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1.  Lunasin Alleviates Allergic Airway Inflammation while Increases Antigen-Specific Tregs 
PLoS ONE  2015;10(2):e0115330.
Lunasin is a naturally occurring peptide isolated from soybeans and has been explored in cancer treatment. Lunasin inhibits NF-κB activation and thus pro-inflammatory cytokine and mediator production in macrophages. In this study we demonstrate that lunasin can effectively suppress allergic airway inflammation in two murine models of asthma. In an OVA+Alum sensitization model, intranasal lunasin treatment at the time of OVA challenges significantly reduced total cells counts in bronchoalveolar lavage (BAL) fluid and eosinophilia, peribronchiolar inflammatory infiltration, goblet cell metaplasia and airway IL-4 production. In an OVA+LPS intranasal sensitization model, lunasin treatment either at the time of sensitization or challenge has similar effects in suppress allergic airway inflammation including significantly reduced total cell and eosinophil counts in BAL fluid, inflammatory gene Fizz1 expression in the lung, and IL-4 production by OVA re-stimulated cells from mediastinal lymph nodes. We further show that intranasal instillation of OVA+lunasin significantly increases OVA-specific regulatory T cell (Treg) accumulation in the lung comparing to OVA only treatment. Taken together, our results suggest lunasin as an anti-inflammatory agent can be potentially used in asthma therapy or as an adjuvant to enhance the induction of antigen-specific Tregs and thus boost the efficacy of allergy immunotherapy.
doi:10.1371/journal.pone.0115330
PMCID: PMC4315393  PMID: 25646897
2.  In Situ Nitrogen Mineralization, Nitrification, and Ammonia Volatilization in Maize Field Fertilized with Urea in Huanghuaihai Region of Northern China 
PLoS ONE  2015;10(1):e0115649.
Nitrogen (N) fertilization potentially affects soil N mineralization and leaching, and can enhance NH3 volatilization, thus impacting crop production. A fertilizer experiment with five levels of N addition (0, 79, 147, 215 and 375 kg N ha-1) was performed in 2009 and 2010 in a maize field in Huanghuaihai region, China, where > 300 kg N ha-1 has been routinely applied to soil during maize growth period of 120 days. Responses of net N mineralization, inorganic N flux (0–10cm), NH3 volatilization, and maize yield to N fertilization were measured. During the growth period, net N mineralization and nitrification varied seasonally, with higher rates occurring in August and coinciding with the R1 stage of maize growth. Soil NO3−-N contributed to more than 60% of inorganic N flux during maize growth. Cumulative NH3 volatilization increased with N additions, with total NH3 volatilization during maize growth accounting for about 4% of added N. Relative to the control, mean maize yield in the fertilizer treatments increased by 17% and 20% in 2009 and 2010, respectively. However, grain yield, aboveground biomass, and plant N accumulation did not increase with added N at levels > 215 kg N ha-1. These results suggest that the current N rate of 300 kg N ha-1 is not only excessive, but also reduces fertilizer efficacy and may contribute to environmental problems such as global warming and eutrophication of ground water and streams.
doi:10.1371/journal.pone.0115649
PMCID: PMC4311962  PMID: 25635864
3.  Centralized isolation of Helicobacter pylori from multiple centers and transport condition influences 
AIM: To evaluate the efficacy of centralized culture and possible influencing factors.
METHODS: From January 2010 to July 2012, 66452 patients with suspected Helicobacter pylori (H. pylori) infection from 26 hospitals in Zhejiang and Jiangsu Provinces in China underwent gastrointestinal endoscopy. Gastric mucosal biopsies were taken from the antrum for culture. These biopsies were transported under natural environmental temperature to the central laboratory in Hangzhou city and divided into three groups based on their transport time: 5, 24 and 48 h. The culture results were reported after 72 h and the positive culture rates were analyzed by a χ2 test. An additional 5736 biopsies from H. pylori-positive patients (5646 rapid urease test-positive and 90 14C-urease breath test-positive) were also cultured for quality control in the central laboratory setting.
RESULTS: The positive culture rate was 31.66% (21036/66452) for the patient samples and 71.72% (4114/5736) for the H. pylori-positive quality control specimens. In the 5 h transport group, the positive culture rate was 30.99% (3865/12471), and 32.84% (14960/45553) in the 24 h transport group. In contrast, the positive culture rate declined significantly in the 48 h transport group (26.25%; P < 0.001). During transportation, the average natural temperature increased from 4.67 to 29.14 °C, while the positive culture rate declined from 36.67% (1462/3987) to 24.12% (1799/7459). When the temperature exceeded 24 °C, the positive culture rate decreased significantly, especially in the 48 h transport group (23.17%).
CONCLUSION: Transportation of specimens within 24 h and below 24 °C is reasonable and acceptable for centralized culture of multicenter H. pylori samples.
doi:10.3748/wjg.v21.i3.944
PMCID: PMC4299348  PMID: 25624729
Centralized isolation; Helicobacter pylori; Influencing factor; Multiple centers; Personalized treatment
4.  Efficacy of prophylactic intravenous ondansetron on the prevention of hypotension during cesarean delivery: a dose-dependent study 
Objective: This study was to determine the optimal dosage of ondansetron for preventing maternal hypotension during cesarean delivery. Methods: One hundred and fifty parturient women scheduled for elective cesarean section were randomly assigned to five groups (n=30). Five minutes prior to spinal anesthesia, women were injected with 5 ml of physiological saline (S), 2 mg (O2), 4 mg (O4), 6 mg (O6), or 8 mg (O8) of ondansetron in saline, respectively. Maternal blood pressure and heart rate were measured at 2-min intervals for 30 min. The serum parameters in umbilical cord blood were analyzed after delivery. Results: Compared with group S, the incidence of maternal hypotension was significantly lower in groups O4 and O6 (P < 0.05). The umbilical venous pH was significantly higher in group O4 (P < 0.05); while the partial pressure of carbon dioxide (Pco2) was significantly lower in groups O4, O6, and O8 (P < 0.05); and the bicarbonate (Hco3 -) and base excess in extracellular fluid (BEecf) were significantly lower in groups O6 and O8 (P < 0.05). Moreover, minimal changes of systolic blood pressure, diastolic blood pressure, and mean arterial blood pressure were observed in group O4 (P < 0.05). Conclusion: The optimal dose of ondansetron preloading was 4 mg during cesarean delivery.
PMCID: PMC4307470  PMID: 25664023
Ondansetron; hypotension; spinal anesthesia; optimal dose
5.  Programmed Cell Death-4 Deficiency Prevents Diet-Induced Obesity, Adipose Tissue Inflammation, and Insulin Resistance 
Diabetes  2013;62(12):4132-4143.
Programmed cell death-4 (PDCD4), a selective protein translation inhibitor, has shown proinflammatory effect in some inflammatory diseases, but its roles in obesity remain unestablished. This study aims to investigate the effects of PDCD4 on obesity, inflammation, and insulin resistance. Surprisingly, high-fat diet (HFD)-fed PDCD4-deficient (PDCD4−/−) mice exhibited an absolutely lean phenotype together with improved insulin sensitivity. Compared with wild-type obese mice, HFD-fed PDCD4−/− mice showed higher energy expenditure, lower epididymal fat weight, and reduced macrophage infiltration inflammatory cytokine secretion in white adipose tissue (WAT). Alleviated hepatic steatosis along with decreased plasma levels of triglyceride and cholesterol was also observed in these mice. Importantly, PDCD4 appeared to disturb lipid metabolism via inhibiting the expression of liver X receptor (LXR)-α, a master modulator of lipid homeostasis, which was elevated in HFD-fed PDCD4−/− mice accompanied by upregulation of its target genes and relieved endoplasmic reticulum stress in WAT. These data demonstrate that PDCD4 deficiency protects mice against diet-induced obesity, WAT inflammation, and insulin resistance through restoring the expression of LXR-α, thereby proposing PDCD4 as a potential target for treating obesity-associated diseases.
doi:10.2337/db13-0097
PMCID: PMC3837052  PMID: 23990362
6.  Hybrid Hydroxyapatite Nanoparticle Colloidal Gels are Injectable Fillers for Bone Tissue Engineering 
Tissue Engineering. Part A  2013;19(23-24):2586-2593.
Injectable bone fillers have emerged as an alternative to the invasive surgery often required to treat bone defects. Current bone fillers may benefit from improvements in dynamic properties such as shear thinning during injection and recovery of material stiffness after placement. Negatively charged inorganic hydroxyapatite (HAp) nanoparticles (NPs) were assembled with positively charged organic poly(d,l-lactic-co-glycolic acid) (PLGA) NPs to create a cohesive colloidal gel. This material is held together by electrostatic forces that may be disrupted by shear to facilitate extrusion, molding, or injection. Scanning electron micrographs of the dried colloidal gels showed a well-organized, three-dimensional porous structure. Rheology tests revealed that certain colloidal gels could recover after being sheared. Human umbilical cord mesenchymal stem cells were also highly viable when seeded on the colloidal gels. HAp/PLGA NP colloidal gels offer an attractive scheme for injectable filling and regeneration of bone tissue.
doi:10.1089/ten.tea.2013.0075
PMCID: PMC3856930  PMID: 23815275
7.  Uniportal video-assisted thoracoscopic surgery right upper lobectomy with systematic lymphadenectomy in a semiprone position 
Journal of Thoracic Disease  2014;6(12):1840-1842.
A 53-year-old male smoker was referred to our hospital with an enlarged lesion in the right upper lung. Computed tomography (CT) showed a 1.5 cm solid lesion with pleural indentation in the right upper lobe adjacent to the oblique fissure. The preoperative clinical diagnosis was stage I primary lung cancer. Uniportal video-assisted thoracoscopic surgery (VATS) right upper lobectomy in a semiprone position was performed in this case. Frozen section examination confirmed the diagnosis of lung adenocarcinoma, and systematic lymphadenectomy was then performed. A chest tube was placed at the posterior part of the incision through the dorsal thoracic cavity to the apex. The postoperative pathologic diagnosis was T2aN0M0 adenocarcinoma.
doi:10.3978/j.issn.2072-1439.2014.11.22
PMCID: PMC4283289  PMID: 25589986
Video-assisted thoracoscopic surgery (VATS); uniportal; lobectomy; lung cancer; lymphadenectomy
8.  Video-assisted thoracic surgery left upper lobectomy with systematic lymphadenectomy 
Journal of Thoracic Disease  2014;6(12):1848-1850.
A 43-year-old man was referred to our hospital after chest computed tomography revealed a 2.5-cm mixed ground-glass opacity peripherally in the left upper lobe of the lung. No metastasis or contraindication for surgery was found. Video-assisted thoracic surgery (VATS) left upper lobectomy was performed, and analysis of the intraoperative frozen section confirmed the diagnosis of adenocarcinoma. Subsequently, systematic lymphadenectomy was performed. By using this method, suction and harmonic scalpel were the only two major instruments needed throughout the operation. The use of suction ensures a clear view, and the harmonic scalpel functions as a combined dissector, grasper, and cutter, which helps avoid changing instruments during the surgery and saves time. Moreover, the use of this technique for three-port VATS lobectomy facilitates the conversion into single-port VATS if needed.
doi:10.3978/j.issn.2072-1439.2014.11.38
PMCID: PMC4283305  PMID: 25589988
Video-assisted thoracic surgery (VATS); lobectomy; lung cancer; harmonic scalpel
9.  Uniportal video assisted thoracoscopic lobectomy: primary experience from an Eastern center 
Journal of Thoracic Disease  2014;6(12):1751-1756.
Background
Uniportal video-assisted thoracoscopic surgery (VATS) lobectomy is an emerging technique for the surgical resection of non-small cell lung cancer (NSCLC). Besides its wide debates on safety and efficacy throughout the world, there were few report on uniportal VATS from the Eastern countries. In this article, we summarized our primary experience on uniportal VATS lobectomy in an Eastern center.
Methods
From October 2013 till February 2014, 54 consecutive uniportal VATS lobectomy were performed in the Department of Thoracic Surgery, Zhongshan Hospital of Fudan University. Patients’ clinical features and operative details were recorded. Post-operatively, the morbidity and mortality were recorded to analyze the safety and efficacy of uniportal VATS lobectomy for NSCLCs.
Results
Among the 54 planned uniportal VATS lobectomy, there was one conversion to mini-thoracotomy due to lymph node sticking. Extra ports were required in two patients. The uniportal VATS lobectomy was achieved in 51 out of 54 patients (94.4%). The average operation duration was 122.2±37.5 min (90-160 min). The average volume of estimated blood loss during the operation was 88.8±47.1 mL (50-200 mL). The mean chest tube duration and hospital stay were 3.2±1.9 days and 4.6±2.0 days, respectively. There was no postoperative mortality in this study. Two patients suffered from prolonged air leakage (5 and 7 days), and one atrial fibrillation was observed in this cohort.
Conclusions
Based on our primary experience, uniportal VATS lobectomy is a safe and effective procedure for the surgical resection of NSCLCs. The surgical refinements and instrumental improvements would facilitate the technique. Further studies based on larger population are required to determine its benefits towards patients with NSCLCs.
doi:10.3978/j.issn.2072-1439.2014.11.20
PMCID: PMC4283325  PMID: 25589969
Lobectomy; minimally invasive surgery; non-small-cell-lung carcinoma (NSCLC)
10.  Selection of Reference Genes for Quantitative Real-Time PCR Normalization in Panax ginseng at Different Stages of Growth and in Different Organs 
PLoS ONE  2014;9(11):e112177.
Quantitative real-time reverse transcription PCR (qRT-PCR) has become a widely used method for gene expression analysis; however, its data interpretation largely depends on the stability of reference genes. The transcriptomics of Panax ginseng, one of the most popular and traditional ingredients used in Chinese medicines, is increasingly being studied. Furthermore, it is vital to establish a series of reliable reference genes when qRT-PCR is used to assess the gene expression profile of ginseng. In this study, we screened out candidate reference genes for ginseng using gene expression data generated by a high-throughput sequencing platform. Based on the statistical tests, 20 reference genes (10 traditional housekeeping genes and 10 novel genes) were selected. These genes were tested for the normalization of expression levels in five growth stages and three distinct plant organs of ginseng by qPCR. These genes were subsequently ranked and compared according to the stability of their expressions using geNorm, NormFinder, and BestKeeper computational programs. Although the best reference genes were found to vary across different samples, CYP and EF-1α were the most stable genes amongst all samples. GAPDH/30S RPS20, CYP/60S RPL13 and CYP/QCR were the optimum pair of reference genes in the roots, stems, and leaves. CYP/60S RPL13, CYP/eIF-5A, aTUB/V-ATP, eIF-5A/SAR1, and aTUB/pol IIa were the most stably expressed combinations in each of the five developmental stages. Our study serves as a foundation for developing an accurate method of qRT-PCR and will benefit future studies on gene expression profiles of Panax Ginseng.
doi:10.1371/journal.pone.0112177
PMCID: PMC4230945  PMID: 25393243
11.  Spatial Variation in Carbon and Nitrogen in Cultivated Soils in Henan Province, China: Potential Effect on Crop Yield 
PLoS ONE  2014;9(10):e109188.
Improved management of soil carbon (C) and nitrogen (N) storage in agro-ecosystems represents an important strategy for ensuring food security and sustainable agricultural development in China. Accurate estimates of the distribution of soil C and N stores and their relationship to crop yield are crucial to developing appropriate cropland management policies. The current study examined the spatial variation of soil organic C (SOC), total soil N (TSN), and associated variables in the surface layer (0–40 cm) of soils from intensive agricultural systems in 19 counties within Henan Province, China, and compared these patterns with crop yield. Mean soil C and N concentrations were 14.9 g kg−1 and 1.37 g kg−1, respectively, whereas soil C and N stores were 4.1 kg m−2 and 0.4 kg m−2, respectively. Total crop production of each county was significantly, positively related to SOC, TSN, soil C and N store, and soil C and N stock. Soil C and N were positively correlated with soil bulk density but negatively correlated with soil porosity. These results indicate that variations in soil C could regulate crop yield in intensive agricultural systems, and that spatial patterns of C and N levels in soils may be regulated by both climatic factors and agro-ecosystem management. When developing suitable management programs, the importance of soil C and N stores and their effects on crop yield should be considered.
doi:10.1371/journal.pone.0109188
PMCID: PMC4188611  PMID: 25289703
12.  Quantifying the expression of tumor marker genes in lung squamous cell cancer with RNA sequencing 
Journal of Thoracic Disease  2014;6(10):1380-1387.
Background
We measured the expression of some commonly used tumor markers with RNA sequencing (RNA-Seq) to identify any that might be useful for the evaluation of squamous cell lung cancer and identify possible correlations between these tumor markers and any clinical characteristics.
Methods
RNA-Seq was performed on five pairs of squamous-cell lung cancer and normal tissues and another 39 squamous-cell lung cancer tissues obtained by our department between September and December, 2012. The expression of 13 commonly used tumor markers was determined.
Results
All of the patients in our study were male. The expressions of CA125, CYFRA21-1, NSE and SCC increased in tumor samples and there were statistically significant differences between squamous cell lung cancer and normal tissues (P=0.008, P<0.001, P<0.001, P=0.001). The expression of β2M and CA15-3 was reduced in squamous cell carcinoma relative to normal tissues and there was no significant difference in the expression of other tumor markers, including AFP, AFU, CT, FER and HE4.
Conclusions
CA125, CYFRA21-1, NSE and SCC may be appropriate tumor markers for squamous cell lung cancer.
doi:10.3978/j.issn.2072-1439.2014.08.27
PMCID: PMC4215159  PMID: 25364514
RNA sequencing (RNA-Seq); tumor marker; squamous cell lung cancer
13.  Engineering Aspergillus oryzae A-4 through the Chromosomal Insertion of Foreign Cellulase Expression Cassette to Improve Conversion of Cellulosic Biomass into Lipids 
PLoS ONE  2014;9(9):e108442.
A genetic modification scheme was designed for Aspergillus oryzae A-4, a natural cellulosic lipids producer, to enhance its lipid production from biomass by putting the spotlight on improving cellulase secretion. Four cellulase genes were separately expressed in A-4 under the control of hlyA promoter, with the help of the successful development of a chromosomal genetic manipulation system. Comparison of cellulase activities of PCR-positive transformants showed that these transformants integrated with celA gene and with celC gene had significantly (p<0.05) higher average FPAase activities than those strains integrated with celB gene and with celD gene. Through the assessment of cellulosic lipids accumulating abilities, celA transformant A2-2 and celC transformant D1-B1 were isolated as promising candidates, which could yield 101%–133% and 35.22%–59.57% higher amount of lipids than the reference strain A-4 (WT) under submerged (SmF) conditions and solid-state (SSF) conditions, respectively. Variability in metabolism associated to the introduction of cellulase gene in A2-2 and D1-B1 was subsequently investigated. It was noted that cellulase expression repressed biomass formation but enhanced lipid accumulation; whereas the inhibitory effect on cell growth would be shielded during cellulosic lipids production owing to the essential role of cellulase in substrate utilization. Different metabolic profiles also existed between A2-2 and D1-B1, which could be attributed to not only different transgene but also biological impacts of different integration. Overall, both simultaneous saccharification and lipid accumulation were enhanced in A2-2 and D1-B1, resulting in efficient conversion of cellulose into lipids. A regulation of cellulase secretion in natural cellulosic lipids producers could be a possible strategy to enhance its lipid production from lignocellulosic biomass.
doi:10.1371/journal.pone.0108442
PMCID: PMC4177402  PMID: 25251435
14.  Genetic engineering of microorganisms for biodiesel production 
Bioengineered  2012;4(5):292-304.
Biodiesel, as one type of renewable energy, is an ideal substitute for petroleum-based diesel fuel and is usually made from triacylglycerides by transesterification with alcohols. Biodiesel production based on microbial fermentation aiming to establish more efficient, less-cost and sustainable biodiesel production strategies is under current investigation by various start-up biotechnology companies and research centers. Genetic engineering plays a key role in the transformation of microbes into the desired cell factories with high efficiency of biodiesel production. Here, we present an overview of principal microorganisms used in the microbial biodiesel production and recent advances in metabolic engineering for the modification required. Overexpression or deletion of the related enzymes for de novo synthesis of biodiesel is highlighted with relevant examples.
doi:10.4161/bioe.23114
PMCID: PMC3813529  PMID: 23222170
genetic engineering; microorganisms; biodiesel; fatty acids; de novo synthesis
15.  Mei-Shin Shih: a surgeon, master, and mentor 
Journal of Thoracic Disease  2014;6(9):1371-1373.
doi:10.3978/j.issn.2072-1439.2014.08.29
PMCID: PMC4178116  PMID: 25276387
16.  Metabolic alteration of the N-glycan structure of a protein from patients with a heterozygous protein deficiency 
Biochimica et biophysica acta  2004;1739(1):43-49.
Glycosylation, an important post-translation modification, could alter biological activity or influence the clearance rates of glycoproteins. We report here the first example of a heterozygous protein deficiency leading to metabolic alteration of N-glycan structures in residual secreted protein. Analysis of C1 esterase inhibitor (C1INH) glycans from normal individuals and patients with hereditary deficiency of C1INH demonstrated identical O-glycan structures but the N-glycans of patients with a heterozygous genetic deficiency were small, highly charged and lacked sialidase releasable N-acetylneuraminic acid. Structural studies indicate that the charge character of these aberrant N-glycan structures may result from the presence of mannose-6-phosphate residues. These residues might facilitate secretion of C1INH through an alternate lysosomal pathway, possibly serving as a compensatory mechanism to enhance plasma levels of C1INH in these deficient patients.
doi:10.1016/j.bbadis.2004.08.006
PMCID: PMC4137563  PMID: 15607116
Glycosylation; C1 esterase inhibitor; N-glycan; O-glycan; Hereditary angioedema; C1 esterase inhibitor deficiency
17.  Solid-Phase Chemoenzymatic Synthesis of C-Sialosides 
The Journal of organic chemistry  2004;69(20):6900-6903.
The chemoenzymatic regioselective acylation of Neu5Ac followed by SmI2-mediated C-glycosylation on a solid support is described for five C-glycosides. This method should facilitate the construction of combinatorial libraries of inhibitors of neuraminidase activity and hemagglutinin interaction as potential antiviral agents.
doi:10.1021/jo0491298
PMCID: PMC4135478  PMID: 15387620
18.  Apollon modulates chemosensitivity in human esophageal squamous cell carcinoma 
Oncotarget  2014;5(16):7183-7197.
Patients with esophageal squamous cell carcinoma (ESCC) are often diagnosed with advanced diseases that respond poorly to chemotherapy. Here we reported that Apollon, a membrane-associated inhibitor of apoptosis protein, was overexpressed in ESCC cell lines and clinical ESCC tissues, and Apollon overexpression clinically correlated with poor response to chemotherapy (P = 0.001), and short overall survival (P = 0.021). Apollon knockdown increased cisplatin/docetaxel-induced apoptosis, mitochondrial dysfunction and cytochrome c release in two ESCC cell lines. Apollon knockdown potentiated cisplatin/docetaxel-induced long-term cell growth inhibition, and enhanced chemosensitivity of ESCC cells to cisplatin/docetaxel in xenograft tumor models. Apollon knockdown also enhanced cisplatin/docetaxel-induced activation of caspase-8 (extrinsic pathway) and caspase-9 (intrinsic pathway) in ESCC cells and xenograft tumor models. Mechanism studies revealed that the effect of Apollon on chemosensitivity is mainly mediated by Smac. Apollon expression strongly and negatively correlated with Smac expression in clinical ESCC tissues (P = 0.001). Apollon targeted Smac for degradation in ESCC cells. The effect of Apollon on chemosensitivity was reversed by Smac knockdown in ESCC cells. Taken together, our data show association of Apollon expression with chemotherapeutic response in ESCC, and provide a strong rationale for combining Apollon antagonism with chemotherapy to treat ESCC.
PMCID: PMC4196194  PMID: 25216531
apoptosis; cancer; IAPs; prognosis; Smac
19.  Synthesis of Double C-Glycoside Analogue of sTn 
The Journal of organic chemistry  2005;70(20):8197-8200.
A sTn double C-glycoside, sTn analogue 2, was synthesized using samarium chemistry developed in our laboratory. Complications in the oxidation reaction affording aldehyde acceptor were overcome by double protection of amide and the use of a room-temperature ionic liquid as solvent. Studies are underway to conjugate the sTn double C-glycoside hapten 2 to KLH carrier protein for biological evaluation as a vaccine.
doi:10.1021/jo050691n
PMCID: PMC4112365  PMID: 16277348
20.  Injectable Nano-Network for Glucose-Mediated Insulin Delivery 
ACS nano  2013;7(5):4194-4201.
Diabetes mellitus, a disorder of glucose regulation, is a global burden affecting 366 million people across the world. An artificial “closed-loop” system able to mimic pancreas activity and release insulin in response to glucose level changes has the potential to improve patient compliance and health. Herein we develop a glucose-mediated release strategy for the self-regulated delivery of insulin using an injectable and acid-degradable polymeric network. Formed by electrostatic interaction between oppositely charged dextran nanoparticles loaded with insulin and glucose-specific enzymes, the nanocomposite-based porous architecture can be dissociated and subsequently release insulin in a hyperglycemic state through the catalytic conversion of glucose into gluconic acid. In vitro insulin release can be modulated in a pulsatile profile in response to glucose concentrations. In vivo studies validated that these formulations provided improved glucose control in type 1 diabetic mice subcutaneously administered with a degradable nano-network. A single injection of the developed nano-network facilitated stabilization of the blood glucose levels in the normoglycemic state (<200 mg/dL) for up to 10 days.
doi:10.1021/nn400630x
PMCID: PMC4107450  PMID: 23638642
drug delivery; diabetes; insulin; glucose-responsive; closed-loop; nano-network
21.  RNAi screening identifies HAT1 as a potential drug target in esophageal squamous cell carcinoma 
Esophageal carcinoma (EC) is one of the most fatal carcinomas of the gastrointestinal tract. Aberrant activity of histone acetyltransferases (HATs)/deacetylases (HDACs) play a critical role in carcinogenesis through the regulation of the genes involved in cell differentiation, proliferation, and apoptosis. However, cellular functions of HATs/HDACs in esophageal cancer and its molecular mechanisms remain unclear. An RNAi screen was used in this study to identify the histone acetyltransferases (HATs) and deacetylases (HDACs) that could be critical for the survival of EC cells. We demonstrated that HAT1 (histone acetyltransferase 1) was an important determinant to regulate the proliferation of human EC Eca-109 cells. Furthermore, we showed that the knockdown of HAT1 induced a G2/M cell cycle arrest, which was associated with the disruption of cell cycle-related events, including the decrease of cyclinD1 as well as alteration in cyclinB1 expression. The expression of HAT1 was validated to be higher in the primary tumors and adjacent tissue as compared to that of the normal esophageal tissue. Furthermore, we found that HAT1 expression was directly correlated with the poor tumor differentiation of EC tissue, which suggested that HAT1 played an important role in esophageal carcinoma and that it could be a novel EC therapeutic target.
PMCID: PMC4129001  PMID: 25120766
Esophageal carcinoma; HAT1; G2-M; tumor differentiation; RNAi screen
22.  Tumor suppressor gene PDCD4 negatively regulates autophagy by inhibiting the expression of autophagy-related gene ATG5 
Autophagy  2013;9(5):743-755.
PDCD4 (programmed cell death protein 4), a suppressor of gene transcription and translation, plays a crucial inhibitory role in several types of human tumors. However, its underlying mechanisms remain unclear. Autophagy, an evolutionarily conserved catabolic process, maintains cellular homeostasis under stress conditions such as starvation and plays a crucial role in tumor initiation and progression. We report here that PDCD4 inhibits autophagy in multiple cell types both in vitro and in vivo, which in turn contributes to its tumor suppressor activity. Importantly, PDCD4 inhibits the expression of an essential autophagy related gene, ATG5 and the formation of an ATG12–ATG5 complex, and its ma3 domains are required for PDCD4-mediated inhibition of autophagy. Unlike most tumor suppressors that act as positive or dual regulators of autophagy, our findings indicate that PDCD4 negatively regulates autophagy by targeting ATG5, which provides a novel mechanism of tumor suppression.
doi:10.4161/auto.24069
PMCID: PMC3669183  PMID: 23486359
PDCD4; tumor suppressor; autophagy; ATG5; proliferation
23.  Cervical triangulating stapled anastomosis: technique and initial experience 
Journal of Thoracic Disease  2014;6(Suppl 3):S350-S354.
Objective
To explore the safety and efficacy of modified cervical triangulating stapled anastomosis (TSA) for gastroesophageal anastomosis (GEA) in minimally invasive esophagectomy (MIE).
Methods
From January 2013 to November 2013, eighty-four patients who underwent three-stage MIE was enrolled. During the cervical stage, either circular stapled (CS) or triangulating stapled (TS) anastomosis was applied for GEA. Clinical features were collected and compared to identify the differences between the two groups.
Results
A total of 84 patients were included in this study. The clinical characteristics were close between the two groups. Intra-operatively, the duration of GEA was close between the two groups (18±3.4 vs. 17±2.7 min, P=0.139). Post-operatively, Cervical anastomotic leakage occurred in one (3.0%) of the 33 TS patients, but in six (11.8%) of the 51 CS patients (P=0.312). The incidence of anastomotic stenosis was 0.0% and 13.7% in the TS and CS groups, respectively (P=0.069). The overall incidence of postoperative complications was significantly lower in TS than that in CS (15.2% vs. 35.3%, P=0.043). There was no difference in the median length of hospital stay or perioperative mortality rate between the two groups.
Conclusions
TSA is a safe and effective alternative for GEA, which would probably lower the incidence of leakage and stenosis following MIE. Further studies based on larger volumes are required to confirm these findings.
doi:10.3978/j.issn.2072-1439.2014.02.06
PMCID: PMC4037421  PMID: 24876941
Esophageal cancer (EC); minimally invasive esophagectomy (MIE); gastroesophageal anastomosis (GEA); triangulating stapled anastomosis (TSA)
24.  Potent anti-angiogenesis and anti-tumor activity of a novel human anti-VEGF antibody, MIL60 
Cellular and Molecular Immunology  2014;11(3):285-293.
Angiogenesis is crucial for tumor development, growth and metastasis. Vascular endothelial growth factor (VEGF) has been implicated in promoting solid tumor growth and metastasis via stimulating tumor-associated angiogenesis, and blocking the activity of VEGF can starve tumors. Avastin, which is a humanized anti-VEGF antibody, has been successfully applied in clinics since 2004. However, the price of Avastin is extremely high for Chinese people. Here, we report a novel human anti-VEGF neutralizing antibody, MIL60, which shows an affinity comparable to that of Avastin (the KD value of MIL60 was 44.5 pM, while that of Avastin was 42.7 pM). MIL60 displays favorable actions in inhibiting VEGF-triggered endothelial cell proliferation (the IC50 value of MIL60 was 31±6.4 ng/ml and that of Avastin was 47±8.1 ng/ml), migration (8 µg/ml or 0.8 µg/ml MIL60 versus the control: P<0.05) and tube formation (2 µg/ml or 0.2 µg/ml MIL60 versus the control: P<0.05) via the VEGFR2 signaling pathway. Moreover, MIL60 was shown to inhibit tumor growth and angiogenesis in vivo in xenograft models of human colon carcinoma and ovarian cancer using immunotherapy and immunohistochemistry analysis (MIL60 versus N.S.: P=0.0007; Avastin versus N.S.: P=0.00046). These data suggest that MIL60 is a potential therapeutic, anti-angiogenic agent. Our work provides a novel anti-VEGF antibody, which can be considered an anti-tumor antibody candidate and a new option for patients with various cancers.
doi:10.1038/cmi.2014.6
PMCID: PMC4085495  PMID: 24608894
angiogenesis; anti-VEGF antibody; cancer
25.  Corneal Biomechanical Assessment Using Corneal Visualization Scheimpflug Technology in Keratoconic and Normal Eyes 
Journal of Ophthalmology  2014;2014:147516.
Purpose. To compare the corneal biomechanical properties of keratoconic patients and age-matched controls using corneal visualization Scheimpflug technology (Corvis ST). Methods. Sixty keratoconic eyes from 47 keratoconus patients and 60 normal eyes from 60 controls were enrolled in this prospective study. Tomography and biomechanical parameters of all eyes were obtained with the Pentacam and Corvis ST, respectively. Intraocular pressure was measured using a Goldmann applanation tonometer. Results. The tomography and biomechanical parameters of the keratoconic corneas were significantly different from those of the normal corneas except for the anterior chamber angle, first applanation length, the highest concavity time, and peak distance. The deformation amplitude was the best predictive parameter (area under the curve: 0.882), with a sensitivity of 81.7%, although there was a significant overlap between keratoconic and normal corneas that ranged from 1.0 to 1.4 mm. In both the keratoconus and control groups, the deformation amplitude was negatively correlated with intraocular pressure, central corneal thickness, and corneal volume at 3 and 5 mm. Conclusions. Corvis ST offers an alternative method for measuring corneal biomechanical properties. The possibility of classifying keratoconus based on deformation amplitude deserves clinical attention.
doi:10.1155/2014/147516
PMCID: PMC3988970  PMID: 24800059

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