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1.  Field comparison of circulating antibody assays versus circulating antigen assays for the detection of schistosomiasis japonica in endemic areas of China 
Parasites & Vectors  2014;7:138.
Schistosomiasis remains a serious public health problem in affected countries, and routine, highly sensitive and cost-effective diagnostic methods are lacking. We evaluated two immunodiagnostic techniques for the detection of Schistosoma japonicum infections: circulating antibody and circulating antigen assays.
A total of 1864 individuals (between 6 and 72 years old) residing in five administrative villages in Hubei province were screened by serum examination with an indirect hemagglutination assay (IHA). The positive individuals (titer ≥20 in IHA) were reconfirmed by stool examination with the Kato-Katz method (three slides from a single stool specimen). Samples of good serum quality and a volume above 0.5 ml were selected for further testing with two immunodiagnostic antibody (DDIA and ELISA) and two antigen (ELISA) assays.
The average antibody positive rate in the five villages was 12.7%, while the average parasitological prevalence was 1.50%; 25 of the 28 egg-positive samples were also circulating antigen-positive. Significant differences were observed between the prevalence according to the Kato-Katz method and all three immunodiagnostic antibody assays (P-value <0.0001). Similar differences were observed between the Kato-Katz method and the two immunodiagnostic antigen assays (P-value <0.0001) and between the antigen and antibody assays (P-value <0.0001).
Both circulating antibody and circulating antigen assays had acceptable performance characteristics. Immunodiagnostic techniques to detect circulating antigens have potential to be deployed for schistosomiasis japonica screening in the endemic areas.
PMCID: PMC3978087  PMID: 24684924
Schistosoma japonicum; Circulating antibody; Circulating antigen; China
2.  Maintenance of Stemness in Oxaliplatin-Resistant Hepatocellular Carcinoma Is Associated with Increased Autocrine of IGF1 
PLoS ONE  2014;9(3):e89686.
Evidence suggests that many types of cancers are composed of different cell types, including cancer stem cells (CSCs). We have previously shown that the chemotherapeutic agent oxaliplatin induced epithelial-mesenchymal transition, which is thought to be an important mechanism for generating CSCs. In the present study, we investigate whether oxaliplatin-treated cancer tissues possess characteristics of CSCs, and explore oxaliplatin resistance in these tissues.
Hepatocellular carcinoma cells (MHCC97H cells) were subcutaneously injected into mice to form tumors, and the mice were intravenously treated with either oxaliplatin or glucose. Five weeks later, the tumors were orthotopically xenografted into livers of other mice, and these mice were treated with either oxaliplatin or glucose. Metastatic potential, sensitivity to oxaliplatin, and expression of CSC-related markers in the xenografted tumor tissues were evaluated. DNA microarrays were used to measure changes in gene expression as a result of oxaliplatin treatment. Additionally, an oxaliplatin-resistant cell line (MHCC97H-OXA) was established to assess insulin-like growth factor 1 secretion, cell invasion, cell colony formation, oxaliplatin sensitivity, and expression of CSC-related markers. The effects of an insulin-like growth factor 1 receptor inhibitor were also assessed.
Oxaliplatin treatment inhibited subcutaneous tumor growth. Tumors from oxaliplatin-treated mice that were subsequently xenografted into livers of other mice exhibited that decreasing sensitivity to oxaliplatin and increasing pulmonary metastatic potential. Among the expression of CSC-related proteins, the gene for insulin-like growth factor 1, was up-regulated expecially in these tumor tissues. Additionally, MHCC97H-OXA cells demonstrated that increasing cell invasion, colony formation, and expression of insulin-like growth factor 1 and CSC-related markers, whereas treatment with an inhibitor of the insulin-like growth factor 1 receptor suppressed these effects.
Maintenance of stemness in oxaliplatin-resistant hepatocellular carcinoma cells is associated with increased autocrine of IGF1.
PMCID: PMC3954560  PMID: 24632571
3.  Prevalence and Determinants of Metabolic Syndrome among Adults in a Rural Area of Northwest China 
PLoS ONE  2014;9(3):e91578.
To evaluate the prevalence and determinants of metabolic syndrome (MetS) among adults in a rural area of Northwest China.
A population-based cross-sectional study was conducted in 2010 among adults aged 18 to 80 years in rural areas of Hanzhong, in Northwest China. Interview, physical and clinical examinations, and fasting blood glucose and lipid measurements were completed for 2990 adults. The definitions of MetS proposed by the Third Report of the National Cholesterol Education Program Expert Panel (Adults Treatment Panel III, ATP III) and the International Diabetes Federation (IDF), and the modified ATP III definition for Asian population were used and compared. Proportions were adjusted for age and sex.
The prevalence of MetS was 7.9%, 10.8% and 15.1% according to ATP III, IDF and modified ATP III criteria, respectively. Agreement between ATP III and IDF criteria and that between ATP III and modified ATP III criteria were moderate (Kappa = 0.52 and 0.64, respectively), whereas agreement between IDF and modified ATP III criteria was good (Kappa = 0.83). The prevalence of MetS increased with age, and was higher in women than in men (10.4% versus 5.4%, 13.6% versus 8.1% and 17.4% versus 12.8%, according to ATP III, IDF and modified ATP III criteria, respectively). The most common MetS component was high blood pressure. Having family history of hypertension, lack of physical activity, high economical level, overweight and obesity were positively associated with MetS.
MetS is prevalent among rural adults in Northwest China and high blood pressure is the most common MetS component. Prevention and treatment of hypertension and MetS should be a public health priority to reduce cardiovascular diseases in rural areas of Northwest China. More attention should be given to the elderly, women, people with family history of hypertension and obese people who are at high risk of MetS.
PMCID: PMC3948893  PMID: 24614618
4.  Effect of Naphthalene Acetic Acid on Adventitious Root Development and Associated Physiological Changes in Stem Cutting of Hemarthria compressa 
PLoS ONE  2014;9(3):e90700.
In order to find a way to induce rooting on cuttings of Hemarthria compressa cv. Ya’an under controlled conditions, a project was carried out to study the effect of naphthalene acetic acid (NAA) on rooting in stem cuttings and related physiological changes during the rooting process of Hemarthria compressa. The cuttings were treated with five concentrations of NAA (0, 100, 200 300, 400 mg/l) at three soaking durations (10, 20, 30 minutes), and cuttings without treatment were considered as control. Samples were planted immediately into pots after treatment. IAA-oxidase (IAAO) activity, peroxidase (POD) activity and polyphenol oxidase (PPO) activity were determined after planting. Results showed that NAA had positive effect on rooting at the concentration of 200 mg/l compared to other concentrations at 30 days after planting (DAP). Among the three soaking durations, 20 minutes (min) of 200 mg/l NAA resulted in higher percentages of rooting, larger numbers of adventitious roots and heavier root dry weight per cutting. The lowest IAAO activity was obtained when soaked at 200 mg/l NAA for 20 min soaking duration. This was consistent with the best rooting ability, indicating that the lower IAAO activity, the higher POD activity and PPO activity could be used as an indicator of better rooting ability for whip grass cuttings and might serve as a good marker for rooting ability in cuttings.
PMCID: PMC3942460  PMID: 24595064
5.  Activation of DSB processing requires phosphorylation of CtIP by ATR 
Molecular cell  2012;49(4):657-667.
DNA double-strand breaks (DSBs) activate a DNA damage response (DDR) that coordinates checkpoint pathways with DNA repair. ATM and ATR kinases are activated sequentially. Homology-directed repair (HDR) is initiated by resection of DSBs to generate 3′ ssDNA overhangs. How resection and HDR are activated during DDR or the roles of ATM and ATR in HDR are not known. Here, we show that CtIP undergoes ATR-dependent hyperphosphorylation in response to DSBs. ATR phosphorylates an invariant threonine, T818 of Xenopus CtIP (T859 in human). Non-phosphorylatable CtIP (T818A) does not bind to chromatin or initiate resection. Our data support a model in which ATM activity is required for an early step in resection leading to ATR activation, CtIP-T818 phosphorylation, and accumulation of CtIP on chromatin. Chromatin binding by modified CtIP precedes extensive resection and full checkpoint activation.
PMCID: PMC3582837  PMID: 23273981
6.  Mitochondrial proteomic analysis of ecdysterone protection against oxidative damage in human lens epithelial cells 
To investigate the protective effects of the natural medicinal monomer ecdysterone (ECR) with estrogenic activity against oxidative damage in human lens epithelial cells B3 (HLE-B3) caused by hydrogen peroxide 21(H2O2) and to pursue the possible mitochondrial proteomic regularity of the protective effects.
HLE-B3 cells were treated with H2O2 (300µmol/L), β-estuarial (E2; 10−8mol/L) and H2O2, ECR (10−6mol/L) and H2O2, or left untreated. Altered expression of all mitochondrial proteins was analyzed by protein array and surface-enhanced laser desorption ionization time of flight mass spectrometry (SELDI-TOF-MS). The mass/charge (M/Z) ratios of each peak were tested by the Kruskal-Wallis rank sum test, and the protein peak value of the M/Z ratio for each treatment by pair comparison was analyzed with the Nemenyi test.
H2O2 up-regulated expression of two protein spots (with M/Z of 6 532 and 6 809). When E2 mitigated the oxidative damage, the expression of one protein spot (M/Z 6 532) was down-regulated. In contrast, ECR down-regulated both of protein spots (M/Z 6 532 and 6 809).
ECR could effectively inhibite H2O2 induced oxidative damage in HLE-B3 cells. The protein spot at M/Z of 6 532 might be the target spot of ECR against oxidative damage induced by H2O2.
PMCID: PMC3949456  PMID: 24634861
ecdysterone; mitochondrial proteomics; lens epithelial cell; senile cataract
7.  The Effect of Environmental Enrichment on Substantia Nigra Gene Expression after Traumatic Brain Injury in Rats 
Journal of Neurotrauma  2013;30(4):259-270.
Experimental investigations into the effects of traumatic brain injury (TBI) have demonstrated significant alterations in dopaminergic systems. Dopaminergic fibers originating within the substantia nigra and ventral tegmental area (VTA) are important for reward learning, addiction, movement, and behavior. However, little is known about the effect of TBI on substantia nigra and VTA function. Environmental enrichment (EE) has been shown to improve functional outcome after TBI, and a number of studies suggest that it may exert some benefits via dopaminergic signaling. To better understand the role of dopamine in chronic TBI pathophysiology and the effect of EE, we examined the mRNA expression profile within the substantia nigra and VTA at 4 weeks post-injury. Specifically, three comparisons were made: 1) TBI versus sham, 2) sham+EE versus sham+standard (STD) housing, and 3) TBI+EE versus TBI+STD. There were differential expressions of 25, 4, and 40 genes in these comparisons, respectively. Chronic alterations in genes post-injury within the substantia nigra and VTA included genes important for cellular membrane homeostasis and transcription. EE-induced gene alterations after TBI included genes important for signal transduction, in particular calcium signaling pathways, membrane homeostasis, and metabolism. Elucidation of these alterations in gene expression within the substantia nigra and VTA provides new insights into chronic changes in dopamine signaling post-TBI, and the potential role of EE in TBI rehabilitation.
PMCID: PMC3579325  PMID: 23094804
dopamine; EE; microarray; TBI
8.  A survey of undernutrition in children under three years of age in rural Western China 
BMC Public Health  2014;14:121.
Childhood undernutrition adversely impacts child health and is one of China’s largest health burdens. However, there is limited information on the current rate of childhood undernutrition in rural Western China. The purpose of this study was to investigate the prevalence of childhood undernutrition and explore its association with socio-economic characteristics in Western China.
A total of 13,532 children of 0 ~ 36 months of age were recruited as subjects from 45 counties and 10 provinces in Western China with a 3-stage probability proportion to size sampling. The composite index of anthropometric failure (CIAF) was used to assess the childhood undernutrition. The association between socio-economic characteristics and childhood undernutrition was analyzed using a two-level logistic regression.
Based on CIAF, the prevalence of undernutrition among children under three years of age in rural Western China in 2005 was 21.7%. The two-level logistic analysis presented a large difference in undernutrition among the 10 provinces with the highest odds ratio in Guizhou (OR: 2.15, 95%CI: 1.50, 3.08). Older children had a higher prevalence of undernutrition. As compared to girls, boys were more likely to be undernourished (OR 1.27, 95% CI: 1.16, 1.39). The likelihood of undernutrition was lower in subjects of Han ethnicity as opposed to subjects of minority ethnicities (OR 0.77, 95%CI: 0.65, 0.90). In addition, the education levels of the mother as well as wealth index were both negatively associated with childhood undernutrition.
Childhood undernutrition still remains a large health challenge in rural Western China. This study has important policy implications for the Chinese government to improve childhood undernutrition in the surveyed areas.
PMCID: PMC3918142  PMID: 24499429
Children; Undernutrition; Western China
9.  Dysplastic Nodules with Glypican-3 Positive Immunostaining: A Risk for Early Hepatocellular Carcinoma 
PLoS ONE  2014;9(1):e87120.
Glypican-3 (GPC3) has been reported to be a novel serum and histochemical marker for HCC. The positivity or negativity for GPC3 in hepatic precancerous lesions, such as dysplastic nodules (DN), has also been described. Moreover, our previous studies have demonstrated that some DN in liver cirrhosis represent monoclonal hyperplasia, and confirmed their neoplastic nature. However, additional studies must be performed to investigate further the relationship between DN with GPC3 positivity and HCC. Thus, we first investigated the expression of GPC3 in 136 HCC and 103 small DN (less than 1 cm in diameter) by immunohistochemical staining and determined the clonality of 81 DN from female patients using X-chromosome inactivation mosaicism and polymorphism of androgen receptor (AR) gene. Then we examined these samples for chromosomal loss of heterozygosity (LOH) at 11 microsatellite polymorphism sites. The results demonstrated that GPC3 immunoreactivity was detected in 103 of 136 HCC (75.7%) and 19 of 103 DN (18.4%), and the positive ratio correlated with HBsAg positivity. Clonality assays showed that 15 GPC3-positive DN from female patients, including 12 high-grade DN (HGDN), and 28 (42.4%) of 66 GPC3-negative DN, were monoclonal. In addition, among 19 GPC3-positive DN, chromosomal LOH was found at loci D6S1008 (100%, 19/19), D8S262 (52.6%, 10/19) and D11S1301 (57.9%, 11/19). However, the LOH frequency in GPC3-negative DN was 5.95% (5/84), 23.8% (20/84), and 4.76% (4/84) in three loci, respectively. Thus, we concluded that GPC3-positive DN, especially GPC3-positive HGDN, was really a late premalignant lesion of HCC.
PMCID: PMC3909016  PMID: 24498024
10.  Combined Effect of Cameo2 and CBP on the Cellular Uptake of Lutein in the Silkworm, Bombyx mori 
PLoS ONE  2014;9(1):e86594.
Formation of yellow-red color cocoons in the silkworm, Bombyx mori, occurs as the result of the selective delivery of carotenoids from the midgut to the silk gland via the hemolymph. This process of pigment transport is thought to be mediated by specific cellular carotenoids carrier proteins. Previous studies indicated that two proteins, Cameo2 and CBP, are associated with the selective transport of lutein from the midgut into the silk gland in Bombyx mori. However, the exact roles of Cameo2 and CBP during the uptake and transport of carotenoids are still unknown. In this study, we investigated the respective contributions of these two proteins to lutein and β-carotene transport in Bombyx mori as well as commercial cell-line. We found that tissues, expressed both Cameo2 and CBP, accumulate lutein. Cells, co-expressed Cameo2 and CBP, absorb 2 fold more lutein (P<0.01) than any other transfected cells, and the rate of cellular uptake of lutein was concentration-dependent and reached saturation. From immunofluorescence staining, confocal microscopy observation and western blot analysis, Cameo2 was localized at the membrane and CBP was expressed in the cytosol. What’s more, bimolecular fluorescence complementation analysis showed that these two proteins directly interacted at cellular level. Therefore, Cameo2 and CBP are necessarily expressed in midguts and silk glands for lutein uptake in Bombyx mori. Cameo2 and CBP, as the membrane protein and the cytosol protein, respectively, have the combined effect to facilitate the cellular uptake of lutein.
PMCID: PMC3903547  PMID: 24475153
11.  Associations between Serum Apelin-12 Levels and Obesity-Related Markers in Chinese Children 
PLoS ONE  2014;9(1):e86577.
To investigate possible correlations between apelin-12 levels and obesity in children in China and associations between apelin-12 and obesity-related markers, including lipids, insulin sensitivity and insulin resistance index (HOMA-IR).
Forty-eight obese and forty non-obese age- and gender-matched Chinese children were enrolled between June 2008 and June 2009. Mean age was 10.42±2.03 and 10.86±2.23 years in obesity and control groups, respectively. Main outcome measures were apelin-12, BMI, lipids, glucose and insulin. HOMA-IR was calculated for all subjects.
All obesity group subjects had significantly higher total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), insulin levels and HOMA-IR (all P<0.05). In separate analyses, obese girls had significantly higher LDL-C, insulin and HOMA-IR than controls, and obese boys had significantly higher TC, TG, insulin and HOMA-IR than controls (all P<0.05). Apelin-12 levels were significantly higher in obese girls compared to controls (P = 0.024), and correlated positively with TG in all obese subjects. Among obese girls, apelin-12 levels correlated positively with TG, insulin and HOMA-IR after adjusting for age and BMI. In all boys (obese and controls) apelin-12 was positively associated with fasting plasma glucose (FPG). No significant correlations were found in either group between apelin-12 levels and other characteristics after adjusting for age, sex, and BMI.
Apelin-12 levels are significantly higher in obese vs. non-obese girls in China and correlate significantly with obesity-related markers insulin, HOMA-IR, and TG. Increased apelin-12 levels may be involved in the pathological mechanism of childhood obesity.
PMCID: PMC3903556  PMID: 24475149
12.  Embryonic Trophoblasts Induce Decidual Regulatory T Cell Differentiation and Maternal–Fetal Tolerance through Thymic Stromal Lymphopoietin Instructing Dendritic Cells 
Physiological pregnancy requires the maternal immune system to recognize and tolerate embryonic Ags. Although multiple mechanisms have been proposed, it is not yet clear how the fetus evades the maternal immune system. In this article, we demonstrate that trophoblast-derived thymic stromal lymphopoietin (TSLP) instructs decidual CD11c+ dendritic cells (dDCs)with increased costimulatory molecules; MHC class II; and Th2/3-type, but not Th1-type, cytokines. TSLP-activated dDCs induce proliferation and differentiation of decidual CD4+CD25− T cells into CD4+CD25+FOXP3+ regulatory T cells (Tregs) through TGF-β1. TSLP-activated dDC–induced Tregs display immunosuppressive features and express Th2-type cytokines. In addition, decidual CD4+CD25+FOXP3+ Tregs promote invasiveness and HLA-G expression of trophoblasts, resulting in preferential production of Th2 cytokines and reduced cytotoxicity in decidual CD56brightCD16− NK cells. Of interest, decreased TSLP expression and reduced numbers of Tregs were observed at the maternal–fetal interface during miscarriage. Our study identifies a novel feedback loop between embryo-derived trophoblasts and maternal decidual leukocytes, which induces a tolerogenic immune response to ensure a successful pregnancy.
PMCID: PMC3918863  PMID: 24453244
13.  Hydrogen Sulfide Prolongs Postharvest Storage of Fresh-Cut Pears (Pyrus pyrifolia) by Alleviation of Oxidative Damage and Inhibition of Fungal Growth 
PLoS ONE  2014;9(1):e85524.
Hydrogen sulfide (H2S) has proved to be a multifunctional signaling molecule in plants and animals. Here, we investigated the role of H2S in the decay of fresh-cut pears (Pyrus pyrifolia). H2S gas released by sodium hydrosulfide (NaHS) prolonged the shelf life of fresh-cut pear slices in a dose-dependent manner. Moreover, H2S maintained higher levels of reducing sugar and soluble protein in pear slices. H2S significantly reduced the accumulation of hydrogen peroxide (H2O2), superoxide radicals (•O2−) and malondialdehyde (MDA). Further investigation showed that H2S fumigation up-regulated the activities of antioxidant enzymes ascorbate peroxidase (APX), catalase (CAT), and guaiacol peroxidase (POD), while it down-regulated those of lipoxygenase (LOX), phenylalanine ammonia lyase (PAL) and polyphenol oxidase (PPO). Furthermore, H2S fumigation effectively inhibited the growth of two fungal pathogens of pear, Aspergillus niger and Penicillium expansum, suggesting that H2S can be developed as an effective fungicide for postharvest storage. The present study implies that H2S is involved in prolonging postharvest storage of pears by acting as an antioxidant and fungicide.
PMCID: PMC3893216  PMID: 24454881
14.  Radiofrequency ablation following first-line transarterial chemoembolization for patients with unresectable hepatocellular carcinoma beyond the Milan criteria 
BMC Gastroenterology  2014;14:11.
Recent studies suggest that a combination of radiofrequency ablation (RFA) and transarterial chemoembolization (TACE) may have theoretical advantages over TACE alone for treatment of hepatocellular carcinoma (HCC). The purpose of this study was to evaluate the effectiveness and safety of radiofrequency ablation following first-line TACE treatment in the management of HCC beyond the Milan Criteria.
Forty-five patients who consecutively underwent RFA following first-line TACE treatment for HCC beyond the Milan criteria were enrolled in this study. RFA was performed within 1–2 months after TACE treatment in patients who had incomplete necrotic tumor nodules. Primary effectiveness, complications, survival rates, and prognostic factors were evaluated retrospectively.
Complete ablation was achieved in 76.2% of the lesions according to 1-month follow-up computed tomography/magnetic resonance imaging evaluation. The mean follow-up period was 30.9 months (range 3–94 months). There were no major complications after RFA therapy. The median overall survival was 29 months (range 20–38 months), with 1-, 2-, and 3-year survival of 89%, 61%, and 43%, respectively. Multivariate analysis revealed that tumor diameter (P = 0.045, hazard ratio [HR] = 0.228, 95% confidence interval [CI]: 0.054-0.968) and pretreatment serum alpha-fetoprotein level (P = 0.024, HR = 2.239, 95% CI: 1.114-4.500) were independent predictors for long-term survival.
HCC beyond the Milan criteria can be completely and safely ablated by radiofrequency ablation following first-line TACE treatment with a low rate of complications and favorable survival outcome. Further assessment of the survival benefits of combination treatment for HCCs beyond the Milan Criteria is warranted.
PMCID: PMC3890612  PMID: 24410841
Hepatocellular carcinoma; Radiofrequency ablation; Transcatheter arterial chemoembolization; Milan criteria
15.  Comparison of concurrent chemoradiotherapy followed by radical surgery and high-dose-rate intracavitary brachytherapy: a retrospective study of 240 patients with FIGO stage IIB cervical carcinoma 
OncoTargets and therapy  2014;7:91-100.
The aim of this study was to compare the long-term survival outcome and late toxicity in patients with FIGO (International Federation of Gynecology and Obstetrics) stage IIB cervical carcinoma after two treatment modalities, ie, concurrent chemoradiotherapy followed by radical surgery and concurrent chemoradiotherapy followed by high-dose-rate intracavitary brachytherapy.
Between November 2004 and November 2011, 240 patients with FIGO stage IIB cervical carcinoma were analyzed, comprising 119 patients treated with concurrent chemoradiotherapy followed by radical surgery (group 1) and 121 patients treated with concurrent chemoradiotherapy followed by high-dose-rate intracavitary brachytherapy (group 2). Local control, overall survival, progression-free survival, and treatment-related complications were compared between the two groups.
The median follow-up duration was 36 months. Concurrent chemoradiotherapy followed by radical surgery showed a survival benefit when comparing group 1 and group 2 (3-year overall survival, 94.9% versus 84.6%, P=0.011; 3-year progression-free survival, 91.0% versus 81.8%, P=0.049, respectively). Three-year local pelvic control was 94.6% in group 1 and 93.3% in group 2 (P=0.325). Prognostic factors in group 1 were: age (≤35 years versus >35 years), 3-year progression-free survival (74.1% versus 90.9%, P=0.037); tumor diameter (≥6 cm versus <6 cm); and 3-year progression-free survival, (60.6% versus 92.9%, P=0.004). Prognostic factors in group 2 were: tumor diameter (≥4 cm versus <4 cm); 3-year overall survival (78.0% versus 94.8%, P=0.043); tumor diameter (≥6 cm versus <6 cm); 3-year progression-free survival (42.9% versus 84.2%, P=0.032); and 3-year overall survival (42.9% versus 87.1%, P=0.013). Further, 50 patients (42.02%) in group 1 and 46 patients (38.02%) in group 2 suffered from late complications. Analysis of the difference in composition of late complications showed that the rate of leg edema was higher in group 1 (35.29% versus 4.96%, P=0.000) while the rate of radiation enteritis was higher in group 2 (30.58% versus 5.04%, P=0.000).
In patients with FIGO stage IIB cervical carcinoma, concurrent chemoradiotherapy followed by radical surgery achieved higher overall survival and progression-free survival rates in comparison with radical radiotherapy associated with concurrent chemotherapy. Tumor diameter could be a common prognostic factor in these two groups of patients.
PMCID: PMC3888351  PMID: 24421644
cervical carcinoma; preoperative concurrent chemoradiotherapy; radical radiotherapy; prognostic factors; late toxicity
16.  POU5F1 Enhances the Invasiveness of Cancer Stem-Like Cells in Lung Adenocarcinoma by Upregulation of MMP-2 Expression 
PLoS ONE  2013;8(12):e83373.
Lung cancer is the leading cause of cancer-related human deaths. Exploration of the mechanisms underlying the metastasis of cancer stem-like cells (CSLCs) will open new avenues in lung cancer diagnosis and therapy. Here, we demonstrated that CSLCs-derived from lung adenocarcinoma (LAC) cells displayed highly invasive and migratory capabilities via expressing high levels of POU5F1 and MMP-2. We found that POU5F1 directly regulated MMP-2 transcription via interaction with the promoter of MMP-2. POU5F1 knockdown in LACSLCs reduced MMP-2 protein abundance, leading to inhibition of the cell invasion, migration and tumorigenesis potentials of LAC cells. Clinically, aberrantly high expressions of POU5F1 and MMP-2 were inversely correlated with the survival of LAC patients, and the double-positive POU5F1 and MMP-2 showed the worst prediction for the patient’s poor survival. These results indicate that POU5F1 can bind to the MMP-2 promoter for the degradation of surrounding extracellular matrix, and therefore promote invasive and migratory capabilities of LACSLCs. Moreover, our data implicate that the pathological detection of the double-positive expressions for POU5F1 and MMP-2 will be useful as diagnostic and prognostic biomarkers in LAC to advance anti-metastasis therapy.
PMCID: PMC3875455  PMID: 24386189
17.  A Mechanism for Actin Filament Severing by Malaria Parasite Actin Depolymerizing Factor 1 via a Low Affinity Binding Interface*  
The Journal of Biological Chemistry  2013;289(7):4043-4054.
Background: Plasmodium falciparum actin depolymerizing factor 1 (PfADF1) severs actin polymers without stable filament-binding, challenging current models for severing.
Results: Cross-linking mass spectrometry of PfADF1 with filamentous actin reveals a novel binding interface required for severing.
Conclusion: Filament severing by PfADF1 is via a previously unidentified binding interface.
Significance: We propose an alternative mechanism for actin filament severing potentially used across eukaryotic cells.
Actin depolymerizing factor (ADF)/cofilins are essential regulators of actin turnover in eukaryotic cells. These multifunctional proteins facilitate both stabilization and severing of filamentous (F)-actin in a concentration-dependent manner. At high concentrations ADF/cofilins bind stably to F-actin longitudinally between two adjacent actin protomers forming what is called a decorative interaction. Low densities of ADF/cofilins, in contrast, result in the optimal severing of the filament. To date, how these two contrasting modalities are achieved by the same protein remains uncertain. Here, we define the proximate amino acids between the actin filament and the malaria parasite ADF/cofilin, PfADF1 from Plasmodium falciparum. PfADF1 is unique among ADF/cofilins in being able to sever F-actin but do so without stable filament binding. Using chemical cross-linking and mass spectrometry (XL-MS) combined with structure reconstruction we describe a previously overlooked binding interface on the actin filament targeted by PfADF1. This site is distinct from the known binding site that defines decoration. Furthermore, total internal reflection fluorescence (TIRF) microscopy imaging of single actin filaments confirms that this novel low affinity site is required for F-actin severing. Exploring beyond malaria parasites, selective blocking of the decoration site with human cofilin (HsCOF1) using cytochalasin D increases its severing rate. HsCOF1 may therefore also use a decoration-independent site for filament severing. Thus our data suggest that a second, low affinity actin-binding site may be universally used by ADF/cofilins for actin filament severing.
PMCID: PMC3924271  PMID: 24371134
Actin; Cofilin; Cytoskeleton; Electron Microscopy (EM); Malaria; Mass Spectrometry (MS); Plasmodium; Protein Cross-linking
18.  HS-173, a Novel PI3K Inhibitor, Attenuates the Activation of Hepatic Stellate Cells in Liver Fibrosis 
Scientific Reports  2013;3:3470.
Hepatic stellate cells (HSCs) are the primary source of matrix components in liver disease such as fibrosis. Phosphatidylinositol 3-kinase (PI3K) signaling in HSCs has been shown to induce fibrogenesis. In this study, we evaluated the anti-fibrotic activity of a novel imidazopyridine analogue (HS-173) in human HSCs as well as mouse liver fibrosis. HS-173 strongly suppressed the growth and proliferation of HSCs and induced the arrest at the G2/M phase and apoptosis in HSCs. Furthermore, it reduced the expression of extracellular matrix components such as collagen type I, which was confirmed by an in vivo study. We also observed that HS-173 blocked the PI3K/Akt signaling pathway in vitro and in vivo. Taken together, HS-173 suppressed fibrotic responses such as cell proliferation and collagen synthesis by blocking PI3K/Akt signaling. Therefore, we suggest that this compound may be an effective therapeutic agent for ameliorating liver fibrosis through the inhibition of PI3K signaling.
PMCID: PMC3858860  PMID: 24326778
19.  Beauvericin Ameliorates Experimental Colitis by Inhibiting Activated T Cells via Downregulation of the PI3K/Akt Signaling Pathway 
PLoS ONE  2013;8(12):e83013.
Crohn's disease is a common, chronic inflammatory bowel condition characterized by remission and relapse. Accumulating evidence indicates that activated T cells play an important role in this disease. In the present study, we aimed to examine the effect of beauvericin, a natural cyclic peptide, on 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice, which mimics Crohn's disease. Beauvericin significantly reduced weight loss, diarrhea and mortality, accompanied with notable alleviation of macroscopic and microscopic signs. In addition, this compound decreased serum levels of tumor necrosis factor (TNF)-α and interferon (IFN)- γ in a concentration-dependent manner in mice with experimental colitis. These effects of beauvericin are attributed to its inhibition on activated T cells. Flow cytometry and immunoblot assay data showed that beauvericin suppressed T-cell proliferation, activation and IFN-γ-STAT1-T-bet signaling and subsequently led to apoptosis of activated T cells by suppressing Bcl-2 and phosphorylated Bad as well as increasing cleavage of caspase-3, -9, -12 and PARP. Furthermore, inhibition of PI3K/Akt signaling, which was an upstream regulator of cell activation and survival in activated T cells, contributed to the effect of beauvericin. Overall, these results supported beauvericin as a novel drug candidate for the treatment of colonic inflammation mainly by targeting PI3K/Akt in activated T cells.
PMCID: PMC3858350  PMID: 24340073
20.  RBOH1-dependent H2O2 production and subsequent activation of MPK1/2 play an important role in acclimation-induced cross-tolerance in tomato 
Journal of Experimental Botany  2013;65(2):595-607.
H2O2 and mitogen-activated protein kinase (MAPK) cascades play important functions in plant stress responses, but their roles in acclimation response remain unclear. This study examined the functions of H2O2 and MPK1/2 in acclimation-induced cross-tolerance in tomato plants. Mild cold, paraquat, and drought as acclimation stimuli enhanced tolerance to more severe subsequent chilling, photooxidative, and drought stresses. Acclimation-induced cross-tolerance was associated with increased transcript levels of RBOH1 and stress- and defence-related genes, elevated apoplastic H2O2 accumulation, increased activity of NADPH oxidase and antioxidant enzymes, reduced glutathione redox state, and activation of MPK1/2 in tomato. Virus-induced gene silencing of RBOH1, MPK1, and MPK2 or MPK1/2 all compromised acclimation-induced cross-tolerance and associated stress responses. Taken together, these results strongly suggest that acclimation-induced cross-tolerance is largely attributed to RBOH1-dependent H2O2 production at the apoplast, which may subsequently activate MPK1/2 to induce stress responses.
PMCID: PMC3904713  PMID: 24323505
Cross-tolerance; hydrogen peroxide; mitogen-activated protein kinase; reactive oxygen species; Respiratory burst oxidase homologue 1; signal transduction; Solanum lycopersicum.
21.  Down-Regulation of OsSPX1 Causes High Sensitivity to Cold and Oxidative Stresses in Rice Seedlings 
PLoS ONE  2013;8(12):e81849.
Rice SPX domain gene, OsSPX1, plays an important role in the phosphate (Pi) signaling network. Our previous work showed that constitutive overexpression of OsSPX1 in tobacco and Arabidopsis plants improved cold tolerance while also decreasing total leaf Pi. In the present study, we generated rice antisense and sense transgenic lines of OsSPX1 and found that down-regulation of OsSPX1 caused high sensitivity to cold and oxidative stresses in rice seedlings. Compared to wild-type and OsSPX1-sense transgenic lines, more hydrogen peroxide accumulated in seedling leaves of OsSPX1-antisense transgenic lines for controls, cold and methyl viologen (MV) treatments. Glutathione as a ROS scavenger could protect the antisense transgenic lines from cold and MV stress. Rice whole genome GeneChip analysis showed that some oxidative-stress marker genes (e.g. glutathione S-transferase and P450s) and Pi-signaling pathway related genes (e.g. OsPHO2) were significantly down-regulated by the antisense of OsSPX1. The microarray results were validated by real-time RT-PCR. Our study indicated that OsSPX1 may be involved in cross-talks between oxidative stress, cold stress and phosphate homeostasis in rice seedling leaves.
PMCID: PMC3849359  PMID: 24312593
22.  Modified Uterine Allotransplantation and Immunosuppression Procedure in the Sheep Model 
PLoS ONE  2013;8(11):e81300.
To develop an orthotopic, allogeneic, uterine transplantation technique and an effective immunosuppressive protocol in the sheep model.
In this pilot study, 10 sexually mature ewes were subjected to laparotomy and total abdominal hysterectomy with oophorectomy to procure uterus allografts. The cold ischemic time was 60 min. End-to-end vascular anastomosis was performed using continuous, non-interlocking sutures. Complete tissue reperfusion was achieved in all animals within 30 s after the vascular re-anastomosis, without any evidence of arterial or venous thrombosis. The immunosuppressive protocol consisted of tacrolimus, mycophenolate mofetil and methylprednisolone tablets. Graft viability was assessed by transrectal ultrasonography and second-look laparotomy at 2 and 4 weeks, respectively.
Viable uterine tissue and vascular patency were observed on transrectal ultrasonography and second-look laparotomy. Histological analysis of the graft tissue (performed in one ewe) revealed normal tissue architecture with a very subtle inflammatory reaction but no edema or stasis.
We have developed a modified procedure that allowed us to successfully perform orthotopic, allogeneic, uterine transplantation in sheep, whose uterine and vascular anatomy (apart from the bicornuate uterus) is similar to the human anatomy, making the ovine model excellent for human uterine transplant research.
PMCID: PMC3838404  PMID: 24278415
23.  A novel cell nuclei segmentation method for 3D C. elegans embryonic time-lapse images 
BMC Bioinformatics  2013;14:328.
Recently a series of algorithms have been developed, providing automatic tools for tracing C. elegans embryonic cell lineage. In these algorithms, 3D images collected from a confocal laser scanning microscope were processed, the output of which is cell lineage with cell division history and cell positions with time. However, current image segmentation algorithms suffer from high error rate especially after 350-cell stage because of low signal-noise ratio as well as low resolution along the Z axis (0.5-1 microns). As a result, correction of the errors becomes a huge burden. These errors are mainly produced in the segmentation of nuclei. Thus development of a more accurate image segmentation algorithm will alleviate the hurdle for automated analysis of cell lineage.
This paper presents a new type of nuclei segmentation method embracing an bi-directional prediction procedure, which can greatly reduce the number of false negative errors, the most common errors in the previous segmentation. In this method, we first use a 2D region growing technique together with the level-set method to generate accurate 2D slices. Then a modified gradient method instead of the existing 3D local maximum method is adopted to detect all the 2D slices located in the nuclei center, each of which corresponds to one nucleus. Finally, the bi-directional pred- iction method based on the images before and after the current time point is introduced into the system to predict the nuclei in low quality parts of the images. The result of our method shows a notable improvement in the accuracy rate. For each nucleus, its precise location, volume and gene expression value (gray value) is also obtained, all of which will be useful in further downstream analyses.
The result of this research demonstrates the advantages of the bi-directional prediction method in the nuclei segmentation over that of StarryNite/MatLab StarryNite. Several other modifications adopted in our nuclei segmentation system are also discussed.
PMCID: PMC3903074  PMID: 24252066
24.  Transcriptional Protein-Protein Cooperativity in POU/HMG/DNA Complexes Revealed by Normal Mode Analysis 
Biomolecular cooperativity is of great scientific interest due to its role in biological processes. Two transcription factors (TFs), Oct-4 and Sox-2, are crucial in transcriptional regulation of embryonic stem cells. In this paper, we analyze how Oct-1 (a similar POU factor) and Sox-2, interact cooperatively at their enhancer binding sites in collective motions. Normal mode analysis (NMA) is implemented to study the collective motions of two complexes with each involving these TFs and an enhancer. The special structure of Oct proteins is analyzed comprehensively, after which each Oct/Sox group is reassembled into two protein pairs. We subsequently propose a segmentation idea to extract the most correlated segments in each pair, using correlations of motion magnitude curves. The median analysis on these correlation values shows the intimacy of subunit POUS (Oct-1) and Sox-2. Using those larger-than-median correlation values, we conduct statistical studies and propose several protein-protein cooperative modes (S and D) coupled with their subtypes. Additional filters are applied and similar results are obtained. A supplementary study on the rotation angle curves reaches an agreement with these modes. Overall, these proposed cooperative modes provide useful information for us to understand the complicated interaction mechanism in the POU/HMG/DNA complexes.
PMCID: PMC3845252  PMID: 24324527
25.  Replication-Dependent and Transcription-Dependent Mechanisms of DNA Double-Strand Break Induction by the Topoisomerase 2-Targeting Drug Etoposide 
PLoS ONE  2013;8(11):e79202.
Etoposide is a DNA topoisomerase 2-targeting drug widely used for the treatment of cancer. The cytoxicity of etoposide correlates with the generation of DNA double-strand breaks (DSBs), but the mechanism of how it induces DSBs in cells is still poorly understood. Catalytically, etoposide inhibits the re-ligation reaction of Top2 after it nicks the two strands of DNA, trapping it in a cleavable complex consisting of two Top2 subunits covalently linked to the 5’ ends of DNA (Top2cc). Top2cc is not directly recognized as a true DSB by cells because the two subunits interact strongly with each other to hold the two ends of DNA together. In this study we have investigated the cellular mechanisms that convert Top2ccs into true DSBs. Our data suggest that there are two mechanisms, one dependent on active replication and the other dependent on proteolysis and transcription. The relative contribution of each mechanism is affected by the concentration of etoposide. We also find that Top2α is the major isoform mediating the replication-dependent mechanism and both Top2α and Top2 mediate the transcription-dependent mechanism. These findings are potentially of great significance to the improvement of etoposide’s efficacy in cancer therapy.
PMCID: PMC3820710  PMID: 24244448

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