Search

Abstract Background Hyperglycaemia associated with myocardial oxidative stress and fibrosis is the main cause of diabetic cardiomyopathy. Empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor has recently been reported to improve glycaemic control in patients with type 2 diabetes in an insulin-independent manner. The aim of this study was to investigate the effect of empagliflozin on myocardium injury and the potential mechanism in type 2 diabetic KK-Ay mice. Methods Thirty diabetic KK-Ay mice were administered empagliflozin (10 mg/kg/day) by oral gavage daily for 8 weeks. After 8 weeks, heart structure and function were evaluated by echocardiography. Oxidants and antioxidants were measured and cardiac fibrosis was analysed using immunohistochemistry, Masson’s trichrome stain and Western blot. Results Results showed that empagliflozin improved diabetic myocardial structure and function, decreased myocardial oxidative stress and ameliorated myocardial fibrosis. Further study indicated that empagliflozin suppressed oxidative stress and fibrosis through inhibition of the transforming growth factor β/Smad pathway and activation of Nrf2/ARE signaling. Conclusions Glycaemic control with empagliflozin significantly ameliorated myocardial oxidative stress injury and cardiac fibrosis in diabetic mice. Taken together, these results indicate that the empagliflozin is a promising agent for the prevention and treatment of diabetic cardiomyopathy.

Unit commitment is fundamental to power system operations, and the problem model is more precise with the consideration of AC power flow constraints. However, unit commitment with AC power flow constraints (ACUC) is intractable, and new formulations and methods that can improve the solution efficiency are still desired. In this paper, we propose a new optimization formulation for ACUC that is based on the inherent semi-continuous variables. Instead of using auxiliary binary variables that indicate the on/off states of generating units, we directly utilize the semi-continuous variables to describe the operation levels of units, and the overall problem is reformulated without changing the original logical relation except for few and close approximations. Therefore, it reduces the number of variables and simplifies the search space compared with the commonly used binary paradigm. As an important result, the proposed formulation can leverage commercial solvers to obtain a solution more effectively. The numerical experiments on the IEEE 39- and 118-bus test systems and a large-scale 739-bus system demonstrate the effectiveness of our model and method.

As a leading cause of vision impairment of the retina, macular edema (ME) has one of the highest clinical demands for treatment. Current treatment of ME relies heavily on invasive techniques resulting in complications and poor patient compliance. To enhance the efficiency of triamcinolone acetonide as eye drop to the posterior segment of the eye, we developed and characterized a novel formulation, namely, triamcinolone acetonide chitosan-coated liposomes (TA-CHL), prepared by the calcium acetate gradient method with some modifications. TA-CHL provided the mean particle size of 135.46 ± 4.49 nm and high entrapment efficiency (90.66 ± 3.21%), exhibited a sustained release profile, excellent physical stability, and no significant toxicity on cornea, conjunctiva, and retina. Optical coherence tomography system (OCT) was used to detect pharmacokinetics of CHL in vivo, indicating that CHL had good potency for drug delivery. Cellular uptake experiments showed CHL had the higher transduction efficiency into HCEC and ARPE-19 than liposomes. TA-CHL was shown to be potentially effective eye drop to contribute to the posterior segment of the eye.

Abstract Background Cyclosporin A (CsA) is a promising therapeutic drug for myocardial ischemia reperfusion injury (MI/RI) because of its definite inhibition to the opening of mitochondrial permeability transition pore (mPTP). However, the application of cyclosporin A to treat MI/RI is limited due to its immunosuppressive effect to other normal organ and tissues. SS31 represents a novel mitochondria-targeted peptide which can guide drug to accumulate into mitochondria. In this paper, mitochondria-targeted nanoparticles (CsA@PLGA-PEG-SS31) were prepared to precisely deliver cyclosporin A into mitochondria of ischemic cardiomyocytes to treat MI/RI. Results CsA@PLGA-PEG-SS31 was prepared by nanoprecipitation. CsA@PLGA-PEG-SS31 showed small particle size (~ 50 nm) and positive charge due to the modification of SS31 on the surface of nanoparticles. CsA@PLGA-PEG-SS31 was stable for more than 30 days and displayed a biphasic drug release pattern. The in vitro results showed that the intracellular uptake of CsA@PLGA-PEG-SS31 was significantly enhanced in hypoxia reoxygenation (H/R) injured H9c2 cells. CsA@PLGA-PEG-SS31 delivered CsA into mitochondria of H/R injured H9c2 cells and subsequently increased the viability of H/R injured H9c2 cell through inhibiting the opening of mPTP and production of reactive oxygen species. In vivo results showed that CsA@PLGA-PEG-SS31 accumulated in ischemic myocardium of MI/RI rat heart. Apoptosis of cardiomyocyte was alleviated in MI/RI rats treated with CsA@PLGA-PEG-SS31, which resulted in the myocardial salvage and improvement of cardiac function. Besides, CsA@PLGA-PEG-SS31 protected myocardium from damage by reducing the recruitment of inflammatory cells and maintaining the integrity of mitochondrial function in MI/RI rats. Conclusion CsA@PLGA-PEG-SS31 exhibited significant cardioprotective effects against MI/RI in rats hearts through protecting mitochondrial integrity, decreasing apoptosis of cardiomyocytes and myocardial infract area. Thus, CsA@PLGA-PEG-SS31 offered a promising therapeutic method for patients with acute myocardial infarction.

Vip3Aa is a novel insecticidal protein secreted by Bacillus thuringiensis (Bt) during its vegetative growth stages. It has high insecticidal activity against lepidopteran pests such as Spodoptera frugiperda, and has no cross-resistance with Cry insecticidal proteins. As a new type of insecticide, it plays an important role in controlling agricultural pests. However, the insecticidal mechanism of the Vip3Aa toxin, especially its definite receptors, have not been fully revealed. In this study, the previously reported Vip3Aa receptor genes Sf-FGFR and Sf-SR-C were knocked out separately using the CRISPR/Cas9 system. Bioassay results showed that the sensitivity of these two knockout strains to Vip3Aa were not significantly changed compared to that of the normal strain. The current results are not consistent with the previously reports that Sf-SR-C and Sf-FGFR were the receptors of Vip3Aa in vitro. This suggests that the Sf-SR-C and Sf-FGFR genes we tested may not be critical in the mode of action of Vip3Aa in vivo in Spodoptera frugiperda.

The production of high-performance, low-cost warm mix additives (WMa) for matrix asphalt remains a challenge. The pyrolysis method was employed to prepare wax-based WMa using waste polypropylene plastic (WPP) as the raw material in this study. Penetration, softening point, ductility, rotational viscosity, and dynamic shear rheological tests were performed to determine the physical and rheological properties of the modified asphalt. The adhesion properties were characterized using the surface free energy (SFE) method. We proved that the pyrolysis temperature and pressure play a synergistic role in the production of wax-based WMa from WPPs. The product prepared at 380 °C and 1.0 MPa (380-1.0) can improve the penetration of matrix asphalt by 61% and reduce the viscosity (135 °C) of matrix asphalt by 48.6%. Furthermore, the modified asphalt shows favorable elasticity, rutting resistance, and adhesion properties; thus, it serves as a promising WMa for asphalt binders.

Dengue fever, caused by any of four dengue viruses (DENV1-4), is a major global burden. Currently, there is no effective vaccine that prevents infection in dengue naïve populations. We tested the ability of two novel adjuvants (Advax-PEI and Advax-2), using aluminum hydroxide (alum) as control, to enhance the immunogenicity of formalin- or psoralen-inactivated (PIV or PsIV) DENV2 vaccines in mice. Mice were vaccinated on days 0 and 30, and serum samples were collected on days 30, 60, 90, and 101. Neutralizing antibodies were determined by microneutralization (MN) assays, and the geometric mean 50% MN (MN50) titers were calculated. For the PIV groups, after one dose MN50 titers were higher in the novel adjuvant groups compared to the alum control, while MN50 titers were comparable between the adjuvant groups after the second dose. For the PsIV groups, both novel adjuvants induced higher MN50 titers than the alum control after the second dose. Spleen cells were collected on days 45 and 101 for enzyme-linked immunospot (ELISPOT) for IFNγ and IL4. Both PIV and PsIV groups elicited different degrees of IFNγ and IL4 responses. Overall, Advax-2 gave the best responses just ahead of Advax-PEI. Given Advax-2’s extensive human experience in other vaccine applications, it will be pursued for further development.

Seed priming is a method for improving seed vigor, which can improve seed germinability, but the disappearance of positive priming effects and decrease of seed longevity during storage may limit its application. To determine the effect of priming on hot pepper seeds and the time during which priming effects can be maintained, it is necessary to monitor and study the variability of primed seeds during storage. In this study, several priming treatments with 3% KNO3, 20% PEG, or 3% KNO3 + 20% PEG and up to 8 months of storage of primed seeds were conducted on seeds of pepper strains No.63, No.73, and No.101. Germinability was improved by priming treatment. The germination percentage of primed seeds did not vary compared to non-primed ones, seeds germinated quickly and had strengthened emergence, especially for those primed with 3% KNO3 solution, which germinated significantly faster and the seedlings grew stronger. During the 8-month storage process, the beneficial effects of priming disappear after 6 months, beyond which the performance of primed seeds is worse than non-primed seeds. After 8 months of storage, the viability of primed pepper seeds dropped sharply. In general, preservation at −4 °C can retain the priming effects to the greatest degree and prevent the seed from losing viability for up to 6 months. Resistance to aging differed across varieties, with No.101 pepper seeds more resistant to aging than the other two varieties, regardless of priming treatment.

Objective: Anlotinib hydrochloride is a multitarget tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor, fibroblast growth factor receptor, platelet-derived growth factor receptor, c-Kit, and c-MET; therefore, it exhibits both antitumor and anti-angiogenetic activities. A phase III trial has shown that anlotinib improved progression-free survival (PFS) and overall survival (OS) in patients with advanced non-small cell lung cancer (NSCLC), who presented with progressive disease or intolerance after standard chemotherapy. This study aimed to analyze the characteristics of patients receiving anlotinib treatment to determine the dominant populations who are fit for the treatment.Methods: Data were collected from March 2015 to January 2017 from a randomized, double-blind, placebo-controlled, multicenter, phase III trial of anlotinib (ALTER0303). A total of 437 patients were enrolled and randomly allocated (2:1) to the anlotinib and placebo groups. Kaplan–Meier analysis and log-rank test were performed to compare PFS and OS. Cox proportional hazards model was adopted for multivariate prognostic analysis. Results: Multivariate analysis indicated that high post-therapeutic peripheral blood granulocyte/lymphocyte ratio and elevated alkaline phosphatase levels were independent risk factors for PFS. Meanwhile, elevated thyroid-stimulating hormone, blood glucose, and triglyceride levels; hypertension; and hand–foot syndrome were independent protective factors of PFS. High post-therapeutic peripheral blood granulocyte/lymphocyte ratio, an Eastern Cooperative Oncology Group (ECOG) score ≥ 2, and the sum of the maximal target lesion length at baseline were independent risk factors of OS, and hypertriglyceridemia was an independent protective factor of OS. Conclusions: This study preliminarily explored the possible factors that affected PFS and OS after anlotinib treatment in patients with advanced refractory NSCLC, and the baseline characteristics of the therapeutically dominant populations were then identified.

Background and objective Epidermal growth factor receptor (EGFR)-based targeted therapy improves the survival of patients with advanced lung adenocarcinoma harboring EGFR mutations. However, factors including treatment or heterogeneity partly contribute to EGFR genetic status alteration between baseline and disease progresses (PD). The aim of this study is to compare difference of EGFR mutations between biopsy and rebiopsy in real world. Methods Data from 61 paired specimens performed EGFR testing in Jilin Provincial Cancer Hospital between January 2015 and December 2017 were collected and analyzed. The specimens were collected at baseline and PD, confirmed by histology or cytology and categorized as tumor tissue, malignant pleural effusion or plasma. All patients were naive and received chemotherapy or targeted therapy as first-line treatment. Amplification Refractory Mutation System (ARMS) was used to detect EGFR mutations. Results EGFR mutation rate in tumor tissue, pleural effusion or blood was 90.2% vs 88.5%, 6.6% vs 6.6% and 3.2% vs 4.9% at baseline or PD respectively and discrepancy was 72% and 36.3% for the same (n=50) or different (n=11) type of specimens. The EGFR mutation rate was 95.1% and 91.8% in patients before and after treatment, and the discrepancy was 63.9%, among which, 69.2% and 92.3% in chemotherapy-treated patients (n=13) with discrepancy to 46.1% (6/13), and 100.0% and 91.7% in EGFR-TKI-treated patients (n=48) with discrepancy to 70.8%. There were four types of alterations in terms of EGFR mutations: wild type turned into mutation (4.9%), mutation disappeared (8.2%), sensitive mutations transformed (1.6%), and new mutations appeared (49.1%). Conclusion In real world, the EGFR mutation status in advanced non-small cell lung cancer (NSCLC) patients altered significantly, due to tissue resources and therapeutic approaches, implying the importance of rebiopsy and real-time detection of EGFR mutation, in order to provide data to guide precise strategy in the following treatment.

Abstract Helmholtz resonators offer an ideal platform for advanced sound absorbers, but their utility has been impeded by inherent frequency range limitations and the lack of function reconfiguration. Here, we introduce a multi-order Helmholtz resonator (MHR) that allows multiple monopolar resonant modes theoretically and experimentally. The combination of these modularized MHRs further creates reconfigurable multi-band anomalous absorbers in a two-port transparent waveguide while maintaining undisturbed air ventilation. In asymmetric absorption state through coupling of artificial sound soft boundary with preposed MHR, sound energy is almost totally absorbed in multiple frequency ranges when sound waves are incident from one side while it is largely reflected back from the opposite side. Interestingly, the original asymmetric absorber would turn into symmetric bidirectional absorber if one post MHR concatenates after the soft boundary. Using combination of identical MHRs, we demonstrate function selective asymmetric/symmetric absorber in multi-bands, highlighting the potential to use MHRs in the design of diverse devices for more versatile applications.

Ionizing radiation is one of the common environmental carcinogens. miRNAs play critical roles in the processes of tumor occurrence, development, metastasis. However, the relationship between radiation-induced carcinogenesis and miRNA rarely reported. This study is aimed to investigate the effect of miRNAs on radiation-induced carcinogenesis. In this study we established the radiation-induced thymic lymphoma mice model. By using miRNA array of RTL tissue and predicting for miRNAs target genes, a miRNA-mRNA crosstalk network was established. Based on this network, we identified a critical miRNA, miR-486, which was the most down-regulated in the radiation-induced carcinogenesis. Then the function of miR-486 was confirmed by using knockout mice and cellular experiments. As a result, miR-486 could inhibit proliferation of mouse lymphoma cells by targeting IGF2BP3 mRNA. The adenovirus over-expression miR-486 vector reduced tumorigenesis in vivo. MiR-486 knockout mice have a strong tendency of radiation-induced carcinogenesis. In conclusion, miR-486 inhibits the proliferation of lymphoma cells and tumorigenesis induced by radiation through targeting IGF2BP3.

Introduction Biliary colic (BC) is a severe pain associated with nausea and vomiting, which is the most common symptom among the gallstone population. This protocol proposes a methodology for conducting a systematic review and meta-analysis that aims to assess the benefits and safety of acupuncture in patients with BC.Methods and analysis Clinical trials will be identified through nine databases from inception to December 2020, using Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Allied and Complementary Medicine Database (AMED), CINAHL, China National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature Database (CBM), VIP Database and Wanfang Database. Search words will be used for the BC and acupuncture. The analysis would include randomised, controlled, clinical trials of adults with BC that were published in either Chinese or English. The primary outcome is to measure pain relief. Two or three reviewers should be in charge of study selection, data extraction and evaluating the risk of bias. RevMan software (V.5.4) will be used to perform the assessment of the risk of bias and data synthesis.Ethics and dissemination Ethics approval will not be required for this review, as it will only involve the collection of literature previously published. The results of this meta-analysis will be disseminated in a peer-reviewed journal or relevant conference, through publication.Trial registration number CRD42020167510.

Qingda granule (QDG), simplified from Qingxuan Jiangya Decoction, is a well-known traditional Chinese medicine formula that has been used for decades to treat hypertension. However, the cardioprotective effects of QDG on Ang II-induced hypertension remain unknown. This study aimed to investigate the effects of QDG on hypertension-induced cardiac hypertrophy and apoptosis, as well as explore its underlying mechanisms. Mice were infused with Ang II (500 ng/kg/min) or saline solution as control, then administered oral QDG (1.145 g/kg/day) or saline for two weeks. QDG treatment attenuated the elevation in blood pressure caused by Ang II, as well as the decreased left ventricle ejection fractions and fractional shortening. Moreover, QDG treatment significantly alleviated the Ang II-induced elevation of the ratio of heart weight to tibia length, as well as cardiac injury, hypertrophy, and apoptosis. In cultured H9C2 cells stimulated with Ang II, QDG partially reversed the increase in cell surface area and number of apoptotic cells, up-regulation of hypertrophy markers ANP and BNP, and activation of caspases-9 and -3. QDG also partially reversed Ang II-induced accumulation of reactive oxygen species (ROS), depolarization of the mitochondrial membrane, release of cytochrome C, up-regulation of Bax, and decrease in levels of p-PI3K, p-AKT, and Bcl-2. These results suggest that QDG can significantly attenuate Ang II-induced hypertension, cardiac hypertrophy and apoptosis, and it may exert these effects in part by suppressing ROS production and activating the PI3K/AKT signaling pathway.

Purpose. Treatment outcomes for advanced liver cancer are poor. Immunotherapy is a treatment strategy that has been widely used to treat other cancers. Studies have shown that CD8+ T lymphocytes are essential factors affecting the efficacy of immunotherapy. We used computational biology methods to determine the coexpressed gene network that promotes CD8+ T lymphocyte infiltration. Method. We obtained the liver cancer gene matrix and clinical follow-up information data from TCGA liver hepatocellular carcinoma FPKM. We obtained single nucleotide polymorphism (SNP) data to evaluate the tumor mutation burden. The “estimate” package and the CIBERSORT algorithm were used to evaluate tumor purity and the proportion of CD8+ T lymphocytes in the liver cancer cohort. We used the gene expression matrix of liver cancer and the relative proportion of CD8+ T lymphocytes as input files and performed WGCNA based on this analysis. The weighted coexpression network identified the most CD8+ T lymphocyte-related coexpression modules in liver cancer. Then, we analyzed the biological processes involved in the module. We determined the coexpression module with CD8+ T lymphocyte infiltration in terms of data and function. We then screened the factors in the coexpression module correlated with CD8+ T lymphocyte content greater than 0.4. Finally, the expression levels of these factors were verified at the protein level using immunohistochemistry and single-cell sequencing. Results. We determined the CD8+ T lymphocyte proportions that correlated with coexpression networks. Four coexpressed genes (C1QC, CD3D, GZMA, and PSMB9) were identified as CD8+ T cell coexpression genes that promoted infiltration of CD8+ T cells. Because the factors in the coexpression network often participate in similar biological processes, we found that these factors were most related to antigen processing and presentation of peptide antigen through functional enrichment. In the clinical phenotype analysis, we found that 18 factors can be used as independent prognostic protective factors. We found that these factors were significantly negatively correlated with tumor purity and negatively correlated with M2 macrophages in the immunophenotyping analysis. Using immunohistochemistry and single-cell sequencing analysis, we found that CD3D antibody staining was weaker in tumor tissues than normal tissues and was related to CD8+ T cells. Conclusion. These coexpressed genes were positively related to the high infiltration proportion of CD8+ T lymphocytes in an antigen presentation process. The biological process might provide new directions for patients who are insensitive to immune therapy.

Background: Carboxyamidotriazole (CAI), a calcium channel blocker, inhibits tumor cell proliferation, metastasis, and angiogenesis. This trial aimed to determine whether CAI combined with conventional chemotherapy could prolong progression-free survival (PFS) in non-small cell lung cancer (NSCLC) patients. Methods: Patients were assigned into groups (3:1 ratio) to receive either chemotherapy + CAI or chemotherapy alone. Cisplatin (25 mg/m 2 ) was administered by intravenous infusion on days 1, 2, and 3, and vinorelbine (25 mg/m 2 ) on days 1 and 8 of each 3-week cycle for four cycles. CAI was administered at 100 mg daily with concomitant chemotherapy; this treatment was continued after chemotherapy was ceased until serious toxicity or disease progression had occurred. PFS was the primary endpoint, and the secondary endpoints were objective response rate (ORR), disease control rate, overall survival (OS), and quality of life. Results: In total, 495 patients were enrolled in the trial: 378 in the chemotherapy + CAI group and 117 in the chemotherapy + placebo group. PFS was significantly greater in the chemotherapy + CAI [median, 134 days; 95% confidence interval (CI) 127–139] than in the chemotherapy + placebo (median, 98 days; 95% CI: 88–125) group, with a hazard ratio of 0.690 (95% CI: 0.539–0.883; p = 0.003). There was no difference in the OS rates of both groups. The ORR was greater in the chemotherapy + CAI group than in the chemotherapy + placebo group (34.6% versus 25.0%, p = 0.042). Adverse events of ⩾grade 3 occurred more frequently in the CAI group [256 (68.1%) versus 64 (55.2%); p = 0.014]. Conclusion: CAI + platinum-based chemotherapy prolonged PFS and could be a useful therapeutic option to treat NSCLC. Clinical Trial Registration: chinadrugtrials.org.cn identifier: CTR20160395

Allogeneic hematopoietic stem cell transplantation is a potentially curative procedure for many malignant diseases. Donor T cells prevent disease recurrence via graft-versus-leukemia (GVL) effect. Donor T cells also contribute to graft-versus-host disease (GVHD), a debilitating and potentially fatal complication. Novel treatment strategies are needed which allow preservation of GVL effects without causing GVHD. Using murine models, we show that targeting IL-2-inducible T cell kinase (ITK) in donor T cells reduces GVHD while preserving GVL effects. Both CD8+ and CD4+ donor T cells from Itk-/- mice produce less inflammatory cytokines and show decrease migration to GVHD target organs such as the liver and small intestine, while maintaining GVL efficacy against primary B-cell acute lymphoblastic leukemia (B-ALL). Itk-/- T cells exhibit reduced expression of IRF4 and decreased JAK/STAT signaling activity but upregulating expression of Eomesodermin (Eomes) and preserve cytotoxicity, necessary for GVL effect. Transcriptome analysis indicates that ITK signaling controls chemokine receptor expression during alloactivation, which in turn affects the ability of donor T cells to migrate to GVHD target organs. Our data suggest that inhibiting ITK could be a therapeutic strategy to reduce GVHD while preserving the beneficial GVL effects following allo-HSCT treatment.

Lung cancer is a malignant tumor that seriously threatens human life and health. Non-small cell lung cancer (NSCLC) accounts for 85 % of all lung cancer cases, and its global 5-year survival rate is only approximately 5%. Thus, the identification of new prognostic biomarkers has become one of the most urgent challenges in NSCLC research. Long noncoding RNAs (LncRNAs) are a kind of noncoding RNA whose length exceeds 200 nucleotides (nt). LncRNAs are transcribed by RNA pol II and can be subjected to posttranscriptional modifications such as blocking, polyadenylation and splicing; moreover, their expression profiles are more specific than those of mRNAs. Emerging evidence confirms that lncRNAs are associated with the occurrence and development of NSCLC and play an important role in NSCLC drug resistance. The purpose of this review was to describe the roles of lncRNAs in the development, diagnosis and prognosis of NSCLC and to explore new evidence of lncRNAs in the treatment of NSCLC drug resistance. This review provides a new perspective of lncRNAs in the treatment of NSCLC.

Introduction Chronic cancer-related pain is one of the most common excruciating symptom that can be caused by the cancer (by the primary tumour or by metastases) or by its treatment (surgery, chemotherapy and radiotherapy). Although multiple clinical trials and systematic reviews have suggested that acupuncture could be effective in treating chronic cancer-related pain, the comparative efficacy and safety of these acupuncture methods remains unclear. We, therefore, performed this study to evaluate and rank the efficacy and safety of different acupuncture methods for chronic cancer-related pain.Methods and analysis Seven databases will be searched, including Cochrane Library, MEDLINE, Embase, Chinese National Knowledge Infrastructure (CNKI), Wanfang Database, the Chongqing VIP Chinese Science and Technology Periodical Database and Chinese Biomedical Literature Database (CBM) from their inception to March 2020. The primary outcome is the change of pain intensity. Bayesian network meta-analysis will be conducted using software R3.5.1. Finally, we will use the Grading of Recommendations Assessment, Development and Evaluation System (GRADE) to assess the quality of evidence.Ethics and dissemination Ethical approval is not required for literature-based studies. The results will be disseminated through peer-reviewed publication.PROSPERO registration number CRD42020165747

Huoxin Pill (HXP), a Traditional Chinese Medicine, is used widely to treat patients with coronary heart disease and angina pectoris in China. However, the underlying protective mechanism of HXP on cardiac apoptosis and fibrosis has never been evaluated. Therefore, the aim of this study was to investigate the role of HXP in a myocardial infarction (MI) mouse model. The mice were randomly divided into 3 groups and subjected to surgical ligation of the left anterior descending (LAD) coronary artery or sham surgery (n = 6 for each group) and treated with HXP (50 mg/kg/day) or saline by gavage for 2 weeks. At 2 weeks post MI, we found that HXP significantly enhanced myocardial function and attenuated the increase of heart weight index (HWI) and pathological changes in MI mice. RNA-sequencing and KEGG pathway analyses identified 660 differentially expressed genes and multiple enriched signaling pathways including p53 and TGF-β. In support of these findings, HXP attenuated cardiac apoptosis and decreased p53 and Bax protein expression, while increasing Bcl-2 protein expression in cardiac tissues of MI mice. Furthermore, HXP treatment inhibited cardiac fibrosis and significantly down-regulated TGF-β1 protein expression and Smad2/3 phosphorylation in cardiac tissues. In summary, HXP can improve cardiac function in mice after MI by attenuating cardiac apoptosis and fibrosis partly via supression of the p53/Bax/Bcl-2 and TGF-β1/Smad2/3 pathways.

Aim: To compare the efficacy, safety, and tolerability of abemaciclib plus endocrine therapy (ET) versus ET alone in postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) from China, Brazil, India, and South Africa. Methods: This randomized, double-blind, phase III study was conducted between 9 December 2016 and 29 March 2019. Postmenopausal women with HR-positive, HER2-negative ABC with no prior systemic therapy in an advanced setting (cohort A) or progression on prior ET (cohort B) received abemaciclib (150 mg twice daily) or placebo plus: anastrozole (1 mg/day) or letrozole (2.5 mg/day) (cohort A) or fulvestrant (500 mg per label) (cohort B). The primary endpoint was progression-free survival (PFS) in cohort A, analyzed using the stratified log-rank test. Secondary endpoints were PFS in cohort B (key secondary endpoint), objective response rate (ORR), and safety. This interim analysis was planned after 119 PFS events in cohort A. Results: In cohort A, 207 patients were randomly assigned to the abemaciclib arm and 99 to the placebo arm. Abemaciclib significantly improved PFS versus placebo (median: not reached versus 14.7 months; hazard ratio 0.499; 95% confidence intervals (CI) 0.346–0.719; p = 0.0001). ORR was 65.9% in the abemaciclib arm and 36.1% in the placebo arm ( p

Guiding qualified farmers to transfer their land is an important way to alleviate the problem of land abandonment, improve land use efficiency, and achieve moderately large-scale land management. Based on the dual perspectives of economic endowment and land endowment, this paper uses the 2015 data of the China Household Finance Survey (CHFS), using the semilogarithmic ordinary least-squares method and the logit model, to explore differences in land transfer decisions under the effect of farmer heterogeneity. The circulation trading market was further improved to provide a reference. The heterogeneity of economic endowment and land endowment significantly affects the decision-making behavior of farmers in transferring land. The higher the land endowment is, the greater the probability that farmers transfer the land out and successfully trade, and they are more inclined to transfer the cultivated land to cooperatives, village collectives, and other institutions through formal channels, leading to a higher unit income of the transfer. Further research shows that land endowment has no significant difference in the impact of land endowment on whether farmers with different livelihood endowments transfer their land, but under the same land endowment, farmers with economic endowment advantages are more able to use their own endowment advantages to transfer their land out through formal channels and obtain higher gains income. Therefore, focusing on improving the conditions of land resources and increasing the endowment of farmers are important means to promote successful transactions in the land transfer market, ensure its sustainable operation, and promote further increase in the income of transfer farmers.

Higher-order topological insulator hosts both gapped edge states and in-gap corner states, which has garnered considerable attentions in the field of condensed matter physics, and most recently is further extended to the classical wave systems. Conventional acoustic metamaterials have intrinsic material and design limitations that prevent them from being used to create such states in subwavelength scale with function reconfigurability. Recently, the acoustic second-order topological insulators (SOTIs) composed of locally resonant metamaterials were reported to solve the problem, where the topological phase transition is induced by shrinking/expanding metamolecules. Here, we propose an acoustic SOTI in subwavelength scale by another protocol, i.e. gliding metamolecules, and the SOTI is pinned in the nontrivial region without the regular topological phase transition. Soda cans metamaterials in free space are utilized to support the spoof surface acoustic waves. With varying the introduced glided angle, the switching from the bulk to edge and corner states can be achieved accordingly. Furthermore, we not only experimentally observe this state switching process, but also illustrate the robustness of the topological corner states against various defects. Our results provide versatile ways to launch acoustic lower-dimensional topological states that might lead to interesting sound concentration applications.

SCLC is an aggressive malignancy with a very poor prognosis and limited effective therapeutic options. Despite the high tumor mutational burden, responses to immunotherapy are rare in SCLC patients, which may be due to the lack of immune surveillance. Here, we aimed to examine the role and mechanism of oncogene MYC in the regulation of NKG2DL, the most relevant NK-activating ligand in SCLC-N. Western Blotting, Immunofluorescence, flow cytometry, quantitative real-time PCR (qRT-PCR), Co-Immunoprecipitation (Co-IP), chromatin immunoprecipitation (ChIP), and Cytotoxicity assay were used on H2227 cells, H446 cells, and other SCLC cell lines, and we found that c-Myc negatively regulated NKG2DL expression in SCLC-N cells. Mechanistically, c-Myc recruited HDAC3 to deacetylate H3K9ac at the promoter regions of MICA and MICB, suppressing the MICA/B expression of SCLC-N cells and the cytotoxicity of NK cells. Treatment with selective HDAC3 inhibitor up-regulated the expression of NKG2DL on SCLC-N cells and increased the cytotoxicity of NK cells. Furthermore, analysis of the CCLE and Kaplan-Meier plotter data performed the negative correlation between MYC and NKG2DL in SCLC-N cells and the correlation with the prognosis of lung cancer patients. Collectively, the results provided the new insight into the role and mechanism of c-Myc/HDAC3 axis in NKG2DL expression and innate immune escape of SCLC-N, suggesting the potential target for SCLC-N immunotherapy.

ATP-binding cassette transporter B1 (ABCB1, or P-glycoprotein) is known to be an important participant in multidrug resistance in mammals, and it also has been proved as a transporter for some insecticides in several lepidopteran insects, yet the precise function of this transporter in Spodoptera frugiperda is unknown. Here, we generated a SfABCB1 knockout strain of the S. frugiperda using the CRISPR/Cas9 system to explore its potential roles in determining susceptibility to chemical insecticides or Bt toxins. Bioassay results showed that the susceptibility of SfABCB1 knockout strain to beta-cypermethrin, chlorantraniliprole and emamectin benzoate were significantly increased compared with the wild-type strain DH19, whereas there were no changes to Bt toxins for Cry1Ab, Cry1Fa and Vip3Aa. Our results revealed that SfABCB1 plays important roles in the susceptibility of S. frugiperda to beta-cypermethrin, chlorantraniliprole and emamectin benzoate, and imply that overexpression of ABCB1 may contribute to beta-cypermethrin, chlorantraniliprole and emamectin benzoate resistance in S. frugiperda.

Objective: This study investigated survival in selected Chinese patients with advanced lung adenocarcinoma who received initial chemotherapy with pemetrexed. We also explored the relationship between genetic biomarkers and pemetrexed efficacy.Methods: We retrospectively collected patients (n = 1,047) enrolled in the Chinese Patient Assistance Program from multiple centers who received pemetrexed alone or combined with platinum as initial chemotherapy and continued pemetrexed maintenance therapy for advanced lung adenocarcinoma from November 2014 to June 2017. The outcomes were duration of treatment (DOT) and overall survival (OS). Clinical features were analyzed for their influence on the treatment effect and prognosis. Next-generation sequencing (NGS) was performed to identify genetic biomarkers associated with the efficacy of pemetrexed.Results: The median DOT was 9.1 months (95% CI: 8.5–9.8), and the median OS was 26.2 months (95% CI: 24.2–28.1). OS was positively correlated with DOT (r = 0.403, P < 0.001). Multivariable analysis showed that smoking status and Eastern Cooperative Oncology Group (ECOG) performance status (PS) were independently associated with DOT; smoking status, ECOG PS, targeted therapy, and EGFR/ALK/ROS1 status were independently associated with OS. NGS in 22 patients with available samples showed genes with high mutation rates were: TP53 (54.5%), EGFR (50.0%), MYC (18.2%), and PIK3CA (13.6%). When grouped based on progression-free survival (PFS) reported in the PARAMOUNT study, the DOT > 6.9 months set was associated with PIK3CA, ALK, BRINP3, CDKN2A, CSMD3, EPHA3, KRAS, and RB1 mutations, while ERBB2 mutation was observed only in the DOT ≤ 6.9 months set.Conclusion: This study shows that initial chemotherapy with pemetrexed is an effective regimen for advanced lung adenocarcinoma in selected Chinese patients. There is no specific genetic profile predicting the benefit of pemetrexed found by NGS. Biomarkers predicting the efficacy of pemetrexed need further exploration.

Growth arrest and DNA damage-inducible beta (GADD45B) is closely linked with cell cycle arrest, DNA repair, cell survival, or apoptosis in response to stress and is known to regulate the mitogen-activated protein kinase (MAPK) pathway. Here, using an RNA sequencing approach, we determined that GADD45B was significantly upregulated in diabetic kidneys, which was accompanied by renal tubular epithelial-mesenchymal transition (EMT) and apoptosis, as well as elevated MAPK pathway activation. In vitro, GADD45B expression in cultured human kidney proximal tubular epithelial cells (HK-2 cells) was also stimulated by high glucose (HG). In addition, overexpression of GADD45B in HK-2 cells exacerbated renal tubular EMT and apoptosis and increased p38 MAPK and c-Jun N-terminal kinases (JNK) activation, whereas knockdown of GADD45B reversed these changes. Notably, the activity of extracellular regulated kinase (ERK) was not affected by GADD45B expression. Furthermore, inhibitors of p38 MAPK (SB203580) and JNK (SP600125) alleviated HG‐ and GADD45B overexpression-induced renal tubular epithelial-mesenchymal transition and apoptosis. These findings indicate a role of GADD45B in diabetes-induced renal tubular EMT and apoptosis via the p38 MAPK and JNK pathways, which may be an important mechanism of diabetic kidney injury.

The aim of the present study was to identify the virulence of glycoprotein B (gB), glycoprotein N (gN), and glycoprotein H (gH) genotypes of cytomegalovirus(CMV) and assess possible relationships between genotypes and CMV-associated thrombocytopenia. CMV gB, gN, and gH strains were determined by nested PCR and restriction length polymorphism from 30 CMV-associated thrombocytopenia infants infected postnatally and 40 non-thrombocytopenic infants. The gN2 (p = 0.043) and gH2 (p = 0.038) genotypes were associated with an elevated risk of developing thrombocytopenia. gB1 genotype was detected in 80.0% (16/20) of infants with moderately to severely symptomatic CMV disease and was associated with severe manifestations in CMV-associated thrombocytopenia infants (p = 0.022). Conversely, the gN1 genotype was detected in 5.0% (1/20) of infants with moderately to severely symptomatic CMV disease and represent less pathogenic CMV strains (p = 0.044). There may be potential associations between the gN2 and gH2 genotypes of CMV and infantile thrombocytopenia, and that the detection of the gB1and gN1 genotypes may help define the severity of CMV disease in infants.

Background: This study investigates the potential predictors of nivolumab plus chemotherapy or multitarget tyrosine kinase inhibitor (TKI) treatment response in patients with recurrent hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC).Methods: Patients with recurrent hepatitis B virus-related HCC who underwent nivolumab plus chemotherapy or TKI treatment between July 2017 and June 2019 at Jinling Hospital in China were retrospectively evaluated and included in this study. These patients also had both complete medical charts and follow-up data available. Overall survival (OS) and progression-free survival (PFS) were calculated from the date of nivolumab initiation. Survival data were compared using log-rank tests, and the associations of patient characteristics with survival were estimated using Cox regression models.Results: A total of 22 HCC patients were included in this cohort and constituted the basis for this analysis. Twenty progressed cases (91%) and 16 deaths (73%) were identified at a median follow-up of 8.8 months (range 1–25). The median OS from the time of nivolumab initiation was 10.7 months (95% CI, 0.8–20.6 months), with a median PFS of 5.1 months (95% CI, 3.1–7.0 months). The patients were divided into two risk groups according to a nomogram built by age, Eastern Cooperative Oncology Group (ECOG) status, hepatectomy status, and transarterial chemoembolization (TACE) use. The median PFS was 8.2 ± 2.8 months in the low-risk group compared with 1.9 ± 0.4 months in the high-risk group (p = 0.0018). The median OS was estimated as 16.8 ± 4.9 months for low-risk patients vs. 8.6 ± 3.5 months for high-risk patients (p = 0.13).Conclusion: Nivolumab combined with chemotherapy or TKI treatment is effective in patients with recurrent hepatitis B virus-related HCC. It is observed that previous TACE treatment is associated with a better PFS, and worse PFS in those patients who received hepatectomy. Prospective studies are warranted to evaluate the effects of nivolumab combined chemotherapy or TKI on recurrent hepatitis B virus-related HCC.

Summary: Feedback circuits are one of the major causes underlying tumor resistance. Thus, compounds that target one oncogenic pathway with simultaneously blocking its compensatory pathway will be of great value for cancer treatment. Here, we develop a new MEK inhibitor designated as KZ-02 that exhibits unexpectedly higher cytotoxicity than its starting compound AZD6244, a well-known MEK inhibitor, in colorectal cancer (CRC). Subsequent kinase selectivity study identified Pim-1 as an additional cellular target for KZ-02. Further studies showed that AZD6244 and Pim-1 1 (a Pim-1 inhibitor) have a synergistic effect on CRC suppression. Mechanistic study revealed that MEK inhibition by AZD6244 leads to increased Pim-1 expression, which could be a general mechanism behind the compromised cell-killing activity of MEK inhibitors. KZ-02, despite increasing Pim-1 mRNA expression, simultaneously promotes Pim-1 proteasomal degradation. Therefore, we uncover a new MEK inhibitor KZ-02 with significantly enhanced antitumor activity by co-targeting MEK and Pim-1.

Early B cell factor 1 (EBF1) has been identified as an upstream transcription factor of the potential oncogene PNO1 and is involved in the growth of colorectal cancer (CRC) cells. However, its expression, biological function, and underlying mechanism of action in most solid tumors remain largely unknown. We postulated that EBF1 has a role in the pathophysiology of CRC. Analysis of EBF1 mRNA expression in CRC tumor samples from several public databases and directly from banked tissues revealed that EBF1 mRNA expression is lower in CRC tissue compared to non-cancerous colorectal tissue. Survival analysis of multiple datasets revealed that low EBF1 expression was correlated with shorter overall survival, relapse-free survival, and event-free survival in CRC patients. Transduction of lentivirus encoding full length EBF1 followed by in vitro and in vivo assays demonstrated that EBF1 over-expression in CRC cell lines suppresses cell growth by inhibiting cell viability, cell survival, and induces cell cycle arrest and apoptosis. Mechanistic investigation indicated that EBF1 over-expression down-regulates PNO1 mRNA and protein expression, as well as transcriptional activity while up-regulating the expression of p53 and p21 proteins. These findings suggest that EBF1 is a novel potential tumor suppressor in CRC with prognostic value for the identification of patients at high-risk of relapse.

BackgroundLymphoma is a common hematological malignancy with many subtypes and considerable heterogeneity. Traditional treatments include chemotherapy, radiotherapy, and surgery. Patients with relapsed, refractory or advanced stage lymphoma have a dismal prognosis. In recent years, chimeric antigen receptors (CARs) have been recognized as powerful tools that redirect antigen-specific T cells independent of human lymphocyte antigen (HLA) restriction and specifically kill tumor cells. Satisfactory results with CAR-based treatments have been achieved in relapsed/refractory B cell leukemia/lymphoma. Our center explored the strategy of subcutaneous injections combined with intravenous drip to overcome certain issues.Case presentationA patient with stage IV refractory and relapsed diffuse large B cell lymphoma was treated with regional and intravenous CAR-T cells. During the observation period, the temperature of the skin at the abdominal wall mass was slightly elevated, and tolerable pain in the injection area was reported. Imaging showed regional liquefactive necrosis. After the sequential administration of ibrutinib and venetoclax, the abdominal wall mass significantly decreased in size.ConclusionThe regional injection of CAR-T cells might be safe and feasible for the treatment of regional lesions in patients with refractory and relapsed advanced lymphoma.

Salmonella enterica cause significant illnesses worldwide. There has been a marked increase in resistance to fluoroquinolones and β-lactams/cephalosporins, antibiotics commonly used to treat salmonellosis. However, S. enterica serovars vary in their resistance to these and other antibiotics. The systemic virulence of some Salmonella serovars is due to a low copy number, IncF plasmid (65–100 kb) that contains the ADP-ribosylating toxin, SpvB. This virulence plasmid is present in only nine Salmonella serovars. It is possible that the spvB-virulence plasmid excludes other plasmids and may explain why antibiotic resistance is slow to develop in certain Salmonella serovars such as S. Enteritidis. The distribution of plasmid entry exclusion genes traS/traT and traY/excA are variable in Salmonella IncF and IncI plasmids, respectively and may account for differences in emergent antimicrobial resistance for some Salmonella serovars. The goal of this study is to determine the contribution of the Salmonella spvB-virulence plasmid in F-plasmid exclusion. From conjugation experiments, S. Typhimurium exhibited lower conjugation frequency with incFI and incFII plasmids when the spvB-virulence plasmid is present. Furthermore, introduction of cloned incFI traS into a “plasmidless” S. Typhimurium LT2 strain and Escherichia coli DH5α excluded incFI plasmid. However, deletion of the virulence plasmid traS did not affect plasmid exclusion significantly compared to a spvB control deletion. In addition, differences in F plasmid conjugation in natural Salmonella isolates did not correlate with IncF or SpvB-virulence plasmid genotype. There appear to be other plasmid or chromosomal genes at play in plasmid exclusion that may be responsible for the slow development of antibiotic resistance in certain serovars.

For precision machinery, the measurement of the relative in-plane displacement of two parallel planes that are separated by several meters is important. In this paper, a theoretical model for measuring the relative in-plane microdisplacement between two parallel planes was developed on the basis of secondary diffraction. Based on this method, we employed a pinhole and a circular-ring as the diffraction screens. The influence of the structural parameters of diffraction screens on the secondary diffraction pattern was analyzed in detail, and the obtained parameters were then used in the experimental measurements. For experimental investigation, a laser beam at 532 nm was used to irradiate a pinhole; the diffracted light was then further diffracted using a circular-ring, and the final diffraction pattern was recorded using a CCD camera. The circular-ring was mounted on the plane to be measured, while the pinhole and the CCD camera remained stationary; the space between the pinhole and the circular-ring was set at 1200 mm. The displacement of the circular-ring can be calculated by comparing the central position of the two diffraction patterns before and after shifting the circular-ring. Over a measurement range of 0–90 µm, the absolute error in the displacement measurement was less than 1.97 µm.

Objective Previous studies have shown that patients with obstructive sleep apnea syndrome (OSAS) may have various vestibular abnormalities, and these mainly present as subclinical lesions. In this study, we attempted to combine ocular vestibular-evoked myogenic potentials (VEMPs) and cervical (VEMPs) to investigate vestibular dysfunction in patients with OSAS. Methods Thirty-eight patients with severe OSAS and 42 healthy controls were enrolled and divided into two groups according to results of polysomnography. All parameters of VEMP graphs were analyzed. Results The response rate of ocular VEMPs was significantly lower in patients with severe OSAS (85.5%) than in controls (96.4%). The mean n1 latency of patients with severe OSAS (10.6 ± 1.0 months) was significantly longer than that of controls (10.2 ± 1.1 months). With regard to cervical VEMP, p1-n1 amplitudes were significantly different between the groups. Other VEMP parameters were not significantly different between the groups. Conclusions VEMPs can potentially be used to evaluate vestibular system lesions at the early stage of OSAS, including not only the vestibular nerve, but also the otolith organs involved.

BACKGROUND:The insect predator Coccinella septempunctata can effectively control many types of pests, such as aphids, whiteflies, and small lepidopteran larvae. We previously found that C. septempunctata fed an artificial diet showed diminished biological properties(e.g. fecundity, egg hatching rate, survival rate, etc.) compared with those fed natural prey (Aphis craccivora), likely due to different nutritional characteristics of the diet. In this study, we used transcriptome sequencing analysis to identify nutrition- and metabolism-related genes of C. septempunctata that were differentially expressed depending on diet. METHODOLOGY/PRINCIPAL FINDINGS:The Illumina HiSeq2000 was used to sequence 691,942,058 total clean reads from artificial diet-fed and A. craccivora-fed C. septempunctata libraries, and the clean reads were assembled using Trinity de novo software (Tabel 2). Comparison of transcriptome sequences revealed that expression of 38,315 genes was affected by the artificial diet, and 1,182 of these genes showed a significant change in expression levels (FDR ≤ 0.05,|log2FC|≥1, "FC" stands for "fold change"). These differentially expressed genes (DEGs) were likely associated with the decreased egg laying capacity, hatching rate, longevity, and increased sex ratio (♀:♂) of adult C. septempunctata observed in the group fed the artificial diet. Furthermore, in the most DEGs metabolic pathways for C. septempunctata feeding on the artificial diet accumulated amino acid metabolic pathways, lipid metabolic pathways, and starch and glucose metabolism were down-regulated. CONCLUSIONS/SIGNIFICANCE:We found some differentially expressed genes and metabolic pathways are related to nutrition, from which a more informative feedback for diet formulation was obtained and the artificial diet could be more efficiently optimized.

Summary: Mitochondrial dysfunctions play major roles in many diseases. However, how mitochondrial stresses are relayed to downstream responses remains unclear. Here we show that the RNA component of mammalian telomerase TERC is imported into mitochondria, processed to a shorter form TERC-53, and then exported back to the cytosol. We found that the import is regulated by PNPASE, and the processing is controlled by mitochondrion-localized RNASET2. Cytosolic TERC-53 levels respond to changes in mitochondrial functions but have no direct effect on these functions. These findings uncover a mitochondrial RNA trafficking pathway and provide a potential mechanism for mitochondria to relay their functional states to other cellular compartments. : The functions of most mitochondrial RNAs imported from the cytosol are poorly understood. Cheng et al. provide evidence that the RNA component of mammalian telomerase TERC is imported into mitochondria, processed to a shorter form TERC-53, and then exported back to the cytosol. The cytosolic TERC-53 level serves as a potential indicator of mitochondrial functions. Keywords: mitochondria, RNA, import, export, processing, mitochondrial dysfunction, retrograde signaling, TERC, telomerase, RNASET2

In the Chinese electric vehicle industrial innovation, the focal firms, which are the key technological, manufacturing and business wise key players, are increasingly involved in the cross-industrial interactions. However, no studies have analysed how they interact across industrial boundaries as well as their consequences. The aim of this article is to explore the focal firms’ cross industrial interactions in the Chinese EV industrial innovation. Relying on the concept of gatekeeping and using the firms’ public information during 2009 and 2014, this study identified that the focal firms’ interaction activities include information-gatekeeping, platform-providing, and benefit-gatekeeping. A framework of ‘industrial gatekeeping’ was developed. It highlights that the focal firms’ gatekeeping in the Chinese EV industry settings are transforming: they do not only concern technological information but also firms’ benefits. Furthermore, the framework extends the scope of gatekeeping to the cross-industrial settings. Practical recommendations for industrial players and insights for policy-makers are provided.

Tumor heterogeneity is one of the characteristics of malignant tumors, which can cause differences in tumor growth rate, invasion, migration, drug sensitivity and prognosis. Discoveries and development upon on tumor-driver genes and targeted therapy paved the way on dealing with cancer diagnosis and treatment. However, the existence of tumor heterogeneity makes malignant tumor more hardly to overcome. It is generally present and far more complicated during the process of cancer recurrence, development and evolution. Thus, it has becoming key areas in precision medicine regarding to designing optimal therapeutic approaches targeting the mechanisms and phenotypes of tumor heterogeneity, based on novel detecting techniques and new concepts and theory. This review summarized the current references on tumor heterogeneity, in order to better understand the function and mechanisms, and eventually manage tumor heterogeneity through various methods.

Vestibular-evoked myogenic potentials (VEMPs) are important methods for evaluating vestibular otolith conduction pathway. Air-conducted sound (ACS) cervical/ocular vestibular-evoked myogenic potentials (cVEMPs/oVEMPs) have been widely used in clinic, bone-conduction vibration stimulation (BCV)- cVEMPs/oVEMPs also began to be used in clinic, but galvanic vestibular stimulation (GVS)-cVEMPs/oVEMPs have not been reported in China. This article reviews the detection and clinical application of GVS-VEMPs.