Publications by authors named "Miao Deng"

35 Publications

Polydopamine-based nanoplatform for photothermal ablation with long-term immune activation against melanoma and its recurrence.

Acta Biomater 2021 Sep 16. Epub 2021 Sep 16.

Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, People's Republic of China. Electronic address:

The high risk of tumor recurrence presents a big challenge in melanoma therapy. Photothermal therapy (PTT) has merged as a powerful weapon against tumor in recent years, which produces tumor-associated antigens (TAA) and recruits dendritic cells (DCs) to tumor sites through immunogenic cell death (ICD) for immune activation. However, due to the lack of activation signals of DCs, the immune effect induced by PTT is not sufficient to inhibit the recurrence and proliferation of tumor. To efficiently cooperate PTT and immunotherapy to circumvent tumor recurrence, here we constructed a polydopamine (PDA) based core-shell nanoplatform loading CpG ODNs to elicit robust photothermal ablation and antitumor immune responses. Cationized polydopamine coated with hyaluronic acid (HA) shell was proven an efficient photothermal agent that increased the surface temperature of tumor by 16 °C and induced ICD. CpG ODNs effectively induced maturation of DCs by elevating the expression of co-stimulating markers. PTT combined with CpG ODNs achieved a remarkable synergistic treatment effect in the maturation of DCs and activation of T cells in melanoma-bearing mice model compared with PTT or CpG ODNs alone. Furthermore, in a tumor recurrence model, photothermal-immune combination therapy increased the infiltration of CTLs in distant tumor compared with PTT or CpG ODNs alone. The combination therapy overcame insufficient immunity at distant tumor caused by PTT alone and relieved immunosuppression microenvironment of the tumor. Hence, the PDA based core-shell nanoplatform presents a potent photo-immunotherapy against proliferation and recurrence of melanoma. STATEMENT OF SIGNIFICANCE: In order to solve the insufficient immunity induced by photothermal therapy (PTT), CpG ODNs were utilized to enhance the weak immune response mediated by PTT through inducing DCs maturation. Hence, we designed a polydopamine (PDA) based core-shell nanoplatform loading CpG ODNs followed by hyaluronic acid named PPP/CpG/HA to elicit robust photothermal ablation and antitumor immune responses. CpG ODNs were delivered to the tumor site through the targeting effect of the HA shell. The core-shell nanoplatform achieved a remarkable synergistic treatment effect in the maturation of DCs and activation of T cells, thereby overcoming insufficient immunity at distant tumor caused by PTT alone. The core-shell nanoplatform presents a potent photo-immunotherapy against proliferation and recurrence of melanoma.
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http://dx.doi.org/10.1016/j.actbio.2021.09.014DOI Listing
September 2021

Co-delivery of autophagy inhibitor and gemcitabine using a pH-activatable core-shell nanobomb inhibits pancreatic cancer progression and metastasis.

Theranostics 2021 4;11(18):8692-8705. Epub 2021 Aug 4.

Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, People's Republic of China.

Metastasis is one of the main reasons for the high mortality associated with pancreatic ductal adenocarcinoma (PDAC), and autophagy regulates the metastatic migration of tumor cells, their invasion of tissues, and their formation of focal adhesions. Inhibiting autophagy may suppress tumor growth and metastasis, but the abundant extracellular matrix hinders the deep penetration of therapeutic agents. To enhance the penetration of drugs that can inhibit metastasis of pancreatic cancer, a pH-responsive drug delivery system was formulated. Gemcitabine (GEM), a first-line chemotherapeutic drug against PDAC, was loaded in 6PA-modified DGL (PDGL) nanoparticles to afford PDGL-GEM. Then PDGL-GEM was co-precipitated with the autophagy inhibitor chloroquine phosphate (CQ) and calcium phosphate to formulate [email protected]/CQ. The size and morphology of the resulting "nanobomb" [email protected]/CQ were characterized, and their uptake into cells, cytotoxicity and ability to inhibit autophagy were analyzed at pH 6.5 and 7.4. The anti-tumor and anti-metastasis effects of the nanobomb were explored on mice carrying Pan 02 pancreatic tumor xenografts or orthotopic tumors. The pH-induced dissolution of calcium phosphate facilitated the release of CQ from the nanobomb and deep penetration of PDGL-GEM. The internalization of PDGL-GEM and subsequent intracellular release of GEM inhibited tumor growth, while CQ downregulated autophagy in tumor cells and fibroblasts. In fact, inhibition of xenograft and orthotopic tumor growth was greater with the complete [email protected]/CQ than with subassemblies lacking GEM or CQ. More importantly, mechanistic studies and suggested that the nanobomb inhibits metastasis by downregulating MMP-2 and paxillin, as well as reducing fibrosis. The pH-sensitive [email protected]/CQ shows potential for inhibiting proliferation and metastasis of pancreatic cancer through an autophagy-dependent pathway.
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http://dx.doi.org/10.7150/thno.60437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419034PMC
August 2021

Efficacy and Mechanism of Buxue Yimu Pills () on Gynecological Anemia: A Combination of Clinical and Network Pharmacology Study.

Chin J Integr Med 2021 Jul 9. Epub 2021 Jul 9.

Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.

Objective: To compare the clinical efficacy and safety of oral administration of Buxue Yimu Pills (BYP, ), ferrous sulfate (FS), and the combination of BYP and FS on gynecological anemia, and investigate the mechanisms using network pharmacology.

Methods: A randomized, controlled, multi-center clinical trial was conducted. Totally 150 patients with hemoglobin of 70-110 g/L due to gynecological conditions were recruited and randomized (using the block randomization method) into Buxue Yimu Pills group (24 g/d), oral iron group (FS Tablets, 0.9 g/d), and combined treatment group (BYP, 24 g/d plus FS Tablets, 0.9 g/d), 50 patients in each group. At the enrollment and 4-week treatment, complete blood count, serum iron indexes were evaluated. Adverse events, liver and renal functions, as well as blood coagulation were observed. Network pharmacology was conducted to identify the active ingredients and explore the potential mechanisms of BYP.

Results: Ten (20%) and 7 (14%) participants discontinued the therapy due to gastrointestinal symptoms in oral iron and combination treatment groups. All 3 groups showed elevated hemoglobin. The patients in the iron group exhibited typically elevated in serum iron and ferritin and decreased in total iron-binding capacity. No change in iron indexes was observed in BYP group. The patients in the combination treatment group neither showed significant changes in serum ferritin nor total iron-binding capacity. No significant adverse reactions were observed in the BYP group. The network pharmacology identified 27 bioactive compounds and 145 targets of BYP on gynecological anemia. Biological processes and pathways including regulation of inflammation, hormone, angiogenesis and hemostasis, response to decreased oxygen levels, effects on myeloma cell, and response to metal ions were identified.

Conclusion: BYP contributes to the practical improvement on gynecological anemia potentially through multi-target mechanisms and optimized iron re-distribution. (Trial registration: No. NCT03232554).
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http://dx.doi.org/10.1007/s11655-021-3296-7DOI Listing
July 2021

Separation of Rare-Earth Ions from Mine Wastewater Using BS Nanoflakes as a Capacitive Deionization Electrode Material.

J Nanosci Nanotechnol 2021 Nov;21(11):5459-5476

College of Materials and Chemistry & Chemical Engineering, Chengdu University of Technology Chengdu 610059, China.

In this study, nanoflakes of BS were fabricated by plasma-assisted reaction of sulfur dichloride in an ionic liquid at room temperature using europium boride as a hard template. The nanoflakes had an average width and thickness of about 3 urn and 9.6 nm, respectively, and a large specific surface area of 1197.2 m² g . They behaved like typical electric double-layer capacitors with a capacitance of 201.2 F g at 0.2 mA cm ² During capacitive deionization to recover rare-earth ions, the nanoflakes had higher adsorption selectivity for Sm than for other competing ions present in real mine waste water. This is due to the strong interaction of the electron-concentered S-groups (S''') of the nanoflakes with S m. This provides an alternative to construct efficient systems to specifically remove Sm from aqueous solution using BS nanoflakes. This process demonstrates that other boron sulfide compounds can be used to recover valuable ions by capacitive deionization.
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http://dx.doi.org/10.1166/jnn.2021.19466DOI Listing
November 2021

pH-Triggered Copper-Free Click Reaction-Mediated Micelle Aggregation for Enhanced Tumor Retention and Elevated Immuno-Chemotherapy against Melanoma.

ACS Appl Mater Interfaces 2021 Apr 9;13(15):18033-18046. Epub 2021 Apr 9.

Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, People's Republic of China.

Natural killer (NK) cell-based immunotherapy presents a promising antitumor strategy and holds potential for combination with chemotherapy. However, the suppressed NK cell activity and poor tumor retention of therapeutics hinder the efficacy. To activate NK cell-based immuno-chemotherapy and enhance the tumor retention, we proposed a pH-responsive self-aggregated nanoparticle for the codelivery of chemotherapeutic doxorubicin (DOX) and the transforming growth factor-β (TGF-β)/Smad3 signaling pathway inhibitor SIS3. Polycaprolactone-poly(ethylene glycol) (PCL-PEG) micelles modified with dibenzylcyclooctyne (DBCO) or azido (N) and coated with acid-cleavable PEG were established. This nanoplatform, namely, [email protected]/SIS3, could remain well dispersed in the neutral systemic circulation, while quickly respond to the acidic tumor microenvironment and intracellular lysosomes, triggering copper-free click reaction-mediated aggregation, leading to the increased tumor accumulation and reduced cellular efflux. In addition, the combination of DOX with SIS3 facilitated by the aggregation strategy resulted in potent inhibition of melanoma tumor growth and significantly increased NK cells, NK cell cytokines, and antitumor T cells in the tumor. Taken together, our study offered a new concept of applying copper-free click chemistry to achieve nanoparticle aggregation and enhance tumor retention, as well as a promising new combined tumor treatment approach of chemotherapy and immunotherapy.
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http://dx.doi.org/10.1021/acsami.1c02567DOI Listing
April 2021

Upregulated miR‑411‑5p levels promote lymph node metastasis by targeting RYBP in head and neck squamous cell carcinoma.

Int J Mol Med 2021 04 4;47(4). Epub 2021 Feb 4.

Department of Oral Medicine, Hospital of Stomatology, Sun Yat‑Sen University, Guangzhou, Guangdong 510055, P.R. China.

Metastasis is the primary cause of the high mortality rates in head and neck squamous cell carcinoma (HNSCC). MicroRNA (miR)‑411‑5p has been discovered to serve an important role in cancer metastases. However, to the best of our knowledge, the association between miR‑411‑5p expression levels and HNSCC metastasis has not been thoroughly investigated. The present study aimed to research the function of miR‑411‑5p in HNSCC metastasis. The results of the present study revealed that miR‑411‑5p expression levels were upregulated in patients with HNSCC with lymph node metastasis and the upregulated expression levels of miR‑411‑5p were positively associated with the metastatic potential of HNSCC. Moreover, miR‑411‑5p promoted HNSCC cell migration, invasion and epithelial‑mesenchymal transition (EMT). The results of the dual‑luciferase reporter assays identified RING1 and YY1 binding protein (RYBP) as a functional downstream target gene for miR‑411‑5p. Therefore, whether miR‑411‑5p downregulated the expression levels of RYBP in HNSCC cells was subsequently investigated. Notably, the silencing of RYBP expression restored the stimulatory effects of miR‑411‑5p on HNSCC cell migration, invasion and EMT. In addition, the mRNA expression levels of miR‑411‑5p and RYBP were found to be inversely correlated in HNSCC samples. In conclusion, the results of the present study indicated that the miR‑411‑5p‑mediated downregulation of RYBP expression levels may exert an important role in HNSCC metastasis and may provide a novel target for the treatment of HNSCC.
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http://dx.doi.org/10.3892/ijmm.2021.4869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891818PMC
April 2021

Enhanced stability and efficacy of GEM-TOS prodrug by co-assembly with antimetastatic shell LMWH-TOS.

Acta Pharm Sin B 2020 Oct 26;10(10):1977-1988. Epub 2019 Jun 26.

Key Laboratory of Drug Targeting and Drug Delivery Systems of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610064, China.

Chemotherapy agents have been widely used for cancer treatment, while the insolubility, instability and toxicity seriously restrict their efficacy. Thus, prodrug strategy was devised. Since some prodrugs are still with poor solubility or stability, a synergy strategy is needed to enhance their efficacy. Gemcitabine (GEM) is a prescribed anticancer drug, however, the rapid clearance, growing resistance and serious side effects limit its clinical efficacy. Conjugating GEM with d--tocopherol succinate (TOS) is an effective solution, while the GEM-TOS (GT) is unstable in aqueous solution. d--Tocopherol polyethylene glycol succinate (TPGS) has been used to enhance the stability, but GT stabilized by TPGS (GTT) has limited effect on tumor metastases. Tumor metastases lead to high mortality in patients suffering from cancers. In order to further achieve antimetastatic effect, an amphiphilic polymer (LT) was synthesized by connecting low-molecular-weight heparin (LMWH) with TOS, and eventually obtained desired self-delivery micellar NPs (GLT) by co-assembly GT with LT. The GLT not only possessed excellent stability, but also inhibited the metastases by acting on different phases of the metastatic cascade. The hydrophobic TOS inhibited the secretion of matrix metalloproteinase-9 (MMP-9), the hydrophilic LMWH inhibited the interaction between tumor cells and platelets. As a result, GLT reduced tumor cells entering the blood and implanting at the distant organs, leading to a much more excellent inhibitory effect on the lung metastasis than GEM and GTT.
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http://dx.doi.org/10.1016/j.apsb.2019.06.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606181PMC
October 2020

Metformin Combined with 4SC-202 Inhibited the Migration and Invasion of OSCC via STAT3/TWIST1.

Onco Targets Ther 2020 29;13:11019-11029. Epub 2020 Oct 29.

Hospital of Stomatology, Sun Yat-Sen University, Guangzhou, People's Republic of China.

Background: Oral squamous cell carcinoma (OSCC), the most common epithelial malignant neoplasm in the head and neck, characterizes with local infiltration and metastasis of lymph nodes. The five-year survival rate of OSCC remains low despite the advances in clinical methods. Thus, it is necessary to develop a new effective therapeutic scheme for OSCC. Our previous results showed that metformin and 4SC-202 synergistically promoted the intrinsic apoptosis of OSCC in vitro and in vivo, but the effects on invasion and migration remained unclear.

Methods: Human OSCC cell lines HSC6 and CAL33 were cultured with metformin (16 mM) or/and 4SC-202 (0.4 μM) for 72 h. STAT3 inhibitor S31-201 was applied at concentration of 60 μM for 48 h. Wound-healing assays and transwell assays were used to determine the invasion and migration ability of OSCC. qRT-PCR and Western blot were performed to detect mRNA levels and protein levels.

Results: Metformin or/and 4SC-202 suppressed the migration and invasion of OSCC cells. Importantly, the expression of TWIST1 was suppressed by metformin and 4SC-202, while the invasion and migration inhibitory effects of metformin and 4SC-202 were countered by the overexpression of TWIST1. In addition, the phosphorylation level of STAT3 decreased after the administration of metformin or/and 4SC-202. Furthermore, inhibition of STAT3 by S31-201 suppressed the expression of TWIST1 and led to a decline in migration and invasion of OSCC, while overexpression of TWIST1 attenuated these effects.

Conclusion: Metformin and 4SC-202 suppressed the invasion and migration of OSCC through inhibition of STAT3/TWIST1, and this scheme can serve as a novel therapeutic strategy for OSCC.
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http://dx.doi.org/10.2147/OTT.S268851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605634PMC
October 2020

Targeting methyltransferase PRMT5 retards the carcinogenesis and metastasis of HNSCC via epigenetically inhibiting Twist1 transcription.

Neoplasia 2020 11 10;22(11):617-629. Epub 2020 Oct 10.

Hostpital of Stomatology, Sun Yat-sen University, Guangzhou, PR China; Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, PR China. Electronic address:

Protein arginine methyltransferase 5 (PRMT5) is an important type II arginine methyltransferase that can play roles in cancers in a highly tissue-specific manner, but its role in the carcinogenesis and metastasis of head and neck squamous cell carcinoma (HNSCC) remains unclear. Here, we detected PRMT5 expression in HNSCC tissues and performed series of in vivo and in vitro assays to investigate the function and mechanism of PRMT5 in HNSCC. We found that PRMT5 was overexpressed in dysplastic and cancer tissues, and associated with lymph node metastasis and worse patient survival. PRMT5 knockdown repressed the malignant phenotype of HNSCC cells in vitro and in vivo. PRMT5 specific inhibitor blocked the formation of precancerous lesion and HNSCC in 4NQO-induced tongue carcinogenesis model, prevented lymph node metastasis in tongue orthotopic xenograft model and inhibited cancer development in subcutaneous xenograft model and Patient-Derived tumor Xenograft (PDX) model. Mechanistically, PRMT5-catalyzed H3R2me2s promotes the enrichment of H3K4me3 in the Twist1 promoter region by recruiting WDR5, and subsequently activates the transcription of Twist1. The rescue experiments indicated that overexpressed Twist1 abrogated the inhibition of cell invasion induced by PRMT5 inhibitor. In summary, this study elucidates that PRMT5 inhibition could reduce H3K4me3-mediated Twist1 transcription and retard the carcinogenesis and metastasis of HNSCC.
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http://dx.doi.org/10.1016/j.neo.2020.09.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557877PMC
November 2020

Prognostic and clinical significance of focal adhesion kinase expression in breast cancer: A systematic review and meta-analysis.

Transl Oncol 2020 Nov 20;13(11):100835. Epub 2020 Jul 20.

Department of Breast Surgery, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, China. Electronic address:

Background: The prognostic significance of focal adhesion kinase (FAK) in breast cancer remains controversial. Here, we conducted a meta-analysis to explore the prognostic value of FAK expression in breast cancer.

Materials And Methods: Possible prognostic significance of protein or mRNA expression of FAK in breast cancer was investigated with searches of electronic databases for relevant publications. Pooled hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) were extracted from eligible studies.

Results: A total of eight eligible studies which included 2604 participants were analyzed in this meta-analysis. Increased expression of FAK protein was found to significantly correlate with shorter overall survival (OS) (HR = 1.43, 95% CI: 1.12-1.83; P = 0.004), and not with disease-free survival (HR = 1.31, 95% CI: 0.92-1.85; P = 0.14). Elevated FAK protein expression was also associated with negative estrogen receptor (ER) expression (OR, 1.34; 95% CI, 1.06-1.68; P = 0.01), negative progesterone receptor (PR) expression (OR, 1.54; 95% CI, 1.22-1.93; P < 0.001), positive human epidermal growth factor receptor 2 (HER2) expression (OR, 1.64; 95% CI, 1.28-2.09; P < 0.001), triple-negative breast cancer (TNBC) (OR, 1.57; 95% CI, 1.14-2.17; P = 0.006), high nuclear grade (OR, 1.70; 95% CI, 1.05-2.78; P = 0.03), high Ki-67 expression level (OR, 2.87; 95% CI, 1.94-4.24; P < 0.001), and positive p53 status (OR, 2.28; 95% CI, 1.58-3.29; P < 0.001).

Conclusion: Our meta-analysis identifies an association between increased FAK protein expression and worse OS among breast cancer patients. Moreover, enhanced FAK expression is associated with negative ER expression, negative PR expression, positive HER2 expression, TNBC, high nuclear grade, high Ki-67 expression level, and positive p53 status in breast carcinoma.
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http://dx.doi.org/10.1016/j.tranon.2020.100835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378698PMC
November 2020

Protective Effects of Lixisenatide against Lipopolysaccharide-Induced Inflammation Response in MAC-T Bovine Mammary Epithelial Cells: A Therapeutic Implication in Mastitis.

Chem Res Toxicol 2020 04 19;33(4):982-987. Epub 2020 Mar 19.

Department of Breast Surgery, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, China.

Mastitis is acute inflammation caused by microbial infections in the mammary glands. This disease is extremely harmful to lactating mothers. The preferred clinical strategy is antibiotic treatment, but this method results in resistance and side effects. Lixisenatide, a kind of glucagon-like peptide-1 (GLP-1) receptor agonist, is typically used for the treatment of type II diabetes. It is unknown whether lixisenatide possesses a beneficial role in mastitis. In the current study, we assessed the protective effects of lixisenatide against lipopolysaccharide (LPS) stimulation in MAC-T bovine mammary epithelial cells (MECs). Our findings show that lixisenatide attenuated LPS-induced oxidative stress by reducing reactive oxygen species (ROS) production and nicotinamide adenine dinucleotide phosphate (NADPH) oxidases-1 (NOX-1) expression in MAC-T MECs. Additionally, lixisenatide inhibited LPS-induced expression and secretion of tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), and interleukin 1β (IL-1β). We also found that lixisenatide suppressed LPS-induced expression of matrix metalloproteinase 2 (MMP-2) and metalloproteinase 9 (MMP-9), and reduced the expression of toll-like receptor 4 (TLR4) (a typical receptor of LPS), its downstream molecule myeloid differentiation factor 88 (MyD88), and the phosphorylation of TGF β-activated kinase 1 (TAK1). Notably, lixisenatide decreased the nuclear levels of nuclear factor-κB (NF-κB) and its transcriptional activity. These findings suggest that lixisenatide might become a possible therapeutic agent for the treatment of mastitis by weakening oxidative stress and the inflammatory response in MECs.
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http://dx.doi.org/10.1021/acs.chemrestox.9b00524DOI Listing
April 2020

Salivary exosomal miR-24-3p serves as a potential detective biomarker for oral squamous cell carcinoma screening.

Biomed Pharmacother 2020 Jan 5;121:109553. Epub 2019 Nov 5.

Department of Oral Medicine, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, PR China; Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, PR China. Electronic address:

Objectives: miRNAs in salivary exosomes are used as novel non-invasive biomarkers for detection strategies of human disease. Here, we aimed to investigate the diagnostic potential of salivary exosomal miRNAs as biomarkers for screening oral squamous cell carcinoma (OSCC) and to explore the underlying mechanisms of OSCC pathogenesis.

Materials And Methods: Differentially expressed miRNAs were obtained from salivary exosomes of four healthy controls and four OSCC patients using miRNA microarray analysis. The expression of miR-24-3p in the salivary exosomes was then verified by qRT-PCR. The diagnostic power was assessed by receiver operating characteristic (ROC) analysis. Cell proliferation was measured using CCK-8 cell viability assay and colony formation assay. The target gene of miR-24-3p was confirmed by dual luciferase reporter assay.

Results: A total of 109 miRNAs were found to be more than 2-fold altered in the salivary of patients and healthy individuals by miRNA microarray. qRT-PCR analysis further confirmed a significant increase of miR-24-3p in the salivary exosomes from 45 preoperative OSCC patients compared to 10 normal controls. ROC analysis showed that miR-24-3p has excellent diagnostic accuracy for OSCC (area under the ROC curve [AUC] = 0.738; P =  0.02). Similarly, we found that miR-24-3p expressed a higher level in OSCC neoplastic tissues, suggesting that circulating miR-24-3p may originate from tumor cells. Furthermore, exogenous exosomal miR-24-3p increased proliferation of recipient malignant cells. Additionally, overexpression of miR-24-3p promoted the proliferation of OSCC cells and regulated the expression of cell cycle-related genes. Dual luciferase reporter assay indicated that miR-24-3p can interact with PER1 directly.

Conclusions: Salivary exosomal miR-24-3p is a potential novel diagnostic biomarker for OSCC, and miR-24-3p can maintain the proliferation of OSCC cells through targeting PER1.
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http://dx.doi.org/10.1016/j.biopha.2019.109553DOI Listing
January 2020

Tumor-Associated Fibroblast-Targeted Regulation and Deep Tumor Delivery of Chemotherapeutic Drugs with a Multifunctional Size-Switchable Nanoparticle.

ACS Appl Mater Interfaces 2019 Oct 16;11(43):39545-39559. Epub 2019 Oct 16.

Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy , Sichuan University , No. 17, Block 3, Southern Renmin Road , Chengdu 610041 , China.

Tumor-associated fibroblasts (TAFs), which form a predominant stromal cellular component of the tumor microenvironment, hinder the delivery of nanomedicine to deep tumor cells and lead to poor prognosis of tumors. However, depletion of TAFs by therapeutic agents results in the secretion of damage response program (DRP) molecules to weaken the efficacy of tumor treatment. This paper reports a multifunctional size-switchable nanoparticle (denoted DGL (dendrigraft poly-l-lysine) (DGL)/[email protected]/GA) for TAF-targeted regulation and deep tumor penetration. After accumulation at the tumor site, in response to overexpressed matrix metalloproteinase-2 (MMP-2) in the tumor microenvironment, gemcitabine (GEM)-conjugated small nanoparticles (DGL/GEM) are released from DGL/[email protected]/GA, leaving 18β-glycyrrhetinic acid (GA)-loaded large nanoparticles (PP/GA). The released DGL/GEM can penetrate to the deep region of the tumor as well as intracellularly release GEM to kill tumor cells. However, residual GA-loaded nanoparticles with lower tumor penetration ability could accumulate around tumor vessels and be preferentially absorbed by TAFs to regulate the secretion of Wnt 16, which is an important DRP molecule. By taking actions on both tumor cells and TAFs, DGL/[email protected]/GA displayed significant and long-term antitumor effect in stroma-rich pancreatic cancer and breast cancer models.
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http://dx.doi.org/10.1021/acsami.9b13957DOI Listing
October 2019

Prognostic value of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio for breast cancer patients: An updated meta-analysis of 17079 individuals.

Cancer Med 2019 08 13;8(9):4135-4148. Epub 2019 Jun 13.

Department of Breast Surgery, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China.

Aims: This study aimed to evaluate the prognostic effect of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) for patients with breast cancer (BC).

Methods: A literature search was performed by searching medical databases. Basic characteristics and prognostic data were extracted from included studies. Primary outcomes, such as overall survival (OS) and disease-free survival (DFS), were synthesized and compared. Subgroup analyses were performed according to pathology, geographical region, cut-off value, and tumor progression.

Results: A total of 39 studies comprising 17079 BC patients were included in this meta-analysis. Among them, 28 studies with 142 64 BC patients investigated predicting role of NLR for OS, showing elevated NLR were associated poor prognosis (hazard ratio [HR]: 1.78, 95% confidence interval [CI]: 1.49-2.13, P < 0.001). Twenty-seven studies containing 115 04 patients explored the role of NLR in predicting DFS, showing elevated NLR was associated with poor DFS with HR of 1.60 (95% CI: 1.42-1.96, P < 0.001). Twelve studies explored the role of PLR in predicting OS, showing patients with higher PLR were associated with a significantly worse prognosis with a pooled HR of 1.32 (95% CI: 1.11-1.57, P = 0.002). Eleven studies with 5013 patients shown patients with elevated PLR were associated shorter DFS (HR: 1.43, 95% CI: 1.09-1.86, P = 0.009). Subgroup analyses shown a greater magnitude of association between NLR and OS in triple-negative BC patients than in HER2-positive ones.

Conclusions: Our study suggested that elevated NLR and PLR were associated with poor OS as well as high risk of recurrence for BC patients. Subgroup analyses confirmed the prognostic effect of NLR and PLR in HER2-positive BC patients. As easily accessible parameters, NLR and PLR should be identified as useful biomarkers in the management of BC.
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http://dx.doi.org/10.1002/cam4.2281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6675722PMC
August 2019

Knockdown of hypoxia-inducible factor-1 alpha by tumor targeted delivery of CRISPR/Cas9 system suppressed the metastasis of pancreatic cancer.

J Control Release 2019 06 14;304:204-215. Epub 2019 May 14.

Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy Sichuan University, Chengdu 610064, China. Electronic address:

The hypoxic tumor microenvironment of pancreatic cancer contributes to the progression and metastasis of tumor cells. Downregulation of hypoxia-inducible factor-1α (HIF-1α) with CRISPR/Cas9 is a promising approach to modulate tumor microenvironment and inhibit tumor metastasis. However, the in vivo delivery of CRISPR/Cas9 system remains a challenge. In the present manuscript, a tumor targeted lipid-based CRISPR/Cas9 delivery system was developed to suppress HIF-1α. Plasmids encoding Cas9 and HIF-1α-targeting sgRNA were successfully constructed and coencapsulated in R8-dGR peptide modified cationic liposome with PTX. R8-dGR-Lip exhibited enhanced BxPC-3 cell targeting and deep penetration into tumor spheroids. R8-dGR-Lip/PTX/pHIF-1α successfully downregulated HIF-1α and its downstream molecules VEGF and MMP-9, leading to enhanced antimetastatic effects. Besides, the blockade of HIF-1α also promoted the cytotoxicity of PTX on BxPC-3 cell lines. Compared with pegylated liposomes, R8-dGR-Lip enhanced the distribution in tumor tissues. The targeted delivery of CRISPR/Cas9-HIF-1α system and PTX significantly inhibited tumor growth. More importantly, inhibition of HIF-1α suppressed the metastasis of pancreatic cancer and prolonged survival time. Since CRISPR/Cas 9-HIF-1α hardly affected HIF-1α expression in normal hepatic cells, the designed R8-dGR-Lip/PTX/pHIF-1α did not induce severe toxicity in vivo. This strategy broadened the in vivo application of CRISPR/Cas9 system. Downregulation of HIF-1α may be a feasible approach for antimetastatic therapy.
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http://dx.doi.org/10.1016/j.jconrel.2019.05.019DOI Listing
June 2019

Metformin and 4SC-202 synergistically promote intrinsic cell apoptosis by accelerating ΔNp63 ubiquitination and degradation in oral squamous cell carcinoma.

Cancer Med 2019 07 25;8(7):3479-3490. Epub 2019 Apr 25.

Department of Oral Medicine, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, P.R. China.

Oral squamous cell carcinoma (OSCC) is the most common and aggressive epithelial tumor in the head and neck region with a rising incidence. Despite the advances in basic science and clinical research, the overall survival rate of OSCC remains low. Thus finding novel effective therapeutic agents for OSCC is necessary. In this study, we investigated the effects and mechanisms of combined metformin and 4SC-202 in OSCC. Our results showed that metformin and 4SC-202 synergistically suppressed the proliferation and promoted the intrinsic apoptosis of OSCC cells in vitro and in vivo. Importantly, the proteasome inhibitor MG132 impeded the ΔNp63-decreasing effects after metformin and 4SC-202 treatment, indicating that metformin and 4SC-202 could promote the degradation of ΔNp63 protein. Moreover, ubiquitination level of ΔNp63 increased after metformin or/and 4SC-202 administration. Furthermore, we revealed that ΔNp63 mediated anticancer effects of metformin and 4SC-202, as overexpression or suppression of ΔNp63 could attenuate or facilitate the apoptosis rate of OSCC under metformin or/and 4SC-202 treatment. Collectively, metformin and 4SC-202 synergistically promote intrinsic apoptosis through accelerating ubiquitin-mediated degradation of ΔNp63 in OSCC, and this co-treatment can serve as a potential therapeutic scheme for OSCC.
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http://dx.doi.org/10.1002/cam4.2206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6601594PMC
July 2019

Combined class I histone deacetylase and mTORC1/C2 inhibition suppresses the initiation and recurrence of oral squamous cell carcinomas by repressing SOX2.

Cancer Lett 2019 07 11;454:108-119. Epub 2019 Apr 11.

Department of Oral Medicine, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, PR China; Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, PR China. Electronic address:

Treatment of oral squamous cell carcinoma (OSCC) remains a challenge because of the lack of effective early treatment strategies and high incidence of relapse. Here, we showed that combined 4SC-202 (a novel selective class I HDAC inhibitor) and INK128 (a selective mTORC1/C2 inhibitor) treatment exhibited synergistic effects on inhibiting cell growth, sphere-forming ability, subcutaneous tumor formation and ALDH1 cancer stem cells (CSCs) in OSCC. The initiation of OSCC was significantly inhibited by combined treatment in 4NQO-induced rat model. In addition, upregulated SOX2 was associated with advanced and metastatic tumors in OSCC patients and was responsible for the drug-resistance property of OSCC cells. The inhibitory effect of combined treatment on cell viability and ALDH1 CSCs were attenuated by SOX2 verexpression. Furthermore, combined treatment can effectively overcome chemoresistance and inhibit the growth of recurrent OSCC in vitro and in vivo. Mechanistically, 4SC-202 and INK128 repressed SOX2 expression through miR-429/miR-1181-mediated mRNA degradation and preventing cap-dependent mRNA translation, respectively. These results suggest that combined class I histone deacetylase and mTORC1/C2 inhibition suppresses the carcinogenesis and recurrence of OSCC by repressing SOX2.
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http://dx.doi.org/10.1016/j.canlet.2019.04.010DOI Listing
July 2019

Low Molecular Weight Heparin-Coated and Dendrimer-Based Core-Shell Nanoplatform with Enhanced Immune Activation and Multiple Anti-Metastatic Effects for Melanoma Treatment.

Theranostics 2019 1;9(2):337-354. Epub 2019 Jan 1.

Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041, China.

High-efficiency treatment for tumor is not easy to achieve owing to the existence of metastasis, which remains the arch-criminal of most tumor deaths. Conventional chemotherapy exhibits insufficient inhibitory efficiency on tumor metastasis and more powerful strategies to conquer metastatic tumors are urgently needed. In this study, a rational chemoimmunotherapy strategy was adopted to treat highly aggressive melanoma based on a newly developed multifunctional nanoplatform. Firstly, immunoadjuvant cytosine-phosphate-guanine oligonucleotides (CpG ODNs) were used to boost the doxorubicin (DOX)-elicited immune responses, which synergistically suppressed tumor growth and metastasis. And the anti-metastatic low molecular weight heparin (LMWH) was also integrated, thus multiple anti-metastatic effects to against tumor metastasis were achieved. G4 PAMAM was serving as the main support to conjugate DOX by pH-sensitive hydrazone bond (PPD) and the synthesized conjugates were confirmed by H-NMR spectra, IR spectra and HRMS. Immunoadjuvant CpG ODNs were loaded by electrostatic adsorption to formulate PPD/CpG. After the coating of anti-metastatic LMWH, the designed LMWH/PPD/CpG was fabricated and characterized. The platelets-related and platelets-unrelated anti-metastatic mechanisms were investigated on B16F10 the immune activation effects, anti-tumor and anti-metastatic efficacy of LMWH/PPD/CpG were evaluated on a B16F10 melanoma xenograft model. DOX elicited tumor-specific immune responses by ICD, and the immunological effects could be further promoted by CpG ODNs, exhibiting enhanced maturation of dendritic cells (DCs) and increased level of cytolytic T lymphocytes (CTLs) . Owing to the coating of LMWH, the platelets-induced epithelial-mesenchymal-like transition of tumor cells was hindered and the actin cytoskeletal arrangement of tumor cells was affected, thus the migration ability of tumor cells was further inhibited. This multifunctional nanoplatform showed enhanced treatment efficiency on melanoma primary tumor and pulmonary metastasis. The immune activation and multiple anti-metastatic effects of LMWH/PPD/CpG establish a novel therapeutic strategy for melanoma. This anti-metastatic nanoplatform could be broadly applied for the co-delivery of other nucleic acids and chemotherapeutic drugs to treat highly aggressive tumors.
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http://dx.doi.org/10.7150/thno.29026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6376190PMC
December 2019

Study on the diagnosis of gout with xanthine and hypoxanthine.

J Clin Lab Anal 2019 Jun 25;33(5):e22868. Epub 2019 Feb 25.

West China Hospital, Sichuan University, Chengdu, China.

Background: Hyperuricemia is the only biochemical index in the classification of acute gouty arthritis in American Rheumatism Association 1977 and the main basis of clinical diagnosis for most doctors. However, nearly half of the time gout occurs without hyperuricemia, especially in an acute attack,which leads to an urgent need to find a new substitute diadynamic criteria of gout. Xanthine and hypoxanthine, as precursors of uric acid, have been reported to be high in gout patients with hyperuricemia and presumed to be gout biomarkers.

Objectives: To further explore the possibility of xanthine and hypoxanthine to be gout biomarkers as substitutes for uric acid.

Methods: A reversed-phase HPLC-UV method was employed for simultaneous quantitative detection of uric acid (UA), xanthine (X), and hypoxanthine (HX) in gout patients' (with and without hyperuricemia) and healthy persons' serum.

Results: The xanthine and hypoxanthine concentrations in gout patients with hyperuricemia and without hyperuricemia are higher than in healthy persons with a P < 0.001.

Conclusions: This study supplements previous researches by confirming that xanthine and hypoxanthine are significantly elevated in gout patients' serum especially in patients' with normouricemia, which supported xanthine and hypoxanthine may have clinical application for the diagnosis of gout.
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http://dx.doi.org/10.1002/jcla.22868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6595306PMC
June 2019

Prognostic and clinical significance of syndecan-1 expression in breast cancer: A systematic review and meta-analysis.

Eur J Surg Oncol 2019 Jul 25;45(7):1132-1137. Epub 2018 Dec 25.

Department of Breast Surgery, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, China. Electronic address:

Background: The prognostic value of syndecan-1 (SDC1, also called CD138) in breast cancer remains controversial. Therefore, we performed a meta-analysis to assess the clinical significance of SDC1 expression in breast cancer.

Materials And Methods: Various databases were searched to evaluate possible correlations between SDC1 protein or mRNA expression and prognostic significance in breast cancer. Pooled hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) were applied to perform a quantitative meta-analysis.

Results: A total of 1305 breast cancer patients from 9 eligible studies were included in this meta-analysis. Significant associations between elevated SDC1 protein expression and poor disease-free survival (DFS) (HR = 1.55, 95% CI: 1.12-2.14; P = 0.007) and overall survival (OS) (HR = 2.08, 95% CI: 1.61-2.69; P < 0.001) were observed. In addition, enhanced SDC1 protein expression correlated with negative estrogen receptor (ER) expression (OR, 2.38; 95% CI, 1.64-3.44; P < 0.001) and positive human epidermal growth factor receptor 2 (HER2) expression (OR, 1.77; 95% CI, 1.14-2.76; P = 0.01). However, increased SDC1 protein expression did not correlate with relapse-free survival (RFS) (HR = 0.33, 95% CI: 0.03-3.13; P = 0.33). There were no additional significant correlations observed between SDC1 protein expression and other clinical factors, including tumor size, lymph node involvement, nuclear grade, and progesterone receptor (PR) expression.

Conclusion: The results of this meta-analysis demonstrate that increased SDC1 protein expression in breast cancer is significantly associated with worse prognosis in terms of DFS and OS, and an aggressive phenotype is associated with negative ER expression and positive HER2 expression.
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http://dx.doi.org/10.1016/j.ejso.2018.12.019DOI Listing
July 2019

Prognostic and clinicopathological value of CXCL12/SDF1 expression in breast cancer: A meta-analysis.

Clin Chim Acta 2018 Sep 22;484:72-80. Epub 2018 May 22.

Department of Breast Surgery, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, China. Electronic address:

Background: Several studies have demonstrated that stromal cell derived factor-1 (SDF1, also known as CXCL12) expression is a biomarker for breast cancer treatment; however, its significance of prognosis is inconsistent. This study uses a meta-analysis to explore the prognostic value of CXCL12/SDF1 expression in breast cancer.

Materials And Methods: PubMed, Embase, Cochrane Library, and Web of Science databases were searched from inception to November 25, 2017. Studies investigating the correlation between CXCL12/SDF1 expression and survival in breast carcinoma were included. The pooled hazard ratio (HR) and 95% confidence interval (95% CI) was used to assess the prognostic value of CXCL12/SDF1 in breast cancer. The pooled odds radio (OR) and 95% CI was applied to evaluate the relationship between CXCL12/SDF1 expression and the clinical characteristics of breast cancer.

Results: Eight eligible studies involving 2205 patients were identified. Higher CXCL12/SDF1 protein expression was associated with better disease-free survival (DFS) (HR, 0.76; 95% CI, 0.68-0.86; P < .0001) and overall survival (OS) (HR, 0.66; 95% CI, 0.49-0.87; P = .004) in breast cancer. Furthermore, higher CXCL12/SDF1 protein expression was associated with positive ER status (OR, 1.92; 95% CI, 1.08-3.45; P = .03), negative HER2 status (OR, 2.64; 95% CI, 1.06-6.59; P = .04), and small tumor size (OR, 2.49; 95% CI, 1.47-4.22; P = .0007) in breast cancer, respectively. However, there were no significant associations between the CXCL12/SDF1 mRNA expression and other prognostic parameters, such as TNM stage, age, PR status, lymph node, and nuclear grade (P > .05 for all).

Conclusions: This present meta-analysis suggests that CXCL12/SDF1 protein expression is a good prognostic biomarker in breast cancer. In addition, the over-expression of CXCL12/SDF1 protein was associated with positive ER status, negative HER2 status and small tumor size.
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http://dx.doi.org/10.1016/j.cca.2018.05.041DOI Listing
September 2018

Prognostic and clinical significance of histone deacetylase 1 expression in breast cancer: A meta-analysis.

Clin Chim Acta 2018 Aug 5;483:209-215. Epub 2018 May 5.

Department of Breast Surgery, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, China. Electronic address:

Background: There are conflicting reports about the role of histone deacetylase 1 (HDAC1) in breast cancer prognosis. Here, we conducted a meta-analysis to investigate the prognostic significance of HDAC1 in breast cancer.

Materials And Methods: We searched different databases to identify studies evaluating the association between HDAC1 expression and its prognostic value in breast cancer. The pooled hazard ratios (HRs) and odds radios (ORs) with 95% confidence intervals (95% CIs) were calculated from these studies to assess specific correlation.

Results: Our meta-analysis of four databases identified 7 eligible studies with 1429 total patients. We found that HDAC1 over-expression did not correlate with disease-free survival (DFS) and overall survival (OS) in breast cancer. Subgroup analysis indicated an association between up-regulated HDAC1 expression and better OS (HR = 0.47, 95% CI: 0.23-0.97; P = 0.04) in Asian breast cancer patients. However, false-positive report probability (FPRP) analysis and trial sequential analysis (TSA) indicated that the results need further validation. Furthermore, HDAC1 over-expression was associated with positive estrogen receptor (ER) expression (OR, 3.30; 95% CI, 1.11-9.83; P = 0.03) and negative human epidermal growth factor receptor 2 (HER2) expression (OR, 1.79; 95% CI, 1.22-2.61; P = 0.003), but there were no significant differences between patients based on age, tumor size, lymph node metastasis, nuclear grade, or progesterone receptor (PR) expression.

Conclusion: Overall, our meta-analysis demonstrated an association between increased HDAC1 expression and better OS in Asian breast cancer patients. In addition, HDAC1 over-expression correlated with positive ER and negative HER2 expression in breast cancer. However, researches in large patients' randomised controlled trials (RCTs) are needed to confirm the results.
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http://dx.doi.org/10.1016/j.cca.2018.05.005DOI Listing
August 2018

Prognostic and clinicopathological value of Twist expression in breast cancer: A meta-analysis.

PLoS One 2017 9;12(10):e0186191. Epub 2017 Oct 9.

The Molecular Medicine Key Laboratory of Liver Injury and Repair, Medical College, Henan University of Science and Technology, Luoyang, China.

Background: Despite initial indications that the transcription factor Twist could be used as a breast cancer prognostic marker, there still exists some controversy about its reliability. Thus, the aim of the present study was to assess the relationship between Twist expression and prognosis in breast carcinoma.

Materials And Methods: We identified eligible studies that reported an association between Twist expression and breast cancer prognosis by searching the literature in PubMed, Embase, the Cochrane Library, and Web of Science databases, through June 5, 2017. Studies investigating Twist protein or mRNA expression as well as reporting survival data in breast cancer were included. The pooled hazard ratio (HR) and odds radio (OR) with a 95% confidence interval (95% CI) were used to estimate associations.

Results: A total of 2,671 patients from seven included studies were assessed, and the data indicated that increased Twist expression significantly correlated with poor overall survival (OS) (HR, 1.15; 95% CI, 1.00-1.33; P = 0.04) in breast cancer. In addition, we also observed a significant correlation of elevated Twist expression with larger tumor size (OR, 1.92; 95% CI, 1.31-2.81; P = 0.0009), lymph node involvement (OR, 3.81; 95% CI, 1.16-12.54; P = 0.03), higher nuclear grade (OR, 1.45; 95% CI, 1.06-2.00; P = 0.02), and positive human epidermal growth factor receptor 2 (HER2) status (OR, 1.49; 95% CI, 1.06-2.09; P = 0.02). However, no correlation between Twist expression and disease-free survival (DFS), age, estrogen receptor (ER) status, and progesterone receptor (PR) status was observed.

Conclusions: Our results demonstrate that Twist over-expression is a statistically significant indicator of OS in breast cancer. In addition, our meta-analysis shows that increased Twist expression is significantly associated with larger tumor size, lymph node involvement, higher nuclear grade, and positive HER2 status.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0186191PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5633195PMC
October 2017

E-cadherin expression phenotypes associated with molecular subtypes in invasive non-lobular breast cancer: evidence from a retrospective study and meta-analysis.

World J Surg Oncol 2017 Aug 1;15(1):139. Epub 2017 Aug 1.

Henan Key Laboratory of Cancer Epigenetics, Cancer Institute, First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang, 471003, China.

Background: This retrospective study and meta-analysis was designed to explore the relationship between E-cadherin (E-cad) expression and the molecular subtypes of invasive non-lobular breast cancer, especially in early-stage invasive ductal carcinoma (IDC).

Methods: A total of 156 post-operative cases of early-stage IDCs were retrospectively collected for the immunohistochemistry (IHC) detection of E-cad expression. The association of E-cad expression with molecular subtypes of early-stage IDCs was analyzed. A literature search was conducted in March 2016 to retrieve publications on E-cad expression in association with molecular subtypes of invasive non-lobular breast cancer, and a meta-analysis was performed to estimate the relational statistics.

Results: E-cad was expressed in 82.7% (129/156) of early-stage IDCs. E-cad expression was closely associated with the molecular types of early-stage IDCs (P < 0.050); moreover, the molecular subtypes were an independent factor influencing E-cad expression in early-stage IDCs. A total of 12 observational studies (including our study) were included in the meta-analysis. The meta-analytical results show a significantly greater risk of E-cad expression loss in triple-negative breast cancer (TNBC) than in other molecular subtypes (TNBC vs. luminal A: RR = 3.45, 95% CI = 2.79-4.26; TNBC vs. luminal B: RR = 2.41, 95% CI = 1.49-3.90; TNBC vs. HER2-enriched: RR = 1.95, 95% CI = 1.24-3.07).

Conclusions: Early-stage IDCs or invasive non-lobular breast cancers with the TNBC molecular phenotype have a higher risk for the loss of E-cad expression than do tumors with non-TNBC molecular phenotypes, suggesting that E-cad expression phenotypes were closely related to molecular subtypes and further studies are needed to clarify the underlying mechanism.
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http://dx.doi.org/10.1186/s12957-017-1210-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5539617PMC
August 2017

Urchin-Like Amorphous Ni2B Alloys: Efficient Antibacterial Materials and Catalysts for Hydrous Hydrazine Decomposition to Produce H2.

J Nanosci Nanotechnol 2016 Mar;16(3):2394-400

Urchin-like amorphous Ni2B alloys were successfully prepared for the first time from a mixture of Ni(NH3)6(2+) and polyvinyl alcohol (PVA) via a solution plasma process (SPP). The as-synthesized samples were characterized by X-ray powder diffraction (XRD), inductively coupled plasma atomic emission spectrometry (ICP-AES) X-ray photoelectron spectroscopy (XPS), scanning transmission electron microscopy (STEM), selected-area electron diffraction patterns (SAED) and nitrogen adsorption-desorption isotherms. In the performance test, the obtained Ni-B urchins showed great antibacterial activities, comparable with those of amikacin and kanamycin, especially towards Pseudomonas aeruginosa (P. aeruginosa). Meanwhile, the magnetic properties of Ni-B urchins are enhanced in comparison with those of conventional Ni-B. During hydrous hydrazine (N2H4) decomposition, the dehydrogenation performance of Ni-B urchins is superior to those of Raney Ni and conventional Ni-B. The enhanced catalytic performance of Ni-B urchins is attributed to their high surface area of active species nickel and the enhanced intrinsic activity resulting from their unique structure.
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http://dx.doi.org/10.1166/jnn.2016.10920DOI Listing
March 2016

Immunohistochemical Determination of p53 Protein Overexpression for Predicting p53 Gene Mutations in Hepatocellular Carcinoma: A Meta-Analysis.

PLoS One 2016 18;11(7):e0159636. Epub 2016 Jul 18.

Henan Key Laboratory of Cancer Epigenetics, Cancer Institute, First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang, Henan, PR China.

Background: Whether increased expression of the tumor suppressor protein p53 indicates a p53 gene mutation in hepatocellular carcinoma (HCC) remains unclear. We conducted a meta-analysis to determine whether p53 protein overexpression detected by immunohistochemistry (IHC) offers a diagnostic prediction for p53 gene mutations in HCC patients.

Methods: Systematic literature searches were conducted with an end date of December 2015. A meta-analysis was performed to estimate the diagnostic accuracy of IHC-determined p53 protein overexpression in the prediction of p53 gene mutations in HCC. Sensitivity, subgroup, and publication bias analyses were also conducted.

Results: Thirty-six studies were included in the meta-analysis. The results showed that the overall sensitivity and specificity for IHC-determined p53 overexpression in the diagnostic prediction of p53 mutations in HCC were 0.83 (95% CI: 0.80-0.86) and 0.74 (95% CI: 0.71-0.76), respectively. The summary positive likelihood ratio (PLR) and negative likelihood ratio (NLR) were 2.65 (95% CI: 2.21-3.18) and 0.36 (95% CI: 0.26-0.50), respectively. The diagnostic odds ratio (DOR) of IHC-determined p53 overexpression in predicting p53 mutations ranged from 0.56 to 105.00 (pooled, 9.77; 95% CI: 6.35-15.02), with significant heterogeneity between the included studies (I2 = 40.7%, P = 0.0067). Moreover, subgroup and sensitivity analyses did not alter the results of the meta-analysis. However, potential publication bias was present in the current meta-analysis.

Conclusion: The upregulation of the tumor suppressor protein p53 was indeed linked to p53 gene mutations. IHC determination of p53 overexpression can predict p53 gene mutations in HCC patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0159636PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4948819PMC
July 2017

Silencing cyclin-dependent kinase inhibitor 3 inhibits the migration of breast cancer cell lines.

Mol Med Rep 2016 Aug 14;14(2):1523-30. Epub 2016 Jun 14.

Department of Breast Surgery, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, Henan 471003, P.R. China.

Cyclin-dependent kinase inhibitor 3 (CDKN3) belongs to the dual-specificity protein phosphatase family, which is hypothesized to regulate cell cycle progression in tumor cells. However, whether CDKN3 is a potential therapeutic target for breast cancer remains to be elucidated. The present in vitro study aimed to investigate the potential roles of CDKN3 in breast cancer. Breast cancer cell lines were used to detect CDKN3 expression, and CDKN3 expression was silenced to investigate its role in cell apoptosis, cell cycle arrest and migration. The underlying mechanisms were screened by detecting proliferating cell nuclear antigen (PCNA), Ras homolog gene family, member A (RhoA), vimentin, B‑cell lymphoma 2 (Bcl‑2) and Bcl‑2‑associated X protein (Bax) expression. CDKN3 was highly expressed in MCF‑7 and BT474 cell lines. The silencing of CDKN3 in MCF‑7 and BT474 cell lines promoted cell apoptosis, induced G1 phase cell cycle arrest and inhibited cell migration. The expression levels of PCNA, RhoA, vimentin and Bcl‑2 were downregulated following CDKN3 silencing. Conversely, Bax expression was increased, as compared with the vehicle control. These results suggest that CDKN3 acts as an oncogene during breast cancer progression. The in vitro silencing of CDKN3 promoted apoptosis, induced G1 phase cell cycle arrest and inhibited cell migration. Possible mechanisms are associated with the regulation of PCNA, Bcl‑2, vimentin, RhoA and Bax expression. CDKN3 may therefore be considered a potential target for the treatment of breast cancer.
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http://dx.doi.org/10.3892/mmr.2016.5401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4940103PMC
August 2016

Anti-aging effect of estrogen on telomerase activity in ovariectomised rats--animal model for menopause.

Gynecol Endocrinol 2015 Jul;31(7):582-5

a Department of Obstetrics and Gynecology , Tianchang People's Hospital , Chuzhou , China and.

Objective: The aim of this study was to investigate the anti-aging effects of exogenous estrogen on telomerase activity in ovariectomized female Sprague-Dawley rats.

Methods: Thirty-three 12-week-old female rats were divided into three groups: the ovariectomized-Treated group (Treated, n = 11), the ovariectomized control group (OVX, n = 11) and the Sham-operated group (Sham, n = 11). The rats in the Treated group were given 0.21 mg/kg estradiol valerate intragastric administration while other two groups were given the amount of physiological saline daily. All of the animals were euthanized 12 weeks after treatment, and abdominal aortic blood samples were taken to assess the level of estradiol (E2), follicle stimulating hormone (FSH). Telomerase activity and telomerase reverse transcriptase (TERT) mRNA expression in the heart, liver, brain tissues of all rats were measured by reverse transcriptional polymerase chain reaction (RT-PCR) and competitive enzyme-linked immunosorbent assay (ELISA).

Results: Compared to the OVX and Sham group, telomerase activity and TERT mRNA levels were significantly increased in the heart, liver and brain tissues of rats in the Treated group (p < 0.05). The telomerase expression was significantly higher in the heart than in liver and brain tissues in the Treated group (p < 0.05).

Conclusion: Based on the findings in the ovariectomized female rats model, exogenous estrogen can significantly up-regulate telomerase activity and TERT mRNA expression to exert the effects of anti-aging.
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http://dx.doi.org/10.3109/09513590.2015.1065478DOI Listing
July 2015

Combination of SF1126 and gefitinib induces apoptosis of triple-negative breast cancer cells through the PI3K/AKT-mTOR pathway.

Anticancer Drugs 2015 Apr;26(4):422-7

Department of Breast Surgery, The First Affiliated Hospital of the Henan University of Science and Technology, Luoyang, Henan, People's Republic of China.

To investigate the apoptotic mechanism of triple-negative breast cancer (TNBC) cells induced by gefitinib and PI3K inhibitor SF1126. MDA-MB-231, MDA-MB-436, and MCF-7 cells were incubated with 0.1 μmol/l gefitinib, 1 μmol/l gefitinib, 10 μmol/l gefitinib, 1 μmol/l SF1126, 0.1 μmol/l gefitinib+1 μmol/l SF1126, 1 μmol/l gefitinib+1 μmol/l SF1126, and 10 μmol/l gefitinib+1 μmol/l SF1126. Then, cell viability and survival were determined using an 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide (MTT) assay and Hoechst staining. The apoptosis-related factors and phosphoinositide-3-kinase/protein kinase B, the mammalian target of rapamycin (PI3K/AKT-mTOR) signaling pathway-related factors were detected by western blot. For TNBC cells, cell viability or survival was not significantly inhibited by gefitinib or SF1126 alone; however, marked cell apoptosis was noted in the gefitinib and SF1126 combination groups, and this effect was dose dependent. Also, the expressions of apoptosis markers, such as cleaved caspase-3, Bcl-2/Bax, were altered by the gefitinib and SF1126 combination. Moreover, phosphorylated AKT (p-AKT) and 70 kDa ribosomal protein S6-kinase (p-p70S6K) were also inhibited by the gefitinib and SF1126 combination, which may be responsible for the apoptosis. Gefitinib combined with SF1126 could induce cell apoptosis in TNBC cells and this effect was mediated through the EGFR-PI3K-AKT-mTOR-p70S6K pathway. Our studies have set the stage for future clinical trials of TNBC therapy by the combination of gefitinib and SF1126.
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http://dx.doi.org/10.1097/CAD.0000000000000202DOI Listing
April 2015

Identification of differently expressed genes with specific SNP Loci for breast cancer by the integration of SNP and gene expression profiling analyses.

Pathol Oncol Res 2015 Apr 19;21(2):469-75. Epub 2014 Nov 19.

Department of Breast Surgery, The First Affiliated Hospital of Henan University Science and Technology, Jinghua Road No. 24, Jianxi District, Luoyang City, 471003, China.

This study aims to explore the relationship between gene polymorphism and breast cancer, and to screen DEGs (differentially expressed genes) with SNPs (single nucleotide polymorphisms) related to breast cancer. The SNPs of 17 patients and the preprocessed SNP profiling GSE 32258 (38 cases of normal breast cells) were combined to identify their correlation with breast cancer using chi-square test. The gene expression profiling batch8_9 (38 cases of patients and 8 cases of normal tissue) was preprocessed with limma package, and the DEGs were filtered out. Then fisher's method was applied to integrate DEGs and SNPs associated with breast cancer. With NetBox software, TRED (Transcriptional Regulatory Element Database) and UCSC (University of California Santa Cruz) database, genes-associated network and transcriptional regulatory network were constructed using cytoscape software. Further, GO (Gene Ontology) and KEGG analyses were performed for genes in the networks by using siggenes. In total, 332 DEGs were identified. There were 160 breast cancer-related SNPs related to 106 genes of gene expression profiling (19 were significant DEGs). Finally, 11co-correlated DEGs were selected. In genes-associated network, 9 significant DEGs were correlated to 23 LINKER genes while, in transcriptional regulatory network, E2F1 had regulatory relationships with 7 DEGs including MTUS1, CD44, CCNB1 and CCND2. KRAS with SNP locus of rs1137282 was involved in 35 KEGG pathways. The genes of MTUS1, CD44, CCNB1, CCND2 and KRAS with specific SNP loci may be used as biomarkers for diagnosis of breast cancer. Besides, E2F1 was recognized as the transcription factor of 7 DEGs including MTUS1, CD44, CCNB1 and CCND2.
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http://dx.doi.org/10.1007/s12253-014-9851-1DOI Listing
April 2015
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