Chromium is a high value metal and the retention of the same during the refining of high carbon ferrochrome as well as high alloy steel has significant economic and environmental impacts. The loss of chromium during the decarburization is generally minimized using argon-oxygen mixtures thereby reducing the oxygen partial pressure (PO2) of the oxidant gas. In the current study, experiments were carried out in an induction furnace and CO2 was introduced with the view to partly reduce PO2 and partly as an oxidizer. During these experiments, the decarburization of molten Cr-alloy was conducted using pure O2, pure CO2 or O2+CO2 mixtures. The results demonstrated that the Cr loss can be minimized under CO2 introduction. The kinetic analysis showed that the mass transfer is effective due to the production of 2CO gas molecules from one CO2 molecule during the reaction which will improve the stirring of the bath. Besides, CO2 reacts with carbon in melt is an endothermic reaction, introduction of CO2 could be a cooler during the refining process, hence the temperature could be controlled by controlling the diluting gas amount, in this case, the over heat of bath refractory could be prevented and the lifetime of refractory could be extended.
DOI : 10.2298/JMMB120813010W Anahtar Kelimeler :
Cr retention, partial pressure, decarburization, temperature control
Cilt: 49 Sayı: 2 Sayfa: 175 - 181
Direct chromium alloying by chromite ore in EAF operation is a promising process in stainless steel production, which has the advantage of resource-saving, energy-saving, and environment-friendly. In the present investigation, iron, carbon, and chromite ore mixture (Fe+C+FeCr2O4) were chosen as the precursor for direct chromium alloying. Thermogravimetric Analysis (TGA) experiments were carried out to investigate the effect of iron content on the reduction kinetics, and the results show that the presence of metallic iron in the precursor will increase the reduction rate of chromite. Up-scaling experiments (100 g and 500 g scale) have been carried out in the induction furnace to further test the effectiveness of using industrial chromite ore for direct chromium alloying. The induction furnace tests confirmed the necessity of adjusting composition of the slags to ensure high yield of chromium in the final products; and chromium yield can reach 90%.
The advantages of using CO2 for the decarburization of high alloy steels have been recognized from environmental and economic view points. The present paper presents the heat and materials balances in the decarburization process with the introduction of CO2 as a diluting gas in Electric Arc Furnace (EAF) process for steel production. The aim is to optimize the amount of CO2 and the materials requirements, which includes the addition of scrap, hot metal and coolant. These estimations are also important to control the bath temperature, thereby prolong the lifetime of the refractory lining of the furnace. The present calculations enable an optimization of the CO2:O2 ratio and materials input in the decarburization of carbon steel melts. Another important extension of the work is the possibility to enhance the addition of hot metal during steel making process. The present results show that addition of up to 20% hot metal is likely to the energy loss due to the introduction of 50% CO2 for a 110 tons EAF resulting in the saving of electric energy.
DOI : 10.2298/JMMB150627002W Anahtar Kelimeler :
heat balance, materials balance, energy saving, electric arc furnace
Cilt: 52 Sayı: 1 Sayfa: 1 - 8
Na Qu,1 Robert J Lee,1,2 Yating Sun,1 Guangsheng Cai,1 Junyang Wang,1 Mengqiao Wang,1 Jiahui Lu,1 Qingfan Meng,1 Lirong Teng,1 Di Wang,1 Lesheng Teng1,3 1School of Life Sciences, Jilin University, Changchun, People’s Republic of China; 2Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH, USA; 3State Key Laboratory of Long-acting and Targeting Drug Delivery System, Yantai, People’s Republic of China Abstract: Cabazitaxel-loaded human serum albumin nanoparticles (Cbz-NPs) were synthesized to overcome vehicle-related toxicity of current clinical formulation of the drug based on Tween-80 (Cbz-Tween). A salting-out method was used for NP synthesis that avoids the use of chlorinated organic solvent and is simpler compared to the methods based on emulsion-solvent evaporation. Cbz-NPs had a narrow particle size distribution, suitable drug loading content (4.9%), and superior blood biocompatibility based on in vitro hemolysis assay. Blood circulation, tumor uptake, and antitumor activity of Cbz-NPs were assessed in prostatic cancer xenograft-bearing nude mice. Cbz-NPs exhibited prolonged blood circulation and greater accumulation of Cbz in tumors along with reduced toxicity compared to Cbz-Tween. Moreover, hematoxylin and eosin histopathological staining of organs revealed consistent results. The levels of blood urea nitrogen and serum creatinine in drug-treated mice showed that Cbz-NPs were less toxic than Cbz-Tween to the kidneys. In conclusion, Cbz-NPs provide a promising therapeutic for prostate cancer. Keywords: cabazitaxel, human serum albumin, nanoparticle, drug delivery, toxicity, prostate cancer
Anahtar Kelimeler :
cabazitaxel, human serum albumin, nanoparticle, drug delivery, toxicity, prostate cancer
Cilt: 2016 Sayı: default Sayfa: 3451 - 3459
Qingping Zhao,1,* Rongbo Qu,2,* Lu Teng,1 Changyou Yin,1 Yuan Yuan11Department of Neurosurgery, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai City, Shandong Province 264000, People’s Republic of China; 2Department of Neurosurgery, Yantai Affiliated Hospital of Binzhou Medical University, Yantai City, Shandong Province 264100, People’s Republic of China *These authors contributed equally to this workObjective: This study aimed to investigate the neuroprotective effect of heme oxygenase-1 (HO-1) on the PI3K/AKT signaling pathway in rats with cerebral hemorrhage.Materials and methods: Adult male Sprague-Dawley rats were randomly divided into: a sham group, a model group and an HO-1 inhibitor group (ZnPP group). Functional defects after surgery were scored according to the Longa5 standard. Hemotoxylin and eosin staining was used to detect whether the model was constructed successfully. Superoxide dismutase (SOD) vitality and malondialdehyde (MDA) content were calculated by the xanthine oxidase method and thiobarbituric acid method, respectively. Blood-brain barrier permeability was measured by Evans Blue. Apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay. The expression of Bcl-2 and BAX was evaluated by immunohistochemistry and the expression of PI3K, p-PI3K, AKT and p-AKT was tested by Western blotting.Results: The rat intracerebral hemorrhage model was successfully constructed. Compared with the model group, the bleeding in the ZnPP group was more serious, the cell edema and deformation were aggravated, and the neurological deficit score in the rat was significantly increased. In addition, the content of Evans blue, MDA, the number of apoptotic cells, the water content of brain tissue and the expression of BAX were significantly increased, while the SOD activity and the expressions of Bcl-2, p-PI3K and p-AKT protein were decreased.Conclusion: HO-1 could protect the nerves of rats with cerebral hemorrhage by regulating the PI3K/AKT signaling pathway.Keywords: PI3K/AKT signaling pathway, HO-1, neuroprotection, hemorrhage
Kuifeng He1, Binbin Cui2, Guangliang Li1, Haohao Wang1, Ketao Jin1, Lisong Teng11Department of Surgical Oncology, First Affiliated Hospital, 2Department of Surgical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, ChinaAbstract: Significant progression has been achieved in the treatment of metastatic colorectal cancer (mCRC) in recent years. This has been partly attributed to successfully incorporating new drugs into combination chemotherapy. In addition to the traditional cytotoxic chemotherapeutic agents, molecularly targeted agents began to play an important role in the treatment of advanced solid tumors. To date, two classes of molecularly targeted agents have been approved for treatment of patients with mCRC: (1) antivascular endothelial growth factor (anti-VEGF) agents (such as bevacizumab and aflibercept) and (2) antiendothelial cell growth factor receptor (anti-EGFR) agents (such as cetuximab and panitumumab). Aflibercept is a new member of anti-VEGF agents which has demonstrated efficacy for treatment of mCRC. With the commencement of clinical trials and basic research into aflibercept, more data from the bedside and the bench have been obtained. This review will outline the application of anti-VEGF agents by reviewing clinic experiences of bevacizumab and aflibercept, and try to add perspectives on the use of anti-VEGF agents in mCRC.Keywords: chemotherapy, tumors, antiangiogenic
Several studies show that nucleosome occupancy patterns around transcription starting sites provide evolutionary and regulatory information about genes. However, as transcription starting sites may not accurately reflect physical nucleosome occupancy patterns, clustering of nucleosome occupancy patterns centered at transcription starting sites may give rise to inaccurate and blurred cluster centers, leading to potentially inaccurate conclusions. In this paper, we propose a joint clustering and alignment method and apply it to clustering of nucleosome occupancy patterns around transcription starting sites. The experimental results using the human genome-wide data show that alignment affects the significant majority of genes and leads to more pronounced local nucleosome occupancy patterns.
Jing Xie,1 Xiaomin Zhang,2 Meiyu Teng,1 Bo Yu,2 Shuang Yang,1 Robert J Lee,1,3 Lesheng Teng1 1College of Life Sciences, Jilin University, Changchun, 2Hangzhou PushiKang Biotechnology Co., Ltd, Hangzhou, People’s Republic of China; 3Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH, USA Abstract: 7-Ethyl-10-hydroxy camptothecin (SN38) is a potent topoisomerase inhibitor and a metabolite of irinotecan. Its clinical development has been hampered by its poor solubility. To address this problem, methoxy poly(ethylene glycol)-2000 (mPEG2K)–SN38 and mPEG2K–poly(lactide) (PLA1.5K)–SN38 conjugates were prepared and then dispersed into an aqueous medium to form micelles. Physicochemical characteristics of SN38–polymer conjugate micelles, for example, micelle diameter, zeta potential, morphology, and drug content, were then evaluated. The results showed that the mean diameters of mPEG2K–SN38 and mPEG2K–PLA1.5K–SN38 micelles were ~130 and 20 nm, respectively. These two micelles had similar drug contents. mPEG2K–PLA1.5K–SN38 micelles were more homogeneous than mPEG2K–SN38 micelles. Moreover, in vitro drug release behavior of the micelles was studied by high performance liquid chromatography. SN38 release from mPEG2K–SN38 micelles was much faster than from mPEG2K–PLA1.5K–SN38 micelles. In vitro cytotoxicity, cellular uptake, and apoptosis assays of the SN38–polymer conjugate micelles were carried out on BEL-7402 human liver cancer cells. In vivo biodistribution and antitumor tumor efficacy studies were carried out in a nude mouse xenograft model derived from BEL-7402 cells. The results showed that mPEG2K–PLA1.5K–SN38 micelles were significantly more effective than mPEG2K–SN38 micelles in tumor inhibition, and the inhibitory effect of mPEG2K–PLA1.5K–SN38 micelles on tumor growth was significantly greater than that of mPEG2K–SN38 micelles (1,042 vs 1,837 mm) at 30 days. In conclusion, mPEG–PLA–SN38 is a promising anticancer agent that warrants further investigation. Keywords: SN38, polymer conjugate, micelles, chemotherapy, liver cancer
Xingyun Su,1 Xiaoxia Jiang,1 Xin Xu,1 Weibin Wang,1 Xiaodong Teng,2 Anwen Shao,3 Lisong Teng1 1Department of Surgical Oncology, 2Department of Pathology, First Affiliated Hospital, 3Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China Abstract: Fine-needle aspiration (FNA) is a reliable method for preoperative diagnosis of thyroid nodules; however, about 10%–40% nodules are classified as indeterminate. The BRAFV600E mutation is the most promising marker for thyroid FNA. This meta-analysis was conducted to investigate the diagnostic value of BRAFV600E analysis in thyroid FNA, especially the indeterminate cases. Systematic searches were performed in PubMed, Web of Science, Scopus, Ovid, Elsevier, and the Cochrane Library databases for relevant studies prior to June 2015, and a total of 88 studies were ultimately included in this meta-analysis. Compared with FNA cytology, the synergism of BRAFV600E testing increased the diagnostic sensitivity from 81.4% to 87.4% and decreased the false-negative rate from 8% to 5.2%. In the indeterminate group, the mutation rate of BRAFV600E was 23% and varied in different subcategories (43.2% in suspicious for malignant cells [SMC], 13.77% in atypia of undetermined significance/follicular lesion of undetermined significance [AUS/FLUS], and 4.43% in follicular neoplasm/suspicious for follicular neoplasm [FN/SFN]). The sensitivity of BRAFV600E analysis was higher in SMC than that in AUS/FLUS and FN/SFN cases (59.4% vs 40.1% vs 19.5% respectively), while specificity was opposite (86.1% vs 99.5% vs 99.7% respectively). The areas under the summary receiver-operating characteristic curve also confirmed the diagnostic value of BRAFV600E testing in SMC and AUS/FLUS rather than FN/SFN cases. Therefore, BRAFV600E analysis can improve the diagnostic accuracy of thyroid FNA, especially indeterminate cases classified as SMC, and select malignancy to guide the extent of surgery. Keywords: thyroid cancer, fine-needle aspiration, BRAFV600E mutation, meta-analysis
Nucleosome position plays a key role in eukaryotic gene regulation, and its precise measurement is critical to understanding all DNA-templated events, but insufficient information has been available to infer nucleosome position at single-base-pair (1-bp) resolution. Brogaard et al. therefore developed an in vivo nucleosome-mapping method, based on the direct incorporation of a label into the nucleosome core, that generates hydroxyl radicals that cleave nucleosomal DNA at defined positions. This method allows direct measurement of nucleosome position with unmatched accuracy. Here we present a new algorithm that uses the Brogaard et al. data to achieve 1-bp resolution by using a joint cleavage pattern of radicals on Watson and Crick strands and can localize nucleosomes that are adjacent to each other. This algorithm provides the highest-resolution nucleosome-position maps to date and will allow detailed analysis of chromatin organization and protein-interaction dynamics.
Xiaoxia Jiang,1,2 Mengjie Wu,1,2 Zhenzhen Xu,1,2 Haohao Wang,1,2 Haiyong Wang,1,2 Xiongfei Yu,1 Zhongqi Li,1 Lisong Teng1,2 1Department of Surgical Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 2Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, People’s Republic of China Background: Aberrant activation of the signal transducer and activator of transcription 3 (STAT3) is frequently seen in patients with gastric cancer (GC), and is generally associated with worse prognosis. HJC0152, a novel STAT3 inhibitor, has shown significant anti-tumor effects in several cancers, although its role in GC remains to be clarified. Methods: The effect of HJC0152 on STAT3 signaling pathway and the biological behaviors of GC cells were evaluated through in vitro and/or in vivo experiments. Meanwhile, RNA sequence analysis was used to further explore its potential anti-tumor mechanisms.Results: HJC0152 inhibited the expression of activated STAT3 and its downstream target genes (c-Myc and clyclinD1) in GC cells, and restrained tumor growth in vivo. HJC0152 treatment induced apoptosis in the STAT3 hyper-activated AGS and MKN45 cell lines, along with down-regulation of survivin and Mcl1, and up-regulation of cleaved-poly(ADP-ribose) polymerase. Moreover, HJC0152 markedly inhibited migration and invasion of these cells. Finally, RNA sequence analysis and protein expression analyses showed that in addition to STAT3 suppression, HJC0152 also exerts its anti-tumor effects at least partly via the mitogen-activated protein kinases pathway. Conclusion: Our findings highlight that HJC0152 is a promising therapeutic agent for GC. Keywords: gastric cancer, inhibitor, HJC0152, STAT3, MAPK
Safia Naz,1,* Mingyu Wang,1,* Yuning Han,1 Bin Hu,1 Liping Teng,2 Juan Zhou,1 Huijie Zhang,1 Jinghua Chen11Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Pharmaceutical Sciences, Jiangnan University, Wuxi, People’s Republic of China; 2Wuxi School of Medicine, Jiangnan University, Wuxi, People’s Republic of China*These authors contributed equally to this workBackground: Drug delivery systems (DDS) capable of targeting both cell and organelle levels are highly desirable for effective cancer therapy. In this study, we developed a novel enzyme-responsive, multistage-targeted anticancer DDS based on mesoporous silica nanoparticles (MSNs), which possessed both CD44-targeting and mitochondrial-targeting properties.Materials and methods: Triphenylphosphine (TPP), a mitochondria-targeting compound, was grafted onto the surface of MSNs firstly. Then, Doxorubicin (Dox) was encapsulated into the pore of MSNs, followed by capping with tumor-targeting molecules hyaluronic acid (HA) through electrostatic interactions to form the final product consist of Dox loaded, TPP attached, HA capped mesoporous silica nanoparticles (MSN-DPH).Results: Our results suggested that MSN-DPH was preferentially taken up by cancer cells via CD44 receptor-mediated endocytosis. Moreover, MSN-DPH mainly accumulated in mitochondria owing to the mitochondrial-targeting ability of TPP. Degradation of HA by overexpressed HAase facilitated the release of Dox in cancer cells. Thus, MSN-DPH efficiently killed the cancer cells while exhibited much lower cytotoxicity to normal cells.Conclusion: This study demonstrates a promising multistage-targeted DDS for cancer chemotherapy.Keywords: mesoporous silica nanoparticles, drug delivery, enzyme-responsive, multistage-targeting, cancer therapy
Jiaxin Liu, Xueyan Zhang, Ge Li, Fei Xu, Shuang Li, Lesheng Teng, Youxin Li, Fengying Sun School of Life Sciences, Jilin University, Changchun, Jilin, People’s Republic of ChinaCorrespondence: Youxin Li; Fengying SunSchool of Life Sciences, Jilin University, 2699 Qianjin Street, Changchun, Jilin 130012, People’s Republic of ChinaTel/Fax +86 431 8515 5320Email firstname.lastname@example.org; email@example.comPurpose: Age-related macular degeneration is a multifactorial disease involving inflammation and choroidal neovascularization. Vascular endothelial growth factor (VEGF) has been regarded as a potential therapeutic target to treat choroidal neovascularization. Dexamethasone can interfere with the expression or action of VEGF while bevacizumab targets and combines with VEGF. We propose electrostatically-conjugated bevacizumab-bearing dexamethasone-loaded poly (D,L-lactide-co-glycolide)/polyethylenimine nanoparticles (eBev-DPPNs) for angiogenic combination treatment of ocular diseases.Methods: We prepared a novel nanoparticle composed of poly (D, L-lactide-co-glycolide) and polyethylenimine and loaded the nanoparticles with dexamethasone. Bevacizumab was adsorbed onto the surfaces of the nanoparticles by electrostatic interactions. The eBev-DPPNs were evaluated according to their size, polydispersity index, zeta potential, morphology, drug loading, release behavior, and stability. The structural stability of bevacizumab on the surface of the nanoparticles was also analyzed. Subsequently, angiogenesis was investigated in the presence of the eBev-DPPNs using cell apoptosis, wound healing, Transwell invasion, and tube formation assays on the human umbilical vein endothelial cells (HUVECs) in vitro and chick embryo chorioallantoic membrane assay in vivo. The eBev-DPPNs intravitreal injection was applied in the laser-induced rabbit choroidal neovascularization (CNV) model to confirm the role for potential intravitreal applications.Results: The eBev-DPPNs was about 200 nm in diameter, with a narrow diameter distribution, and the surface charge was neutral (0.85 ± 0.37mV), which made the eBev-DPPNs stable under physiological conditions. The apoptosis, migration, invasion, and tube formation assays showed that the eBev-DPPNs had a good anti-angiogenic effect on HUVECs. The eBev-DPPNs also provided a strong inhibitory effect on VEGF secretion from HUVECs. Moreover, in vivo chick embryo chorioallantoic membrane assay showed eBev-DPPNs greatly reduced the amount of blood vessels. The leakage area of CNV decreased in the eBev-DPPNs group on rabbit CNV model.Conclusion: The eBev-DPPNs are a promising novel anti-angiogenesis therapeutic for potential intravitreal applications such as age-related macular degeneration.Keywords: nanoparticles, dexamethasone, bevacizumab, anti-angiogenesis, VEGF
Junbin Zhang, Jiayin Ruan, Weibin Wang, Yimin Lu, Haiyong Wang, Xiongfei Yu, Haohao Wang, Lisong Teng Department of Surgical Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People’s Republic of ChinaCorrespondence: Haohao Wang; Lisong Teng Tel/Fax +86 57187236881Email firstname.lastname@example.org; email@example.comPurpose: To investigate the prognostic value of combined serum carcinoembryonic antigen (CEA) levels and fibrinogen/albumin ratio (FAR) in patients with resectable gastric cancer (GC).Introduction: This retrospective study evaluated the CEA, fibrinogen, and albumin levels and other clinicopathological features of GC patients. The prognostic significance of these factors for overall survival (OS) was assessed using Kaplan–Meier curves and univariate and multivariate Cox proportional models.Patients and Methods: A total of 267 patients were included. The optimal cutoff values of CEA and FAR were 3.2 ng/mL and 0.086, respectively. Patients were stratified into three groups based on this cutoff value: CEA-FAR=0 (CEA < 3.2 ng/mL and FAR < 0.086), CEA-FAR=1 (CEA ≥ 3.2 ng/mL or FAR ≥ 0.086), and CEA-FAR=2 (CEA ≥ 3.2 ng/mL and FAR ≥ 0.086).Results: Higher CEA-FAR was strongly associated with age, tumor size, tumor invasion, lymph node status, and TNM stage (all P< 0.05). The OS rates differed significantly between these 3 groups (88.9% vs 65.0% vs 46.9%, P< 0.001). Multivariate analysis showed that CEA-FAR was an independent prognostic factor for OS (P< 0.001). The area under the curve was larger for CEA-FAR than for either CEA or FAR alone (0.683, 0.644, and 0.669, respectively).Conclusion: Preoperative CEA-FAR could be a potential blood marker for predicting tumor progression and the prognosis of GC patients. Patients with a higher CEA-FAR should undergo extensive follow-up.Keywords: gastric carcinoma, patients, survival, risk factor
Zhonghai Guan,1 Xiongfei Yu,1 Haohao Wang,1 Haiyong Wang,1 Jing Zhang,1 Guangliang Li,2 Jiang Cao,3 Lisong Teng1 1Department of Surgical Oncology, First Affiliated Hospital, College of Medicine, Zhejiang University, 2Department of Medicine Oncology, Zhejiang Cancer Hospital, 3Clinical Research Center, The 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China Abstract: Liposarcoma (LPS) is the most common type of soft-tissue sarcoma. Complete surgical resection is the only curative means for localized disease; however, both radiation and conventional cytotoxic chemotherapy remain controversial for metastatic or unresectable disease. An increasing number of trials with novel targeted therapy of LPS have provided encouraging data during recent years. This review will provide an overview of the advances in our understanding of LPS and summarize the results of recent trials with novel therapies targeting different genetic and molecular aberrations for different subtypes of LPS. Keywords: well-/dedifferentiated, myxoid/round cell, pleomorphic, soft-tissue sarcoma
Xingyun Su,1 Xiaoxia Jiang,1 Weibin Wang,1 Haiyong Wang,1 Xin Xu,2 Aihui Lin,1 Xiaodong Teng,3 Huiling Wu,4 Lisong Teng1 1Department of Surgical Oncology, 2Department of Medical Oncology, 3Department of Pathology, 4Department of Plastic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China Abstract: The clinicopathological and prognostic significance of telomerase reverse transcriptase (TERT) promoter mutations have been widely investigated in thyroid cancer; however, the results are still discrepant. Systematic searches were performed in PubMed, Web of Science, Scopus, Ovid, and the Cochran Library databases for relevant articles prior to April 2016. Mutation rates were synthesized by R statistical software. The odds ratio or standardized mean difference with 95% confidence interval was pooled by Stata. A total of 22 studies with 4,907 cases were included in this meta-analysis. TERT promoter mutations tended to present in aggressive histological types including poorly differentiated thyroid cancer (33.37%), anaplastic thyroid cancer (38.69%), and tall-cell variant papillary thyroid cancer (30.23%). These promoter mutations were likely to exist in older patients and males and were well associated with larger tumor size, extrathyroidal extension, vascular invasion, lymph node metastasis, distant metastasis, advanced tumor stage, disease recurrence/persistence, and mortality. In addition, TERT promoter mutations (especially C228T) tended to coexist with BRAFV600E mutation, which indicated more aggressive tumor behavior. Therefore, TERT promoter mutations may be promising biomarkers for early diagnosis, risk stratification, prognostic prediction, and management of thyroid cancer. Keywords: TERT promoter mutations, thyroid cancer, clinicopathological features, prognosis, BRAFV600E mutation
Ye Bi,1 Robert J Lee,1,2 Xinyu Wang,1 Yating Sun,1 Mengqiao Wang,1 Lianlian Li,1 Chenliang Li,1 Jing Xie,1 Lesheng Teng1 1School of Life Sciences, Jilin University, Changchun, Jilin, People’s Republic of China; 2Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH, USA Purpose: A liposome-based siRNA–drug combination was evaluated as a potential therapeutic strategy to improve the curative effect. Methods: A topoisomerase inhibitor SN38 prodrug was combined with a survivin siRNA through codelivery using transferrin (Tf)-L-SN38/P/siRNA. In this combination, SN38 was conjugated to the cell penetrating peptide TAT through a polyethylene glycol (PEG) linker to synthesize TAT-PEG-SN38. The amphiphilic TAT-PEG-SN38 was used as an ingredient of liposomes to improve the cellular uptake. Protamine was added to form an electrostatic complex with siRNA in the core of the liposomes. Tf was introduced to enable tumor cell targeting of liposomes (Tf-L-SN38/P/siRNA). Results: Tf-L-SN38/P/siRNA exhibited a particle size of 148 nm and a ζ-potential of +7.8 mV. The cellular uptake and antitumor activity were dependent on Tf receptor targeting, TAT-PEG-SN38, and siRNA codelivery. Tf-L-SN38/P/siRNA was shown to be considerably more effective than liposomes carrying individual components. This combination induced potent tumor inhibition (76.8%) in HeLa cell xenograft tumor-bearing nude mice. Conclusion: These data indicated that Tf-L-SN38/P/siRNA was an effective system for codelivery of SN38 and a survivin siRNA and that its therapeutic potential deserved further evaluation. Keywords: SN38, survivin, siRNA, transferrin, prodrug
Jinlong Zhao,1 Menghui Zhao,1 Changhui Yu,1 Xueyan Zhang,1 Jiaxin Liu,1 Xinwei Cheng,2 Robert J Lee,1,2 Fengying Sun,1 Lesheng Teng,1 Youxin Li1 1School of Life Sciences, Jilin University, Changchun, China; 2College of Pharmacy, Ohio State University, Columbus, OH, USA Abstract: Rheumatoid arthritis (RA) is an autoimmune disease characterized by progressive cartilage and bone destruction. Activated macrophages that overexpress folic acid (FA) receptors play an important role in RA, due to their abundance in inflamed synovial membrane and joints. In an effort to deliver drugs to the inflamed tissues, multifunctional FA receptor-targeting and pH-responsive nanocarriers were developed. They were composed of lipids, polyethylene glycol (PEG)–poly(lactic-co-glycolic acid) (PLGA) forming a hydrophilic shell, FA around the hydrophilic shell as a targeting ligand, and poly(cyclohexane-1,4-diylacetone dimethylene ketal) (PCADK) and PLGA as a hydrophobic core. PCADK also acts as a pH-responsive material. Methotrexate (Mtx) was encapsulated in the nanoparticles, which exhibited pH-responsive release in vitro. Cellular uptake and cytotoxicity experiments revealed that FA-PEG-PLGA/PCADK–lipid nanoparticles loaded with Mtx (FA-PPLNPs) exhibited superior cellular uptake and higher cytotoxicity to activated macrophages than PPLNPs/Mtx. The therapeutic effect of FA-PPLNPs/Mtx in RA was confirmed in an adjuvant-induced arthritis rat model. These results suggest that the multifunctional folate receptor-targeting and pH-responsive nanocarriers are promising for the treatment of RA. Keywords: rheumatoid arthritis, methotrexate, nanoparticles, folate, pH-responsive, PCADK
Context Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder as a result of mutation in genes encoding either the ACTH receptor [melanocortin 2 receptor (MC2R)] or its accessory protein [melanocortin 2 receptor accessory protein (MRAP)]. The disorder is known as FGD type 1 and 2, respectively.
Minglong Wang,1,* Yanxi Luo,2,* Ting Sun,2 Chenyu Mao,1 Yili Jiang,2 Xiongfei Yu,1 Zhongqi Li,1 Tian Xie,3 Fusheng Wu,1 Hui Yan,2,3 Lisong Teng1 1Department of Surgical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 2Institute of Materia Medica, Zhejiang Academy of Medical Sciences, Hangzhou, People’s Republic of China; 3Holistic Integrative Pharmacy Institutes, Hangzhou Normal University, Hangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lisong TengDepartment of Surgical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, People’s Republic of ChinaEmail firstname.lastname@example.orgHui YanInstitute of Materia Medica, Zhejiang Academy of Medical Sciences, Hangzhou 310013, People’s Republic of ChinaEmail email@example.comBackground/Aims: Anti-tumor vaccines have been shown to be effective in cancer therapeutics ever since the anti-HPV vaccine was developed. Compared to conventional chemotherapy, anti-tumor vaccines can specifically target cancer cells and they have lower side effects. We developed a recombinant vaccinia virus (VACV) (Western Reserve) WR strain, and we tested its anti-tumor effects in an animal model.Methods: A recombinant VACV WR strain expressing mutant survivin T34A (SurT34A) and FilC was constructed and validated. Its oncolytic effect was tested in vitro using a CCK-8 assay, and its tolerance and anti-tumor effects were tested in a murine gastric cancer model. The proportion of lymphocytes in the spleen and tumor was determined after antibody-mediated immuno-depletion.Results: The recombinant VACV showed a stronger replication ability in tumor cells, and it was safe in vivo, even at high doses. The combination of vv-SurT34A and vv-FilC resulted in a stronger anti-tumor effect compared to either construct alone. However, the inhibitory effect of vv-SurT34A was stronger than the combination. The recombinant VACV activated the host immune response, as indicated by lymphocyte infiltration in the spleen and tumor tissues.Conclusion: The recombinant VACV WR strain expressing SurT34A and FilC is a safe and effective anti-tumor vaccine.Keywords: vaccinia virus WR strain, survivin T34A, FilC, anti-tumor effect
Yating Sun,1 Yarong Zhao,1 Shanshan Teng,1 Fei Hao,1 Huan Zhang,1 Fanchao Meng,1 Xiuting Zhao,1 Xiaolong Zheng,1 Ye Bi,1 Yicheng Yao,2 Robert J Lee,1,3 Lesheng Teng1 1School of Life Sciences, Jilin University, Changchun, Jilin, China; 2Acalanes High School, Lafayette, CA, USA; 3Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH, USA Background: We previously developed cabazitaxel (CTX)-loaded human serum albumin nanoparticles (NPs-CTX) via a self-assembly method, and these NPs showed efficacy in prostate cancer therapy. Many studies have shown that the levels of folic acid (FA) receptor on the surface of various tumor cells are high. Therefore, FA-modified NPs-CTX may have enhanced antitumor effects compared with unmodified NPs-CTX. Methods: NPs-CTX were first prepared via self-assembly, and FA was conjugated on the surface of NPs-CTX through the -NH2 groups of the NPs to produce FA-NPs-CTX. The FA-NPs-CTX were evaluated in tumor cells with high FA receptor (FR) expression in vitro and in vivo. Results: Both NPs-CTX and FA-NPs-CTX exhibited good stability and morphology. Drug release from the NPs was not affected by FA conjugation. Compared with CTX dissolved in a mixture of Tween 80 and 13% ethanol (w/w) at a ratio of 1:4 (v/v) (Tween-CTX), the two nanoformulations had lower lytic activity against normal red blood cells. However, FA-NPs-CTX showed greater inhibition of tumor cells with overexpressed FR, compared with NPs-CTX, in the cytotoxicity experiments. Moreover, the cellular uptake of FA-NPs-CTX was enhanced through FR-mediated endocytosis in HeLa cells in vitro and HeLa xenograft tumors in vivo. Although Tween-CTX exhibited tumor growth inhibition similar to FA-NPs-CTX in vivo, this inhibition also caused adverse side effects; the median lethal dose (LD50) of Tween-CTX to mice was 5.68 mg/kg, while FA-NPs-CTX-treated mice survived at doses exceeding 400 mg/kg. Conclusion: The results showed that FA-NPs-CTX caused inhibition of tumor growth in a manner similar to that of Tween-CTX; however, the safety and tolerability of CTX were greatly improved by FA conjugation compared with those of Tween-CTX. In summary, FA-NPs-CTX have great potential in CTX delivery, and this formulation is a promising candidate for the treatment of cancers with high FR levels. Keywords: folic acid, human serum albumin, nanoparticles, cabazitaxel, folic acid receptor