Publications by authors named "Ge Qin"

46 Publications

Pharmacokinetic and pharmacodynamic evaluation of the new prolonged-release leuprorelin acetate microspheres for injection compared with Enantone® in healthy Chinese male volunteers.

Expert Opin Drug Metab Toxicol 2021 Sep 10;17(9):1149-1156. Epub 2021 Aug 10.

First-in-Human Clinical Trial Wards in the National Institute of Clinical Drug Trials, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, China.

Purpose: To compare the pharmacokinetics, pharmacodynamics and safety of the new prolonged-release leuprorelin acetate microspheres for injection (3.75 mg) with the reference product Enantone® (3.75 mg).

Method: 48 healthy male volunteers were enrolled and randomly received a single 3.75 mg dose of the test drug or Enantone®.

Results: There were no significant differences in C, AUC and AUC between the test group and reference group (P > 0.05). The 90% confidence intervals of the two groups were 87.49%~112.74%, 97.15%~154.25%, and 80.85%~109.01%, respectively. Twenty-eight days after administration, both groups reached 100.0% castration level; there was no difference in the time from administration to reaching castration level between the two groups (P > 0.05); However, the difference between the two groups in the duration of castration level was statistically significant (P < 0.05). There were no major or serious adverse events, and the severity was mild to moderate.

Conclusion: The pharmacokinetic characteristics of leuprorelin in two groups were consistent. The two groups exhibited similar inhibitory effects on testosterone and more subjects in the test group maintained a longer castration time than those in the reference group.
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http://dx.doi.org/10.1080/17425255.2021.1948534DOI Listing
September 2021

CPSF4 promotes triple negative breast cancer metastasis by upregulating MDM4.

Signal Transduct Target Ther 2021 05 19;6(1):184. Epub 2021 May 19.

Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.

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http://dx.doi.org/10.1038/s41392-021-00565-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131696PMC
May 2021

Antifibrotic Effect of a Novel Selective 11β-HSD2 Inhibitor (WZ51) in a rat Model of Myocardial Fibrosis.

Front Pharmacol 2021 22;12:629818. Epub 2021 Mar 22.

Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.

Myocardial fibrosis (MF) is one of the leading causes of end-stage heart disease. Many studies have confirmed that inflammation caused by aldosterone may play an important role in the process of MF. A selective 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) enzyme inhibitor can reduce the inactivation of cortisol, allowing cortisol to compete for mineralocorticoid receptors. This study investigated the protective effect of a novel selective 11βHSD2 inhibitor (WZ51) on MF and described its underlying mechanism. The administration of WZ51 in rats with MF significantly alleviated myocardial injury, accompanied by a decrease in lactate dehydrogenase and the creatine kinase myocardial band. Furthermore, WZ51 significantly inhibited the development of MF and increased the protein level of 11β-HSD2. The results of this study demonstrate that 11β-HSD2 plays an important pathological role in MF. Thus, WZ51 may be a potential therapeutic agent for the treatment of this condition.
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http://dx.doi.org/10.3389/fphar.2021.629818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8022133PMC
March 2021

Identification and characterization of critical genes associated with tamoxifen resistance in breast cancer.

PeerJ 2020 4;8:e10468. Epub 2020 Dec 4.

Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.

Background: Tamoxifen resistance in breast cancer is an unsolved problem in clinical practice. The aim of this study was to determine the potential mechanisms of tamoxifen resistance through bioinformatics analysis.

Methods: Gene expression profiles of tamoxifen-resistant MCF-7/TR and MCF-7 cells were acquired from the Gene Expression Omnibus dataset GSE26459, and differentially expressed genes (DEGs) were detected with R software. We conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses using Database for Annotation, Visualization and Integrated Discovery. A protein-protein interaction (PPI) network was generated, and we analyzed hub genes in the network with the Search Tool for the Retrieval of Interacting Genes database. Finally, we used siRNAs to silence the target genes and conducted the MTS assay.

Results: We identified 865 DEGs, 399 of which were upregulated. GO analysis indicated that most genes are related to telomere organization, extracellular exosomes, and binding-related items for protein heterodimerization. PPI network construction revealed that the top 10 hub genes-, and -might be associated with tamoxifen resistance. Consistently, RT-qPCR analysis indicated that the expression of these 10 genes was increased in MCF-7/TR cells comparing with MCF-7 cells. Four hub genes ( and ) were related to overall survival in patients who accepted tamoxifen. In addition, knockdown of HSPH1 by siRNA may lead to reduced growth of MCF-7/TR cell with a trend close to significance ( = 0.07), indicating that upregulation of HSPH1 may play a role in tamoxifen resistance.

Conclusion: This study revealed a number of critical hub genes that might serve as therapeutic targets in breast cancer resistant to tamoxifen and provided potential directions for uncovering the mechanisms of tamoxifen resistance.
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http://dx.doi.org/10.7717/peerj.10468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720728PMC
December 2020

A randomized Phase I pharmacokinetic trial comparing the potential biosimilar trastuzumab (SIBP-01) with the reference product (Herceptin®) in healthy Chinese male volunteers.

Expert Opin Drug Metab Toxicol 2020 Oct 26;16(10):997-1003. Epub 2020 Aug 26.

Department of Pharmaceutical Analysis, School of Pharmacy, China Pharmaceutical University , Nanjing, Jiangsu, China.

Objectives: This study aimed to evaluate the bioequivalence, safety, tolerability and immunogenicity of the biosimilar trastuzumab (SIBP-01) compared to Herceptin®.

Methods: In this Phase I randomized double-blind parallel-group trial, 100 healthy male volunteers were randomized in a1:1 ratio to receive a single 6 mg•kg-1 intravenous dose of SIBP-01 or Herceptin®. Serum concentrationswere analyzed using a validated ELISA.

Results: The two groups had similar baseline characteristics. The geometric mean ratios (90% CI) of C, AUC and AUC between the trial group and the reference group were 93.55%-104.27%, 91.98%-102.35% and 91.88%-102.34%, respectively; the geometric mean ratios (90% CI) of AUC and AUC in the sensitivity analysis were 92.29%-102.63% and 91.81%-102.16%, respectively. These values were within the prespecified equivalence margins, establishing the bioequivalence of SIBP-1 and Herceptin®. AEs were similar across all subjects in the SIBP-01 and Herceptin® arms, with treatment-related AEs reported by 72.00% and 80.00%, respectively. In each group, there was one AE that caused a subject to discontinue the study.

Expert Opinion: Trastuzumab (Herceptin®) is significantly more effective than chemotherapy in reducing exacerbations and tumor cell growth, and its adverse events are far lower than chemotherapy. Herceptin®is very expensive for most patients in China. The protein molecular primary structure of the biosimilar trastuzumab (SIBP-01) is consistent with Herceptin®, with highly similar high level structure, biologocal activity and purity.But there are few studies comparing the bioequivalence of SIBP-01 and Herceptin® in healthy subjects and cancer patients 2.

Conclusions: This study showed the PK similarity of SIBP-01 to Herceptin®. SIBP-01 was safe and well tolerated in healthy male volunteers, with no significant differences from the reference drug in safety or immunogenicity 4.
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http://dx.doi.org/10.1080/17425255.2020.1807935DOI Listing
October 2020

[Changes of nasal nitric oxide in the treatment of allergic rhinitis with hydrogen-rich saline lavage of nasal cavity].

Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi 2020 Mar;34(3):244-247

Department of Otorhinolaryngology Head and Neck Surgery,Tongji Hospital,Tongji Medical University(Shanghai Tongji Hospital),Shanghai,200065,China.

To observe the effect of hydrogen-rich saline on the concentration of nitric oxide in the nose, and to explore the mechanism of its treatment of allergic rhinitis. Twenty patients with moderate to severe persistent allergic rhinitis were enrolled in a randomized, double-blind, self-controlled study. The nasal cavity was lavaged with hydrogen-rich normal saline and normal saline, and the nasal nitric oxide(nNO) value was tested weekly. The test value of nNO was correlated with the diagnosis and curative effect of allergic rhinitis. The difference of nNO test values before and after treatment of the two lavage fluids was statistically significant(<0.01). Hydrogen-rich saline lavage can cause nNO change in nasal cavity which may be used in the treatment of allergic rhinitis.
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http://dx.doi.org/10.13201/j.issn.2096-7993.2020.03.014DOI Listing
March 2020

Enhanced anti-tumor efficacy of 5-aminolevulinic acid-gold nanoparticles-mediated photodynamic therapy in cutaneous squamous cell carcinoma cells.

Braz J Med Biol Res 2020 27;53(5):e8457. Epub 2020 Apr 27.

Department of Dermatology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.

The objective of this study was to investigate whether the conjugation of gold nanoparticles (GNPs) to 5-aminolevulinic acid (5-ALA) could enhance the anti-tumor efficiency of photodynamic therapy (PDT) in epidermoid carcinoma cells. The mRNA and protein expression levels were determined by quantitative real-time PCR and western blot, respectively. Cell viability, apoptosis, invasion, and migration were determined by MTT assay, flow cytometry, transwell invasion assay, and migration assay, respectively. Singlet oxygen generation was detected by the singlet oxygen sensor green reagent assay. Our results showed that PDT with 5-ALA and GNPs-conjugated 5-ALA (5-ALA-GNPs) significantly suppressed cell viability, increased cell apoptosis and singlet oxygen generation in both HaCat and A431 cells, and PDT with 5-ALA and 5-ALA-GNPs had more profound effects in A431 cells than that in HaCat cells. More importantly, 5-ALA-GNPs treatment potentiated the effects of PDT on cell viability, cell apoptosis, and singlet oxygen generation in A431 cells compared to 5-ALA treatment. Further in vitro assays showed that PDT with 5-ALA-GNPs significantly decreased expression of STAT3 and Bcl-2 and increased expression of Bax in A431 cells compared with PDT with 5-ALA. In addition, 5-ALA-GNPs treatment enhanced the inhibitory effects of PDT on cell invasion and migration and Wnt/β-catenin signaling activities in A431 cells compared to 5-ALA treatment. In conclusion, our results suggested that GNPs conjugated to 5-ALA significantly enhanced the anti-tumor efficacy of PDT in A431 cells, which may represent a better strategy to improve the outcomes of patients with cutaneous squamous cell carcinoma.
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http://dx.doi.org/10.1590/1414-431x20208457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205413PMC
June 2020

NPM1 upregulates the transcription of PD-L1 and suppresses T cell activity in triple-negative breast cancer.

Nat Commun 2020 04 3;11(1):1669. Epub 2020 Apr 3.

Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.

Programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) interaction plays a crucial role in tumor-associated immune escape. Here, we verify that triple-negative breast cancer (TNBC) has higher PD-L1 expression than other subtypes. We then discover that nucleophosmin (NPM1) binds to PD-L1 promoter specifically in TNBC cells and activates PD-L1 transcription, thus inhibiting T cell activity in vitro and in vivo. Furthermore, we demonstrate that PARP1 suppresses PD-L1 transcription through its interaction with the nucleic acid binding domain of NPM1, which is required for the binding of NPM1 at PD-L1 promoter. Consistently, the PARP1 inhibitor olaparib elevates PD-L1 expression in TNBC and exerts a better effect with anti-PD-L1 therapy. Together, our research has revealed NPM1 as a transcription regulator of PD-L1 in TNBC, which could lead to potential therapeutic strategies to enhance the efficacy of cancer immunotherapy.
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http://dx.doi.org/10.1038/s41467-020-15364-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125142PMC
April 2020

A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19.

N Engl J Med 2020 05 18;382(19):1787-1799. Epub 2020 Mar 18.

From the Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, National Clinical Research Center for Respiratory Diseases (B.C., Yeming Wang, G.F., F.Z., X.G., Z.L., Y.Z., Hui Li, L.S., C.W.), and the Institute of Clinical Medical Sciences (G.F., X.G.), China-Japan Friendship Hospital, the Institute of Respiratory Medicine, Chinese Academy of Medical Sciences (B.C., Yeming Wang, F.Z., Z.L., Y.Z., Hui Li, C.W.), the Clinical and Research Center of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University (Xingwang Li), Peking University Clinical Research Institute, Peking University First Hospital (C.D.), Tsinghua University School of Medicine (Jiuyang Xu), Beijing University of Chinese Medicine (L.S.), NHC Key Laboratory of Systems Biology of Pathogens and Christophe Merieux Laboratory, Institute of Pathogen Biology, Chinese Academy of Medical Sciences (L.G.), and Peking Union Medical College (L.G., C.W.), Beijing, and Jin Yin-tan Hospital, Wuhan (D.W., W.L., Jingli Wang, L.R., B.S., Y.C., M.W., Jiaan Xia, N.C., Jie Xiang, T.Y., T.B., X.X., L.Z., C.L., Y.Y., H.C., Huadong Li, H.H., S.T., F.G., Y.L., Yuan Wei, K.W., K.L., X.Z., X.D., Z.Q., Sixia Lu, X.H., S.R., Shanshan Luo, Jing Wu, Lu Peng, F.C., Lihong Pan, J.Z., C.J., Juan Wang, Xia Liu, S.W., X.W., Q.G., J.H., H.Z., F.Q., C.H., D.Z.) - all in China; Lancaster University, Lancaster (T.J.), and the University of Oxford, Oxford (P.W.H.) - both in the United Kingdom; and the University of Virginia School of Medicine, Charlottesville (F.G.H.).

Background: No therapeutics have yet been proven effective for the treatment of severe illness caused by SARS-CoV-2.

Methods: We conducted a randomized, controlled, open-label trial involving hospitalized adult patients with confirmed SARS-CoV-2 infection, which causes the respiratory illness Covid-19, and an oxygen saturation (Sao) of 94% or less while they were breathing ambient air or a ratio of the partial pressure of oxygen (Pao) to the fraction of inspired oxygen (Fio) of less than 300 mm Hg. Patients were randomly assigned in a 1:1 ratio to receive either lopinavir-ritonavir (400 mg and 100 mg, respectively) twice a day for 14 days, in addition to standard care, or standard care alone. The primary end point was the time to clinical improvement, defined as the time from randomization to either an improvement of two points on a seven-category ordinal scale or discharge from the hospital, whichever came first.

Results: A total of 199 patients with laboratory-confirmed SARS-CoV-2 infection underwent randomization; 99 were assigned to the lopinavir-ritonavir group, and 100 to the standard-care group. Treatment with lopinavir-ritonavir was not associated with a difference from standard care in the time to clinical improvement (hazard ratio for clinical improvement, 1.31; 95% confidence interval [CI], 0.95 to 1.80). Mortality at 28 days was similar in the lopinavir-ritonavir group and the standard-care group (19.2% vs. 25.0%; difference, -5.8 percentage points; 95% CI, -17.3 to 5.7). The percentages of patients with detectable viral RNA at various time points were similar. In a modified intention-to-treat analysis, lopinavir-ritonavir led to a median time to clinical improvement that was shorter by 1 day than that observed with standard care (hazard ratio, 1.39; 95% CI, 1.00 to 1.91). Gastrointestinal adverse events were more common in the lopinavir-ritonavir group, but serious adverse events were more common in the standard-care group. Lopinavir-ritonavir treatment was stopped early in 13 patients (13.8%) because of adverse events.

Conclusions: In hospitalized adult patients with severe Covid-19, no benefit was observed with lopinavir-ritonavir treatment beyond standard care. Future trials in patients with severe illness may help to confirm or exclude the possibility of a treatment benefit. (Funded by Major Projects of National Science and Technology on New Drug Creation and Development and others; Chinese Clinical Trial Register number, ChiCTR2000029308.).
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http://dx.doi.org/10.1056/NEJMoa2001282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7121492PMC
May 2020

Targeting the CK1α/CBX4 axis for metastasis in osteosarcoma.

Nat Commun 2020 02 28;11(1):1141. Epub 2020 Feb 28.

State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.

Osteosarcoma, an aggressive malignant cancer, has a high lung metastasis rate and lacks therapeutic target. Here, we reported that chromobox homolog 4 (CBX4) was overexpressed in osteosarcoma cell lines and tissues. CBX4 promoted metastasis by transcriptionally up-regulating Runx2 via the recruitment of GCN5 to the Runx2 promoter. The phosphorylation of CBX4 at T437 by casein kinase 1α (CK1α) facilitated its ubiquitination at both K178 and K280 and subsequent degradation by CHIP, and this phosphorylation of CBX4 could be reduced by TNFα. Consistently, CK1α suppressed cell migration and invasion through inhibition of CBX4. There was a reverse correlation between CK1α and CBX4 in osteosarcoma tissues, and CK1α was a valuable marker to predict clinical outcomes in osteosarcoma patients with metastasis. Pyrvinium pamoate (PP) as a selective activator of CK1α could inhibit osteosarcoma metastasis via the CK1α/CBX4 axis. Our findings indicate that targeting the CK1α/CBX4 axis may benefit osteosarcoma patients with metastasis.
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http://dx.doi.org/10.1038/s41467-020-14870-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048933PMC
February 2020

Administration of Lapatinib with Food Increases Its Plasma Concentration in Chinese Patients with Metastatic Breast Cancer: A Prospective Phase II Study.

Oncologist 2020 09 14;25(9):e1286-e1291. Epub 2020 Feb 14.

Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China.

Lessons Learned: Administration of lapatinib with food significantly increased its plasma concentration in Chinese patients with metastatic breast cancer. There were no serious adverse events during the study and no significant differences in lapatinib-related adverse events between the fasted and fed states.

Background: Lapatinib, a small molecular reversible dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth receptor 2 (HER2), was approved for use in combination with capecitabine to treat metastatic HER2-positive breast cancer. Administration of lapatinib in the fasted state was recommended; however, our preliminary phase II trial data showed that administration of lapatinib with food increased its concentration.

Methods: This study was a single-center, open-label, and prospective self-controlled clinical study. Ten Chinese patients with metastatic breast cancer were enrolled from June 2017 to April 2018. They were required to receive lapatinib plus physician's choice of chemotherapy. Patients were required to take lapatinib orally on an empty stomach continually for 10 days, and then take lapatinib with food continually for the next 10 days. Plasma concentration was measured by liquid chromatography on the 9th and 10th day of each state.

Results: Area under the concentration-time curve (AUC) of the fasted state and the fed state was 21.23 ± 8.91 mg*h/L (coefficient of variation (CV)% 42%) and 60.60 ± 16.64 mg*h/L (CV% 27%), respectively. The mean plasma concentration in the fasted state was 0.88 ± 0.39 mg/L (CV% 45%), and that in the fed state was 2.53 ± 0.77 mg/L (CV% 30%). Compared with taking lapatinib on an empty stomach, receiving lapatinib with food significantly increased the plasma concentration of lapatinib (Wilcoxon match-paired test, p = .005). In addition, there were no serious adverse events during the study or significant difference in lapatinib-related adverse events between the two states.

Conclusion: Our study shows that receiving lapatinib with food can increase its plasma concentration with no significantly increased drug-related toxicity. We suggest that a larger-sample-size clinical trial is needed to fully understand the effect of administration of lapatinib with food.
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http://dx.doi.org/10.1634/theoncologist.2020-0044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485350PMC
September 2020

Through-Mask Electrochemical Micromachining with Reciprocating Foamed Cathode.

Micromachines (Basel) 2020 Feb 11;11(2). Epub 2020 Feb 11.

Institute of Non-traditional Machining & Equipment, Henan Polytechnic University, Jiaozuo 454000, China.

A through-mask electrochemical micromachining process with a foamed cathode (foamed-cathode through-mask electrochemical micromachining (TMEMM)) has recently been proposed involving micro-scale surface microstructures with a high geometric consistency that are fabricated on the curved-surface workpiece. In this paper, to make the foamed-cathode TMEMM process more cost-efficient in the applications, significant modifications are made to this process and an upgraded version of the foamed-cathode TMEMM process is developed. In this modified process, the sandwich-like unit (including the foamed cathode, mask, and workpiece) is closely assembled by the magnetic field force instead of the conventionally-used mechanical force and is kept moving up-and-down inside the electrolyte, avoiding the use of the traditional pump-driven circulation for the electrode process. Experiments are carried out to evaluate the machining effect of this modified TMEMM for fabricating micro-dimples. The research results verify that this modified TMEMM process can produce highly uniform micro-dimples whose minimum CV (coefficient of variation) values in depth and in diameter are 5.4% and 1.9%, respectively, with smooth surfaces of the minimum Ra being 0.21-0.35 µm. These values are smaller than those previously reported. This results in the positive effects on the mass transfer driven by magnetohydrodynamic convection induced by the magnetic field within the interelectrode and the foamed electrode.
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http://dx.doi.org/10.3390/mi11020188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7074634PMC
February 2020

Facile Fabrication of Highly Perforated Hollow Metallic Cylinder with Changeable Micro-Orifices by Electroforming-Extrusion Molding Hybrid Process.

Micromachines (Basel) 2020 Jan 9;11(1). Epub 2020 Jan 9.

Institute of Non-traditional Machining & Equipment, Henan Polytechnic University, Jiaozuo 454000, China.

A seamless thin-walled hollow metallic cylinder with array of micro-perforations is one of the key components for some products. Normally, these micro-perforations are formed by removing material from the given metallic hollow cylinder (pipe or tube) one by one or row by row. To efficiently and flexibly manufacture such a highly perforated hollow cylinder, this paper proposed a hybrid technique combining extrusion moulding process and electroforming process. In the hybrid technique, the extrusion moulding process was used to create polymer extrusion patterns on the outside surface of the given stainless steel (SS) pipe, and then the electroforming process was carried out using the SS pipe as the mandrel. The formation of the polymer extrusion patterns was simulated and extruding molding experiments were carried out to examine the feasibility of the various mandrels. Electroforming experiments were implemented to verify the achievement of the seamless perforated thin-walled hollow cylinder. It was found that five different types of polymer extrusion pattern were able to be obtained on the same extruding pipe just by adjusting some extruding conditions and parameters, and correspondingly four types of perforated hollow cylinder with different tapered orifices are produced after the electroforming process. The obtainable perforations are: perforation with double conic-orifices, perforation with hemispheric orifice and conic orifice, unidirectionally tapered perforation, and straight-walled perforation. The geometric profile of the extrusion patterns is highly dependent on the processing conditions and parameters. The proposed hybrid process represents a promising alternative process to fabricate seamless thin-walled perforated hollow metallic cylinder efficiently, flexibly, and with low cost.
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http://dx.doi.org/10.3390/mi11010070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019942PMC
January 2020

Numerical Analysis and Experimental Study on Fabrication of High Aspect Ratio Tapered Ultrafine Holes by Over-Growth Electroforming Process.

Micromachines (Basel) 2019 Nov 27;10(12). Epub 2019 Nov 27.

Institute of Non-traditional Machining & Equipment, Henan Polytechnic University, Jiaozuo 454000, China.

High aspect ratio (HAR) ultrafine tapered holes (diameter ≤5 μm; AR ≥5) are the most important elements for some high-tech perforated metallic products, but they are very difficult to manufacture. Therefore, this paper proposes a nontraditional over-growth electroforming process. The formation mechanism of the HAR ultrafine tapered holes is investigated, and the factors controlling the geometric shape evolution are analyzed numerically. It was found that the geometric shape and dimensions of the holes are highly dependent on the diameter and thickness of the photoresist film patterns, but are hardly affected by the spacing between two neighboring patterns; the achievable diameter for a given hole depth becomes small with the increasing pattern diameter, but it becomes big with the increasing pattern thickness. These correlations can be well interpreted by the established two empirical equations that characterize the relationship between the minimum orifice of the tapered hole and the structural parameters of the photoresist film patterns previously formed on the substrate. Application of the fabricated 1500 tapered holes with 3-μm diameter and 17-AR as the nozzles of the medical precision nebulizer is also examined. The studies show that the over-growth electroforming process is highly applicable in fabricating the perforated metallic plate with HAR ultrafine tapered holes.
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http://dx.doi.org/10.3390/mi10120824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953087PMC
November 2019

Synergistically Enhanced Inhibitory Effects of Pullulan Nanoparticle-Mediated Co-Delivery of Lovastatin and Doxorubicin to Triple-Negative Breast Cancer Cells.

Nanoscale Res Lett 2019 Sep 13;14(1):314. Epub 2019 Sep 13.

Key Laboratory of Translational Cancer Stem Cell Research, Department of Basic Medical Sciences, Hunan Normal University School of Medicine, Changsha, 410013, Hunan, China.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that is prone to drug resistance and difficult to treat. In this study, we grafted water-soluble pullulan with lovastatin (LV) to develop a novel amphiphilic conjugate, pullulan-encapsulated LV (PLV). The PLV conjugate was synthesized with three different ratios of pullulan to LV and characterized by Fourier transform infrared (FTIR). The degree of substitution (DS) of LV in terms of molar ratio was 7.87%, 3.58%, and 3.06% for PLV (1/2), PLV (1/3), and PLV (1/4), respectively, by proton NMR analysis. We selected the PLV (1/2) conjugate to prepare doxorubicin (DXR)-loaded PLV nanoparticles (PLV/DXR NPs) because of its superior properties. The average size and zeta potential for PLV (1/2) NPs were 177.6 nm and - 11.66 mV, respectively, determined by dynamic light scattering, and those for PLV/DXR NPs were 225.6 nm and - 10.51 mV, respectively. In vitro drug release profiling showed that PLV/DXR NPs sustainably released DXR within 72 h, which was more robust at pH 5.4 (97.90%) than pH 7.4 (76.15%). In the cytotoxicity study, PLV/DXR NPs showed greater inhibition of proliferation of TNBC MDA-MB-231 than non-TNBC MDA-MB-453 cells (IC 0.60 vs 11.05 μM). FITC-loaded PLV/DXR NPs were prepared to investigate cellular uptake: both cell lines showed a time-dependent uptake of NPs, but the number of NPs entering MDA-MB-231 cells was greater than that entering the MDA-MB-453 cells. Pullulan-based NP co-delivery of LV and DXR could efficiently inhibit TNBC cells, which may help in designing a powerful drug delivery system for treating TNBC.
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http://dx.doi.org/10.1186/s11671-019-3146-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6744545PMC
September 2019

Green Ferrate(VI) for Multiple Treatments of Fracturing Wastewater: Demulsification, Visbreaking, and Chemical Oxygen Demand Removal.

Int J Mol Sci 2019 Apr 15;20(8). Epub 2019 Apr 15.

Institute of New Energy Chemistry and Environmental Science, College of Chemistry & Chemical Engineering, Northeast Petroleum University, Daqing 163318, China.

Fracturing wastewater is often highly emulsified, viscous, and has a high chemical oxygen demand (COD), which makes it difficult to treat and recycle. Ferrate(VI) is a green oxidant that has a high redox potential and has been adopted for the efficient oxidation of fracturing wastewater to achieve triple effects: demulsification, visbreaking, and COD removal. Firstly, optimal conditions were identified to build a model for fast and efficient treatment. Secondly, wastewater treatment using ferrate oxidation was investigated via demulsification, visbreaking, and COD removal. Finally, a mechanism for ferrate oxidation was proposed for the three effects using Fourier-transform infrared (FT-IR) spectroscopy and scanning electron microscopy (SEM). The theoretical and experimental data demonstrated that the ferrate oxidation achieved the three desired effects. When ferrate was added, the demulsification efficiency increased from 56.2% to 91.8%, the total viscosity dropped from 1.45 cp to 1.10 cp, and the total removal rate of COD significantly increased to 74.2%. A mechanistic analysis showed that the strongly-oxidizing ferrate easily and efficiently oxidized the O/W interfacial film materials, viscous polymers, and compounds responsible for the COD, which was a promising result for the triple effects.
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http://dx.doi.org/10.3390/ijms20081857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6515217PMC
April 2019

Panobinostat (LBH589) inhibits Wnt/β-catenin signaling pathway via upregulating APCL expression in breast cancer.

Cell Signal 2019 07 14;59:62-75. Epub 2019 Mar 14.

State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China. Electronic address:

Breast cancer is the most common malignant disease among women worldwide and the novel therapeutic agents are urgently needed. Panobinostat (LBH589), a pan-HDACs inhibitor, has shown promising anti-tumor effect in recent years. However, the targets of this compound are largely unclear because of its low selectivity. In consideration of the transcription promoting activity of panobinostat, we speculated that specific tumor suppressor genes might be upregulated after panobinostat treatment. In this study, we verified the inhibition effect of panobinostat in different subtypes of breast cancer cells in vivo and in vitro. We found that panobinostat suppressed proliferation, migration as well as invasion, and induced apoptosis in both TNBC and non-TNBC cells. Consistently, panobinostat inhibited breast cancer growth and metastasis in mouse models. Mechanistically, we found APCL transcription and expression was significantly upregulated in panobinostat treated cells by RNA microarray analysis, while knockdown of APCL resulted in reduced sensitivity to panobinostat in breast cancer cells. APCL is a wnt/β-catenin pathway regulator that promotes β-catenin ubiquitylation and degradation. We found that panobinostat inhibited β-catenin expression by increasing its ubiquitylation and thus reducing its half-life. In addition, the expression of β-catenin activated targets including c-Jun, c-Myc, Cyclin D1 and CD44 were also decreased by panobinostat treatment in breast cancer cells. These results suggested that panobinostat inhibited tumor growth and metastasis via upregulating APCL expression in breast cancer cells, which was a novel and crucial mechanism of panobinostat.
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http://dx.doi.org/10.1016/j.cellsig.2019.03.014DOI Listing
July 2019

Melatonin synergizes BRAF-targeting agent vemurafenib in melanoma treatment by inhibiting iNOS/hTERT signaling and cancer-stem cell traits.

J Exp Clin Cancer Res 2019 Feb 4;38(1):48. Epub 2019 Feb 4.

State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Centre, Guangzhou, China.

Background: As the selective inhibitor of BRAF kinase, vemurafenib exhibits effective antitumor activities in patients with V600 BRAF mutant melanomas. However, acquired drug resistance invariably develops after its initial treatment.

Methods: Immunohistochemical staining was performed to detect the expression of iNOS and hTERT, p-p65, Epcam, CD44, PCNA in mice with melanoma xenografts. The proliferation and migration of melanoma cells were detected by MTT, tumorsphere culture, cell cycle, cell apoptosis, AO/EB assay and colony formation, transwell assay and scratch assay in vitro, and tumor growth differences were observed in xenograft nude mice. Changes in the expression of key molecules in the iNOS/hTERT signaling pathways were detected by western blot. Nucleus-cytoplasm separation, and immunofluorescence analyses were conducted to explore the location of p50/p65 in melanoma cell lines. Flow cytometry assay were performed to determine the expression of CD44. Pull down assay and ChIP assay were performed to detect the binding ability of p65 at iNOS and hTERT promoters. Additionally, hTERT promoter-driven luciferase plasmids were transfected in to melanoma cells with indicated treatment to determine luciferase activity of hTERT.

Results: Melatonin significantly and synergistically enhanced vemurafenib-mediated inhibitions of proliferation, colony formation, migration and invasion and promoted vemurafenib-induced apoptosis, cell cycle arresting and stemness weakening in melanoma cells. Further mechanism study revealed that melatonin enhanced the antitumor effect of vemurafenib by abrogating nucleus translocation of NF-κB p50/p65 and their binding at iNOS and hTERT promoters, thereby suppressing the expression of iNOS and hTERT. The elevated anti-tumor capacity of vemurafenib upon co-treatment with melatonin was also evaluated and confirmed in mice with melanoma xenografts.

Conclusions: Collectively, our results demonstrate melatonin synergizes the antitumor effect of vemurafenib in human melanoma by inhibiting cell proliferation and cancer-stem cell traits via targeting NF-κB/iNOS/hTERT signaling pathway, and suggest the potential of melatonin in antagonizing the toxicity of vemurafenib and augmenting its sensitivities in melanoma treatment.
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http://dx.doi.org/10.1186/s13046-019-1036-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6360719PMC
February 2019

CDK4/6 inhibitor palbociclib enhances the effect of pyrotinib in HER2-positive breast cancer.

Cancer Lett 2019 04 21;447:130-140. Epub 2019 Jan 21.

Sun Yat-Sen University Cancer Center, The State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, PR China. Electronic address:

Human epidermal growth factor receptor 2 (HER2) is amplified in about 20% breast cancers. Treat of HER2 positive breast cancers has been greatly promoted in last few years, but the accompany HER2 blockade has hindered the therapeutic effect. Pyrotinib is a pan-HER kinase inhibitor that suppresses signaling through the RAS/RAF/MEK/MAPK and PI3K/AKT pathways. Palbociclib is a CDK4/6 inhibitor that inhibits cell cycle progression and cancer cell proliferation in ER+ breast cancers. We hypothesized that the combination of pan-HER kinase inhibitors and CDK4/6 inhibitors would show synergistic antitumor activity in vivo in vitro. Our data show that a combination of palbociclib and pyrotinib was highly synergistic in inhibiting cancer proliferation and colony formation. The combined treatment also induced significant decreases in pAKT and pHER3 activation, induced G0-G1 cell cycle arrest, and increased rates of apoptosis. In the xenograft model, the combination treatment demonstrated greater antitumor activity than either agent alone, with no apparent increase in toxicity. Our results offer a preclinical rationale clinical investigation of the effectiveness of a combination treatment of palbociclib with pyrotinib for breast cancer treatment.
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http://dx.doi.org/10.1016/j.canlet.2019.01.005DOI Listing
April 2019

Melatonin inhibits MLL-rearranged leukemia via RBFOX3/hTERT and NF-κB/COX-2 signaling pathways.

Cancer Lett 2019 02 11;443:167-178. Epub 2018 Dec 11.

Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China; State Key Laboratory of Targeted Drug for Tumors of Guangdong Province, Guangzhou Double Bioproduct Inc., Guangzhou, China. Electronic address:

MLL-rearranged leukemia is an aggressive malignancy associated with poor outcome, which is refractory to conventional treatment. Melatonin has been proven to exert anti-tumor activity, but the effect of melatonin on MLL-r leukemia and the underlying mechanism remain poorly understood. In this study, melatonin inhibited cell proliferation and induced apoptosis by activating the caspase-dependent apoptotic pathway in MLL-r leukemia cells. Mechanistic investigations revealed that melatonin suppressed the expression of hTERT by abrogating the binding activity of RBFOX3 to the hTERT promoter. Melatonin also blocked NF-κB nuclear translocation and suppressed NF-κB binding to the COX-2 promoter, thereby suppressing the expression of COX-2. In addition, clinical samples revealed that melatonin exerts anti-leukemic activity in primary MLL-r leukemia blasts ex vivo. In vivo, the mice treated with melatonin experienced a larger reduction in leukemic burden than the control group in a MLL-r leukemia xenograft mouse model. Collectively, these results suggest that melatonin inhibits MLL-rearranged leukemia through suppressing the RBFOX3/hTERT and NF-κB/COX-2 signaling pathways. Our findings provide new insights into the role of melatonin for MLL-r leukemia treatment.
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http://dx.doi.org/10.1016/j.canlet.2018.11.037DOI Listing
February 2019

Pullulan-Based Nanoparticle-HSA Complex Formation and Drug Release Influenced by Surface Charge.

Nanoscale Res Lett 2018 Oct 10;13(1):317. Epub 2018 Oct 10.

Department of Pharmacology, Hubei University of Medicine, Shiyan, 442000, Hubei, China.

The nanomaterial composition of nanoparticles and their protein adsorption in the blood is of great significance in the design of drug-loaded nanoparticles. To explore the interaction between the different surface components of nanoparticles (NPs) and protein, we synthesized three kinds of pullulan NP polymers: cholesteric hydrophobically (CH) modified pullulan (CHP), CH-modified animated pullulan (CHAP), and CH-modified carboxylated pullulan (CHSP). Pullulan NPs were prepared by the dialysis method. Dynamic light scattering was used to determine the charge and size of the three NPs. The size of NPs was altered by the number of charge groups when polymers contain the same degree of cholesterol substitution. The zeta potentials were + 12.9, - 15.4, and - 0.698 mV for CHAP, CHSP, and CHP, respectively, and the dimensions were 116.9, 156.9, and 73.1 nm, respectively. Isothermal titration calorimetry was used to determine the thermodynamic changes of NPs with different surface charge, and the effect of human serum albumin (HSA) on the titration was investigated. The changes of enthalpy and entropy demonstrated an interaction between NPs and HSA; the binding constant (K) for CHSP, CHP, and CHAP was 1.41, 27.7, and 412 × 10 M, respectively, with the positive charge for CHAP-HSA, uncharged for CHP-HSA, and negative charge for CHSP-HSA complex. Fluorescence and circular dichroism spectroscopy were used to determine the protein structure change after the complexation between NPs and HSA. The NP and HSA complexation is a complicated process composed of protein α-helical content reduction and the peptide chain extension; CHP NPs had the largest reduction in HSA α-helical content. The drug release rates of all compounds of NP and HSA were significantly lower than those of free drug and drug-loaded NPs after 48 h. The highest and lowest rates were observed in CHSP-HSA and CHP-HSA, respectively. The drug release was significantly influenced by the adsorption of HSA on NPs, and the size and surface charge of NPs played an important role in this process.
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http://dx.doi.org/10.1186/s11671-018-2729-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6179976PMC
October 2018

Clinical value of circulating mutations for patients with metastatic breast cancer: a meta-analysis.

Cancer Manag Res 2018 14;10:2573-2580. Epub 2018 Aug 14.

Sun Yat-Sen University Cancer Center, The State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, People's Republic of China,

Background: The clinical implication of plasma ESR1 mutations in the estrogen receptor (ER)-positive metastatic breast cancer (MBC) patients who had progressed after prior aromatase inhibitor (AI)-based therapy remains controversial. We conducted the first meta-analysis to investigate the prognostic significance and predictive role of plasma ESR1 mutations in MBC patients with prior exposure to AI therapy.

Materials And Methods: We searched PubMed, Embase, and Cochrane Library databases for eligible studies. Meta-analysis was conducted to calculate combined hazard ratios (HRs) with 95% CIs for progression-free survival (PFS) and overall survival (OS). Subgroup and sensitivity analyses were also performed.

Results: This study enrolled a total of 1,530 patients with ER-positive MBC cases from six articles, including 429 ESR1 mutation carriers (28.04%). Meta-analysis demonstrated that plasma ESR1 mutation carriers had significantly worse PFS (HR: 1.40, 95% CI: 1.17-1.66; <0.0001) and OS (HR: 1.65, 95% CI: 1.36-2.01; <0.0001) compared to wild-type ESR1. Subgroup analysis showed that plasma ESR1 mutations were associated with shorter PFS after AI-based treatment, but were not significantly predictive of outcome on fulvestrant-containing therapy (HR: 1.26, 95% CI: 0.98-1.62; =0.077). As for different ESR1 mutations, D538G mutation implied significantly worse PFS (HR: 1.50, 95% CI: 1.18-1.91; =0.01), while Y537S mutation was not correlated with PFS (HR: 1.65, 95% CI: 0.87-1.73; =0.134).

Conclusion: The meta-analysis indicated that plasma ESR1 mutation assessment may have prognostic significance and clinical value in guiding further endocrine therapy choice in ER+ MBC patients who received prior AI therapy.
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http://dx.doi.org/10.2147/CMAR.S173193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097501PMC
August 2018

Activator Protein-2β Promotes Tumor Growth and Predicts Poor Prognosis in Breast Cancer.

Cell Physiol Biochem 2018 4;47(5):1925-1935. Epub 2018 Jul 4.

Institute of Cancer Stem Cell & The Second Affiliated Hospital, Dalian Medical University, Dalian, China.

Background/aims: Activator protein-2 (AP-2) transcription factors have been proved to be essential in maintaining cellular homeostasis and regulating the transformation from normal growth to neoplasia. However, the role of AP-2β, a key member of AP-2 family, in breast cancer is rarely reported.

Methods: The effect of AP-2 on cell growth, migration and invasion in breast cancer cells were measured by MTT, colony formation, wound-healing and transwell assays, respectively. The expression levels of AP-2β and other specific markers in breast cancer cell lines and tissue microarrays from the patients were detected using RT-PCR, Western blot and immunohistochemical staining. The regulation of AP-2β on tumor growth in vivo was analyzed in a mouse xenograft model.

Results: We demonstrated the tumor-promoting function of AP-2β in breast cancer. AP-2β was found to be highly expressed in breast cancer cell lines and tumor tissues of breast cancer patients. The shRNA-mediated silencing of AP-2β led to the dramatic inhibition of cell proliferation, colony formation ability, migration and invasiveness in breast cancer cells accompanied by the down-regulated expression of some key proteins involved in cancer progression, including p75, MMP-2, MMP-9, C-Jun, p-ERK and STAT3. Overexpression of AP-2β markedly up-regulated the levels of these proteins. Consistent with the in vitro study, the silencing or overexpression of AP-2β blocked or promoted tumor growth in the mice with xenografts of breast cancers. Notably, the high AP-2β expression levels was correlated with poor prognosis and advanced malignancy in patients with breast cancer.

Conclusions: Our study demonstrates that AP-2β promotes tumor growth and predicts poor prognosis, and may represent a potential therapeutic target for breast cancer.
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http://dx.doi.org/10.1159/000491463DOI Listing
August 2018

Co-delivery of gambogenic acid and VEGF-siRNA with anionic liposome and polyethylenimine complexes to HepG2 cells.

J Liposome Res 2019 Dec 23;29(4):322-331. Epub 2019 Sep 23.

The Collage of Pharmacy, Anhui University of Chinese Medicine , Hefei , China.

The combination of two or more different mechanisms of drugs in the treatment of cancer has become one of the effective methods. The purpose of this study was to successfully prepare a non-viral delivery system that could efficiently co-delivery siRNA and gambogenic acid (GNA) to improve the anti-cancer efficiency in HepG2 cells. The delivery system was prepared by a two-step method. First, the GNA-anionic liposome took shape by a solvent evaporation method, and then the liposome was bound to the PEI/siRNA complex by electrostatic interaction to form the final carrier system (lipopolyplexes). Agarose gel electrophoresis, MTT, particle size and zeta potential were detected to analyse the lipopolyplexes formation. The transfection efficiency of siRNA was determined by confocal laser scanning microscopy and flow cytometry. Western blotting was used to assess the VEGF protein expression levels of HepG2 cells. The cell apoptosis assay was used to assess the anti-tumour superiority of lipopolyplexes. GNA-PEI/siRNA-liposome (lipopolyplexes) are significantly less cytotoxicity compared to PEI mediated carriers. Simultaneously, the results of flow cytometry and confocal laser scanning microscopy indicated that the lipopolyplexes could successfully carry siRNA into the cytoplasm, and the western-blot result evidence that the delivery system has a potential for VEGF to express down. Also compared with the control group, the results of apoptosis test suggest that the lipopolyplexes can significantly promote cell apoptosis. The delivery system has a potential in the combination of various drugs for cancer therapy in future.
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http://dx.doi.org/10.1080/08982104.2018.1473423DOI Listing
December 2019

RBFOX3 Regulates the Chemosensitivity of Cancer Cells to 5-Fluorouracil via the PI3K/AKT, EMT and Cytochrome-C/Caspase Pathways.

Cell Physiol Biochem 2018 18;46(4):1365-1380. Epub 2018 Apr 18.

Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.

Background/aims: RBFOX3, an RNA-binding fox protein, plays an important role in the differentiation of neuronal development, but its role in the chemosensitivity of hepatocellular carcinoma (HCC) to 5-FU is unknown.

Methods: In this study, we examined the biological functions of RBFOX3 and its effect on the chemosensitivity of HCC cells to 5-FU in vitro and in a mouse xenograft model.

Results: RBFOX3 was found to have elevated expression in HCC cell lines and tissue samples, and its knockdown inhibited HCC cell proliferation. Moreover, knockdown of RBFOX3 improved the inhibitory effect of 5-fluorouracil (5-FU) on cell proliferation, migration and invasion, and enhanced the apoptosis induced by 5-FU. However, overexpression of RBFOX3 reduced the inhibitory effect of 5-fluorouracil (5-FU) on cell proliferation, migration and invasion, and decreased the apoptosis induced by 5-FU. We further elucidated that RBFOX3 knockdown synergized with 5-FU to inhibit the growth and invasion of HCC cells through PI3K/AKT and epithelial-mesenchymal transition (EMT) signaling, and promote apoptosis by activating the cytochrome-c/caspase signaling pathway. Finally, we validated that RBFOX3 regulated 5-FU-mediated cytotoxicity in HCC in mouse xenograft models.

Conclusions: The findings from this study indicate that RBFOX3 regulates the chemosensitivity of HCC to 5-FU in vitro and in vivo. Therefore, targeting RBFOX3 may improve the inhibition of HCC growth and progression by 5-FU, and provide a novel potential therapeutic strategy for HCC.
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http://dx.doi.org/10.1159/000489153DOI Listing
July 2018

MAD2L2 inhibits colorectal cancer growth by promoting NCOA3 ubiquitination and degradation.

Mol Oncol 2018 03 13;12(3):391-405. Epub 2018 Feb 13.

Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.

Nuclear receptor coactivator 3 (NCOA3) is a transcriptional coactivator that has elevated expression in multiple tumor types, including colorectal cancer (CRC). However, the molecular mechanisms that regulate the tumorigenic functions of NCOA3 in CRC remain largely unknown. In this study, we aimed to discover and identify the novel regulatory proteins of NCOA3 and explore their mechanisms of action. Immunoprecipitation (IP) coupled with mass spectrometry (IP-MS) analysis was used to detect, identify, and verify the proteins that interacted with NCOA3 in CRC cells. The biological functions of the candidate proteins and the underlying molecular mechanism were investigated in CRC cells and mouse model in vitro and in vivo. The clinical significance of NCOA3 and its interaction partner protein in CRC patients was also studied. We identified mitotic arrest deficient 2-like protein 2 (MAD2L2, also known as MAD2B or REV7), with two signal peptide sequences of LIPLK and EVYPVGIFQK, to be an interaction partner of NCOA3. Overexpression of MAD2L2 suppressed the proliferation, migration, and clonogenicity of CRC cells by inducing the degradation of NCOA3. The mechanism study showed that increased MAD2L2 expression in CRC cells activated p38, which was required for the phosphorylation of NCOA3 that led to its ubiquitination and degradation by the proteasome. Moreover, we found that MAD2L2 predicted favorable prognosis in CRC patients. We have discovered a novel role of MAD2L2 in the regulation of NCOA3 degradation and proposed that MAD2L2 serves as a tumor suppressor in CRC.
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http://dx.doi.org/10.1002/1878-0261.12173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5830628PMC
March 2018

Downregulation of NMI promotes tumor growth and predicts poor prognosis in human lung adenocarcinomas.

Mol Cancer 2017 10 12;16(1):158. Epub 2017 Oct 12.

Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.

Background: N-myc (and STAT) interactor (NMI) plays vital roles in tumor growth, progression, and metastasis. In this study, we identified NMI as a potential tumor suppressor in lung cancer and explored its molecular mechanism involved in lung cancer progression.

Methods: Human lung cancer cell lines and a mouse xenograft model was used to study the effect of NMI on tumor growth. The expression of NMI, COX-2 and relevant signaling proteins were examined by Western blot. Tissue microarray immunohistochemical analysis was performed to assess the correlation between NMI and COX-2 expression in lung cancer patients.

Results: NMI was highly expressed in normal lung cells and tissues, but lowly expressed in lung cancer cells and tissues. Overexpression of NMI induced apoptosis, suppressed lung cancer cell growth and migration, which were mediated by up-regulation of the cleaved caspase-3/9 and down-regulation of phosphorylated PI3K/AKT, MMP2/MMP9, β-cadherin, and COX-2/PGE2. In contrast, knockdown of NMI promoted lung cancer cell colony formation and migration, which were correlated with the increased expression of phosphorylated PI3K/AKT, MMP2/MMP9, β-cadherin and COX-2/PGE2. Further study showed that NMI suppressed COX-2 expression through inhibition of the p50/p65 NF-κB acetylation mediated by p300. The xenograft lung cancer mouse models also confirmed the NMI-mediated suppression of tumor growth by inhibiting COX-2 signaling. Moreover, tissue microarray immunohistochemical analysis of lung adenocarcinomas also demonstrated a negative correlation between NMI and COX-2 expression. Kaplan-Meier analysis indicated that the patients with high level of NMI had a significantly better prognosis.

Conclusions: Our study showed that NMI suppressed tumor growth by inhibiting PI3K/AKT, MMP2/MMP9, COX-2/PGE2 signaling pathways and p300-mediated NF-κB acetylation, and predicted a favorable prognosis in human lung adenocarcinomas, suggesting that NMI was a potential tumor suppressor in lung cancer.
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http://dx.doi.org/10.1186/s12943-017-0705-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5639741PMC
October 2017

Origin and Evolution of Aquitard Porewater in the Western Coastal Plain of Bohai Bay, China.

Ground Water 2017 11 14;55(6):917-925. Epub 2017 Sep 14.

School of Environmental Studies, China University of Geosciences, Wuhan, 430074, China.

High-salinity paleowater from low-permeability aquitards in coastal areas can be a major threat to groundwater resources; however, such water has rarely been studied. The chemical and isotopic compositions of porewater extracted from a 200-m-thick Quaternary sedimentary sequence in the western coastal plain of Bohai Bay, China, were analyzed to investigate the salinity origin and chemical evolution of porewater in aquitards. Porewater samples derived at depths shallower than 32 m are characterized by Cl-Na type saline water (total dissolved solids [TDS], 10.9-84.3 g/L), whereas those at depths greater than 32 m comprise Cl·SO -Na type brackish water (TDS, 2.2-6.3 g/L). Saline porewater is interpreted as evaporated seawater prior to halite saturation, as evidenced by Cl-Br relationships. Although substantial dilution of saline porewater with meteoric water is supported by a wider Cl range and δ H-δ O covariance, the original marine waters were not completely flushed out. The deeper brackish porewater is determined to be a mixture of fresher porewater and brine groundwater and had a component of old brine of less than 10%, as indicated by a mixing model defined using δ H and Cl tracers. Porewater δ H-δ O relationships and negative deuterium excess ranging from -25.9‰ to -2.9‰ indicate the existence of an arid climate since Late Pleistocene in Tianjin Plain. The aquitard porewaters were chemically modified through water-rock interactions due to the long residence time.
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http://dx.doi.org/10.1111/gwat.12590DOI Listing
November 2017

RBFOX3 Promotes Tumor Growth and Progression via hTERT Signaling and Predicts a Poor Prognosis in Hepatocellular Carcinoma.

Theranostics 2017 22;7(12):3138-3154. Epub 2017 Jul 22.

Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.

Activation of the telomere maintenance mechanism is a key hallmark of cancer. Human telomerase reverse transcriptase (hTERT) is the catalytic subunit of telomerase, which is highly expressed in more than 80% of tumors, including hepatocellular carcinoma (HCC). However, the exact mechanisms by which hTERT is up-regulated in HCCs and promotes tumor growth and progression is not fully understood. The aim of this study was to discover the novel molecular targets that modulate hTERT signaling and HCC growth. In this study, we pulled down and identified RBFOX3 (RNA binding protein fox-1 homolog 3) as a novel hTERT promoter-binding protein in HCC cells using biotin-streptavidin-agarose pull-down and proteomics approach, and validated it as a regulatory factor for hTERT signaling and tumor growth in HCCs. Knockdown of RBFOX3 suppressed the promoter activity and expression of hTERT and consequently inhibited the growth and progression of HCC cells and . The suppression of HCC growth mediated by RBFOX3 knockdown could be rescued by hTERT overexpression. Conversely, exogenous overexpression of RBFOX3 activated the promoter activity and expression of hTERT and promoted the growth and progression of HCC cells. Moreover, we found that RBFOX3 interacted with AP-2β to regulate the expression of hTERT. Furthermore, we demonstrated that RBFOX3 expression was higher in the tumor tissues of HCC patients compared to the corresponding paracancer tissues, and was positively correlated with hTERT expression. Kaplan-Meier analysis showed that the HCC patients with high levels of RBFOX3 and hTERT had poor prognosis. Collectively, our data indicate that RBFOX3 promotes HCC growth and progression and predicts a poor prognosis by activating the hTERT signaling, and suggest that the RBFOX3/hTERT pathway may be a potential therapeutic target for HCC patients.
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http://dx.doi.org/10.7150/thno.19506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5566111PMC
April 2018

KMT2A promotes melanoma cell growth by targeting hTERT signaling pathway.

Cell Death Dis 2017 07 20;8(7):e2940. Epub 2017 Jul 20.

Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.

Melanoma is an aggressive cutaneous malignancy, illuminating the exact mechanisms and finding novel therapeutic targets are urgently needed. In this study, we identified KMT2A as a potential target, which promoted the growth of human melanoma cells. KMT2A knockdown significantly inhibited cell viability and cell migration and induced apoptosis, whereas KMT2A overexpression effectively promoted cell proliferation in various melanoma cell lines. Further study showed that KMT2A regulated melanoma cell growth by targeting the hTERT-dependent signal pathway. Knockdown of KMT2A markedly inhibited the promoter activity and expression of hTERT, and hTERT overexpression rescued the viability inhibition caused by KMT2A knockdown. Moreover, KMT2A knockdown suppressed tumorsphere formation and the expression of cancer stem cell markers, which was also reversed by hTERT overexpression. In addition, the results from a xenograft mouse model confirmed that KMT2A promoted melanoma growth via hTERT signaling. Finally, analyses of clinical samples demonstrated that the expression of KMT2A and hTERT were positively correlated in melanoma tumor tissues, and KMT2A high expression predicted poor prognosis in melanoma patients. Collectively, our results indicate that KMT2A promotes melanoma growth by activating the hTERT signaling, suggesting that the KMT2A/hTERT signaling pathway may be a potential therapeutic target for melanoma.
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http://dx.doi.org/10.1038/cddis.2017.285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5550845PMC
July 2017
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