by a hydrothermal method and dispersed in a poly(vinylidene difluoride-co-hexafluoropropylene) (P(VDF-HFP)) matrix. The increased fraction of β-phase and the alignment of BNT nanofibers perpendicular to the direction of the applied electric field lead to an enhanced dielectric strength, compared to spherical BNT/P(VDF-FHP) nanoparticles and pure P(VDF-HFP), and experimental measurements are compared with numerical simulations. The results demonstrate that the nanofiber nanocomposites exhibited an ultra-high discharged energy density (12.7 J cm−3) and provide an innovative approach to produce high-energy storage density materials.

Interfacial modification is a good approach to improve the dielectric properties of nanocomposites. However, there are few reports to study the influence of interfacial modified thickness. In this study, the graft-from strategy was adopted to introduce the rigid liquid crystalline fluoropolymer (poly[2,5-bis[(4-trifluoromethoxyphenyl)-oxycarbonyl]] styrene (PTFMS) onto the surface of carbon nanotubes (CNT). The shell thickness increased from 20 ± 3 to 62 ± 6 nm via controlling the ratio of monomer to the initiator. The results indicated that the dielectric properties of the P(VDF-CTFE) nanocomposites with the modified CNT were significantly enhanced compared with those original CNT, and the maximum dielectric constant of nanocomposites with 1.25 vol% CNT@PTFMS containing the thickest thickness reached 36 at 40 Hz due to the highest micro-capacitors, which was 360% than the neat P(VDF-CTFE). This work provides the perspective to understand the relationship between the shell thickness and dielectric property of polymer nanocomposites based on conductive fillers.

Purpose: Due to a lack of recognized molecular targets for therapy, patients with triple-negative breast cancer (TNBC), unlike other subtypes of breast cancers, generally have not benefited from the advances made with targeted agents. The CXCR4/SDF-1 axis is involved in tumor growth and metastasis of TNBC. Therefore, down-regulation of the expression of CXCR4 in cancer cells is a potential therapeutic strategy for inhibiting primary tumor growth and metastasis of TNBC. In order to identify bioactive compounds that inhibit the expression of CXCR4 in traditional Chinese medicines, we investigated the capacity of saikosaponin A (SSA), one of the active ingredients isolated from Radix bupleuri, to affect CXCR4 expression and function in TNBC cells. Methods: Analyses of cell growth, migration, invasion, and protein expression were performed. Knockdowns by small interfering RNA (siRNA) and non-invasive bioluminescence were also used. Results: SSA reduced proliferation and colony formation of SUM149 and MDA-MB-231 cells. SSA inhibited migration and invasion of TNBC cells. For mice, SSA inhibited primary tumor growth and reduced lung metastasis of highly metastatic, triple-negative 4T1-luc cells. SSA inhibited CXCR4 expression but did not regulate CXCR7 expression in vitro and in vivo. The inhibitory effects on the migration and invasion of TNBC cells were reversed by down-regulation of CXCR4 expression. In addition, SSA inactivated the Akt/mTOR signaling pathway and inhibited MMP-9 and MMP-2 expression. Conclusions: The results show that SSA exerts an anti-TNBC effect through the inhibition of CXCR4 expression and thus has the potential to be a candidate therapeutic agent for TNBC patients.

Chemoresistance has been the biggest obstacle in ovarian cancer treatment, and STAT3 may play an important role in chemoresistance of multiple cancers, but the underlying mechanism of STAT3 in ovarian cancer chemoresistance has long been truly illusive, particularly in association with p53 and RAS signaling. In this study, by using wild type, constitutive active, and dominant negative STAT3 constructs, wild-type p53, and RAS-mutant V12, we performed a series of in vitro and in vivo experiments by gene overexpression, drug treatment, and animal assays. We found that phosphorylation of STAT3 Y705 but not S727 promoted cancer cell EMT and metastasis through the Slug-mediated regulation of E-cadherin and Vimentin. The phosphorylation of STAT3 at Y705 also activated the MAPK and PI3K/AKT signaling to inhibit the ERS-mediated autophagy through down-regulation of pPERK, pelf2α, ATF6α, and IRE1α, which led to increased cisplatin resistance. Induction of wild type p53 in STAT3-DN-transfected cells further diminished the chemoresistance and tumor growth through the upregulation of the MAPK- and PI3K/AKT-mediated ERS and autophagy. Introduction of STAT3-DN deprived the RASV12-induced ERS, autophagy, oncogenicity, and cisplatin resistance, whereas introduction of p53 in STAT3-DN/RASV12 expressing cells induced additional tumor retardation and cisplatin sensitivity. Thus, our data provide strong evidence that the crosstalk between STAT3 and p53/RAS signaling controls ovarian cancer cell metastasis and cisplatin resistance via the Slug/MAPK/PI3K/AKT-mediated regulation of EMT and autophagy.

Unlike other breast cancer subtypes, triple-negative breast cancer (TNBC) has no specific targets and is characterized as one of the most aggressive subtypes of breast cancer that disproportionately accounts for the majority of breast cancer-related deaths. Current conventional chemotherapeutics target the bulk tumor population, but not the cancer stem cells (CSCs) that are capable of initiating new tumors to cause disease relapse. Recent studies have identified distinct epithelial-like (E) ALDH+ CSCs, mesenchymal-like (M) CD44+/CD24− CSCs, and hybrid E/M ALDH+/CD44+/CD24− CSCs. These subtypes of CSCs exhibit differential signal pathway regulations, possess plasticity, and respond differently to treatment. As such, co-inhibition of different subtypes of CSCs is key to viable therapy. This review serves to highlight different pathway regulations in E and M CSCs in TNBC, and to further describe their role in disease progression. Potential inhibitors targeting E and/or M CSCs based on clinical trials are summarized for further investigation. Since future research needs to adopt suitable tumor models and take into account the divergence of E and M CSCs for the development of effective treatments, TNBC models for clinically translatable studies are further discussed.

The CNC machining technology of the upper shell of electro-hydraulic servo valve is complex, and the machining accuracy is required to be high. According to the existing cutting tools and machine tools, the CNC machining process with CNC lathe and 4-axis machining center is designed. First of all, the aluminum alloy blank is roughened and finished on the CNC lathe. After the processing is completed, the two ends of the blank are processed on the CNC lathe, and rough milling, fine milling, drilling and boring processing are carried out with the 4-axis machining center. After the 3D CAD model of the upper shell is constructed, the tool path of rough machining and finish machining is generated by MasterCAM software, and then the G code is generated by the post processor and input to the machining center for machining. The NC machining technology of the upper shell can effectively improve the machining efficiency and accuracy.