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1.  Childhood sexual abuse and the risk for recurrent major depression in Chinese women 
Psychological Medicine  2011;42(2):409-417.
Studies in Western countries have repeatedly shown that women with a history of childhood sexual abuse (CSA) are at increased risk for developing major depression (MD). Would this relationship be found in China?
Three levels of CSA (non-genital, genital, and intercourse) were assessed by self-report in two groups of Han Chinese women: 1970 clinically ascertained with recurrent MD and 2597 matched controls. Diagnostic and other risk factor information was assessed at personal interview. Odds ratios (ORs) were calculated by logistic regression and regression coefficients by linear or Poisson regression.
Any form of CSA was significantly associated with recurrent MD [OR 3.26, 95% confidence interval (CI) 1.95–5.45]. This association strengthened with increasing CSA severity: non-genital (OR 2.47, 95% CI 1.17–5.23), genital (OR 2.77, 95% CI 1.32–5.83) and intercourse (OR 13.35, 95% CI 1.83–97.42). The association between any form of CSA and MD remained significant after accounting for parental history of depression, childhood emotional neglect (CEN), childhood physical abuse (CPA) and parent–child relationship. Among the depressed women, those with CSA had an earlier age of onset, longer depressive episodes and an increased risk for generalized anxiety disorder (GAD; OR 1.92, 95% CI 1.39–2.66) and dysthymia (OR 2.16, 95% CI 1.52–3.09).
In Chinese women CSA is strongly associated with MD and this association increases with greater severity of CSA. Depressed women with CSA have an earlier age of onset, longer depressive episodes and increased co-morbidity with GAD and dysthymia. Although reporting biases cannot be ruled out, our results are consistent with the hypothesis that, as in Western countries, CSA substantially increases the risk for MD in China.
PMCID: PMC3250087  PMID: 21835095
Childhood sexual abuse; co-morbidity; major depression
2.  Effects of Post-harvest Storage Duration and Variety on Nutrient Digestibility and Energy Content Wheat in Finishing Pigs 
This study was conducted to investigate the effects of post-harvest storage duration and wheat variety on the digestibility and energy content of new season wheat fed to finishing pigs. Two wheat varieties (Shi and Zhong) were harvested in 2013 and stored in the warehouse of the Fengning Pig Experimental Base at China Agricultural University for 3, 6, 9, or 12 mo. For each storage period, 12 barrows were placed in metabolism crates and allotted to diets containing 1 of the 2 wheat varieties in a randomized complete block design. The experimental diets contained 97.34% wheat and 2.66% of a vitamin and trace mineral premix. With an extension of storage duration from 3 mo to 12 mo, the gross energy (GE) and crude protein (CP) of the wheat decreased by 2.0% and 12.01%, respectively, while the concentration of neutral detergent fiber (NDF), acid detergent fiber (ADF) and starch content increased by 30.26%, 19.08%, and 2.46%, respectively. Total non-starch polysaccharide, total arabinose, total xylose and total mannose contents decreased by 46.27%, 45.80%, 41.71%, and 75.66%, respectively. However, there were no significant differences in the chemical composition between the two wheat varieties with the exception of ADF which was approximately 13.37% lower in Shi. With an extension of storage duration from 3 mo to 12 mo, the digestible energy (DE), metabolizable energy (ME) content and the apparent total tract digestibility of GE, CP, dry matter, organic matter, ether extract, ADF and metabolizability of energy in wheat decreased linearly (p<0.01) by 5.74%, 7.60%, 3.75%, 3.88%, 3.50%, 2.47%, 26.22%, 27.62%, and 3.94%, respectively. But the digestibility of NDF changed quadratically (p<0.01). There was an interaction between wheat variety and storage time for CP digestibility (p<0.05), such that the CP digestibility of variety Zhong was stable during 9 mo of storage, while the CP digestibility of variety Shi decreased (p<0.05). In conclusion, the GE, DE, and ME of wheat was stable during the first 3 to 6 mo of post-harvest storage, and decreased during the following 6 to 12 mo of storage under the conditions of this study.
PMCID: PMC4554857  PMID: 26323405
Digestibility; Digestible and Metabolizable Energy; Finishing Pigs; Post-harvest Storage; Wheat
3.  The impact of plasma epstein–barr virus DNA and fibrinogen on nasopharyngeal carcinoma prognosis: an observational study 
British Journal of Cancer  2014;111(6):1102-1111.
The impact of combining plasma fibrinogen levels with Epstein–Barr Virus DNA (EBV DNA) levels on the prognosis for patients with nasopharyngeal carcinoma (NPC) was evaluated.
In this observational study, 2563 patients with non-metastatic NPC were evaluated for the effects of circulating plasma fibrinogen and EBV DNA levels on disease-free survival (DFS), distant metastasis-free survival (DMFS), and overall survival (OS).
Compared with the bottom biomarker tertiles, TNM stage-adjusted hazard ratios (HR, 95% confidence intervals (CIs)) for predicting DFS in fibrinogen tertiles 2 to 3 were 1.26 (1.00 to 1.60) and 1.81 (1.45 to 2.26), respectively; HR for EBV DNA tertiles 2 to 3 were 1.49 (1.12 to 1.98) and 4.24 (3.27 to 5.49), respectively. After additional adjustment for established risk factors, both biomarkers were still associated (P for trend <0.001) with reduced DFS (HR: 1.79, 95% CI, 1.43 to 2.25 for top fibrinogen tertiles; HR: 4.04, 95% CI: 3.10 to 5.27 for top EBV DNA tertiles compared with the bottom tertiles). For patients with advanced-stage disease, those with high fibrinogen levels (⩾3.34 g l−1) presented with worse DFS, regardless of EBV DNA ⩾4000 or <4000 copies ml−1 subgroup. Similar findings were observed for DMFS and OS.
Circulating fibrinogen and EBV DNA significantly correlate with NPC patients survival. Combined fibrinogen and EBV DNA data lead to improved prognostic prediction in advanced-stage disease.
PMCID: PMC4453843  PMID: 25051405
nasopharyngeal carcinoma; EBV DNA; fibrinogen; survival
4.  Pathway-selective antagonism of proteinase activated receptor 2 
British Journal of Pharmacology  2014;171(17):4112-4124.
Background and Purpose
Proteinase activated receptor 2 (PAR2) is a GPCR associated with inflammation, metabolism and disease. Clues to understanding how to block PAR2 signalling associated with disease without inhibiting PAR2 activation in normal physiology could be provided by studies of biased signalling.
Experimental Approach
PAR2 ligand GB88 was profiled for PAR2 agonist and antagonist properties by several functional assays associated with intracellular G-protein-coupled signalling in vitro in three cell types and with PAR2-induced rat paw oedema in vivo.
Key Results
In HT29 cells, GB88 was a PAR2 antagonist in terms of Ca2+ mobilization and PKC phosphorylation, but a PAR2 agonist in attenuating forskolin-induced cAMP accumulation, increasing ERK1/2 phosphorylation, RhoA activation, myosin phosphatase phosphorylation and actin filament rearrangement. In CHO-hPAR2 cells, GB88 inhibited Ca2+ release, but activated Gi/o and increased ERK1/2 phosphorylation. In human kidney tubule cells, GB88 inhibited cytokine secretion (IL6, IL8, GM-CSF, TNF-α) mediated by PAR2. A rat paw oedema induced by PAR2 agonists was also inhibited by orally administered GB88 and compared with effects of locally administered inhibitors of G-protein coupled pathways.
Conclusions and Implications
GB88 is a biased antagonist of PAR2 that selectively inhibits PAR2/Gq/11/Ca2+/PKC signalling, leading to anti-inflammatory activity in vivo, while being an agonist in activating three other PAR2-activated pathways (cAMP, ERK, Rho) in human cells. These findings highlight opportunities to design drugs to block specific PAR2-linked signalling pathways in disease, without blocking beneficial PAR2 signalling in normal physiology, and to dissect PAR2-associated mechanisms of disease in vivo.
PMCID: PMC4243983  PMID: 24821440
protease; protease inhibitor; peptide; proteinase activated receptor 2; antagonist; agonist; GPCR; inflammation; biased signalling; cell signalling
5.  Association of Carotid Intima–media Thickness and Atherosclerotic Plaque with Periodontal Status 
Journal of Dental Research  2014;93(8):744-751.
Studies have suggested an association between clinical/subclinical atherosclerosis and periodontal status. The purpose of this study was to investigate the association among maximal carotid intima–media thickness (cIMT), atherosclerotic plaque, and periodontal status in Chinese elderly patients. A cross-sectional study was conducted of 847 participants (age, 70.64 ± 9.03 yr) with ≥10 teeth. A questionnaire survey, routine biochemical tests, a periodontal examination, and maximal cIMT measurement were performed for each. Traditional risk factors for atherogenesis were considered in the statistical analysis. Mean plaque index, which reflects oral hygiene, was correlated with maximal cIMT and atherosclerotic plaque in the study sample overall (β = 0.068, p < .001; OR = 2.051, p < .001) and in euglycemic participants (β = 0.066, p = .008; odds ratio = 2.122, p = .009). In hyperglycemic participants, multiple linear regression analysis (p = .006) and multivariate logistic regression analysis (p = .025) revealed a linear and dose-dependent association between mean clinical attachment loss and maximal cIMT after adjustment for traditional risk factors. Each 1-mm increase in mean clinical attachment loss corresponded to a 0.018-mm increase in maximal cIMT. The risk of atherosclerotic plaque increased by 18.3% with each 1-mm increase in mean clinical attachment loss. Other indicators of periodontal exposure, including percentage of sites with attachment loss ≥ 3 to 5 mm (3%-5%), were also correlated with cIMT and atherosclerotic plaque in hyperglycemic patients. In this elderly population, a linear and dose-dependent association among mean clinical attachment loss, attachment loss 3% to 5%, maximal cIMT, and atherosclerotic plaque was verified in those with hyperglycemia. Poor oral hygiene was correlated with maximal cIMT and atherosclerotic plaque in all participants, including those with normal blood glucose.
PMCID: PMC4293759  PMID: 24935064
atherosclerosis; periodontitis; periodontal attachment loss; oral hygiene; hyperglycemia; cardiovascular diseases
6.  An itinerant antiferromagnetic metal without magnetic constituents 
Nature Communications  2015;6:7701.
The origin of magnetism in metals has been traditionally discussed in two diametrically opposite limits: itinerant and local moments. Surprisingly, there are very few known examples of materials that are close to the itinerant limit, and their properties are not universally understood. In the case of the two such examples discovered several decades ago, the itinerant ferromagnets ZrZn2 and Sc3In, the understanding of their magnetic ground states draws on the existence of 3d electrons subject to strong spin fluctuations. Similarly, in Cr, an elemental itinerant antiferromagnet with a spin density wave ground state, its 3d electron character has been deemed crucial to it being magnetic. Here, we report evidence for an itinerant antiferromagnetic metal with no magnetic constituents: TiAu. Antiferromagnetic order occurs below a Néel temperature of 36 K, about an order of magnitude smaller than in Cr, rendering the spin fluctuations in TiAu more important at low temperatures. This itinerant antiferromagnet challenges the currently limited understanding of weak itinerant antiferromagnetism, while providing insights into the effects of spin fluctuations in itinerant–electron systems.
Sc3In and ZrZn2 are the only two known itinerant ferromagnets that form from non-magnetic constituents. Now, Svanidze et al., evidence itinerant antiferromagnetism in TiAu below 36 K using thermodynamic, transport, muon-based and neutron-based measurements, and density functional analysis.
PMCID: PMC4510670  PMID: 26166042
7.  TBLR1 is a novel prognostic marker and promotes epithelial–mesenchymal transition in cervical cancer 
Wang, J | Ou, J | Guo, Y | Dai, T | Li, X | Liu, J | Xia, M | Liu, L | He, M
British Journal of Cancer  2014;111(1):112-124.
Invasion and metastasis remain a critical issue in cervical cancer. However, the underlying mechanism of it in cervical cancer remains unclear. The newly discovered protein, TBLR1, plays a crucial role in regulating various key cellular functions.
In this study, western blot, real-time RT–PCR, immunohistochemical staining, 3D morphogenesis Matrigel culture, wound healing and Boyden chamber invasion assays, xenografted tumour model, luciferase assays, and chromatin immunoprecipitation assays were used.
The expression of TBLR1 in cervical cancer cell lines and tissues was significantly upregulated at both the RNA and protein levels compared with that in normal cervical cells. Statistical analysis suggested that TBLR1 as an independent prognostic factor was significantly correlated with the clinical stage, survival time and recurrence. Moreover, overexpression of TBLR1 in Hela and Siha cell lines promoted invasion in vitro and in vivo with the increases of the mesenchymal factors vimentin and fibronectin and decreases of the epithelial marker α-catenin. In contrast, RNAi-mediated knockdown of TBLR1 inhibited epithelial–mesenchymal transition in vitro and in vivo. Further study indicated that this might be mediated via the NF-κB and Wnt/β-Catenin signalling pathway, and involve regulation of Snail and Twist.
The TBLR1 protein may be a prognostic marker in cervical cancer and play an important role in the invasion and metastasis of human cervical cancer.
PMCID: PMC4090741  PMID: 24874481
cervical cancer; pelvic lymph node metastasis; epithelial–mesenchymal transition; TBLR1
8.  Effects of Inclusion Levels of Wheat Bran and Body Weight on Ileal and Fecal Digestibility in Growing Pigs 
The objective of this study was to determine the effects of graded inclusions of wheat bran (0%, 9.65%, 48.25% wheat bran) and two growth stages (from 32.5 to 47.2 kg and 59.4 to 78.7 kg, respectively) on the apparent ileal digestibility (AID), apparent total tract digestibility (ATTD) and hindgut fermentation of nutrients and energy in growing pigs. Six light pigs (initial body weight [BW] 32.5±2.1 kg) and six heavy pigs (initial BW 59.4±3.2 kg) were surgically prepared with a T-cannula in the distal ileum. A difference method was used to calculate the nutrient and energy digestibility of wheat bran by means of comparison with a basal diet consisting of corn-soybean meal (0% wheat bran). Two additional diets were formulated by replacing 9.65% and 48.25% wheat bran by the basal diet, respectively. Each group of pigs was allotted to a 6×3 Youden square design, and pigs were fed to three experimental diets during three 11-d periods. Hindgut fermentation values were calculated as the differences between ATTD and AID values. For the wheat bran diets, the AID and ATTD of dry matter (DM), ash, organic matter (OM), carbohydrates (CHO), gross energy (GE), and digestible energy (DE) decreased with increasing inclusion levels of wheat bran (p<0.05). While only AID of CHO and ATTD of DM, ash, OM, CHO, GE, and DE content differed (p<0.05) when considering the BW effect. For the wheat bran ingredient, there was a wider variation effect (p<0.01) on the nutrient and energy digestibility of wheat bran in 9.65% inclusion level due to the coefficient of variation (CV) of the nutrient and energy digestibility being higher at 9.65% compared to 48.25% inclusion level of wheat bran. Digestible energy content of wheat bran at 48.25% inclusion level (4.8 and 6.7 MJ/kg of DM, respectively) fermented by hindgut was significantly higher (p<0.05) than that in 9.65% wheat bran inclusion level (2.56 and 2.12 MJ/kg of DM, respectively), which was also affected (p<0.05) by two growth stages. This increase in hindgut fermentation caused the difference in ileal DE (p<0.05) to disappear at total tract level. All in all, increasing wheat bran levels in diets negatively influences the digestibility of some nutrients in pigs, while it positively affects the DE fermentation in the hindgut.
PMCID: PMC4412981  PMID: 25925062
Digestive Sites; Hindgut Fermentation; Dietary Fiber; Digestibility; Wheat Bran; Growth Stage
9.  Comparison of radiological and clinical features of temporal lobe necrosis in nasopharyngeal carcinoma patients treated with 2D radiotherapy or intensity-modulated radiotherapy 
British Journal of Cancer  2014;110(11):2633-2639.
To compare the imaging and clinical features of temporal lobe necrosis (TLN) in nasopharyngeal carcinoma (NPC) patients treated with two-dimensional radiotherapy (2D-RT) or those with intensity-modulated radiotherapy (IMRT).
We retrospectively analysed NPC patients who underwent 2D-RT (72 patients, 128 temporal lobes) or IMRT (36 patients, 50 lobes) and developed radiation-induced, MRI-confirmed TLN.
White-matter lesions (WMLs), contrast-enhanced lesions, cysts and local mass effects were present in 128 out of 128 vs 48 out of 50 (P=0.078), 123 out of 128 vs 47 out of 50 (P=0.688), 10 out of 128 vs 1 out of 50 (P=0.185) and 57 out of 128 vs 13 out of 50 (P=0.023) temporal lobes, respectively, in the 2D-RT and IMRT groups. The WMLs were more extensive in the 2D-RT group (P<0.001). The maximum diameter of contrast-enhanced lesions was greater in the 2D-RT group (P<0.001), and these lesions tended to extend far away from the nasopharynx. The WMLs and enhancement had no impact on cyst development (both P=1). Local mass effects were always accompanied with contrast-enhanced lesions (P=0.024) but were not correlated with WMLs or cysts (P=0.523 and 0.341, respectively). There were no between-group differences in clinical features (all P-values>0.05), whereas the difference in the incidence of severe debility was of marginal significance (18.1% vs 5.6%, P=0.077).
The IMRT-induced TLN was less extensive and milder than 2D-RT-induced TLN, but both had similar clinical features.
PMCID: PMC4037838  PMID: 24809780
temporal lobe necrosis; nasopharyngeal carcinoma; radiotherapy; radiological features; clinical features
10.  Multipoint targeting of the PI3K/mTOR pathway in mesothelioma 
British Journal of Cancer  2014;110(10):2479-2488.
Mesothelioma is a notoriously chemotherapy-resistant neoplasm, as is evident in the dismal overall survival for patients with those of asbestos-associated disease. We previously demonstrated co-activation of multiple receptor tyrosine kinases (RTKs), including epidermal growth factor receptor (EGFR), MET, and AXL in mesothelioma cell lines, suggesting that these kinases could serve as novel therapeutic targets. Although clinical trials have not shown activity for EGFR inhibitors in mesothelioma, concurrent inhibition of various activated RTKs has pro-apoptotic and anti-proliferative effects in mesothelioma cell lines. Thus, we hypothesised that a coordinated network of multi-RTK activation contributes to mesothelioma tumorigenesis.
Activation of PI3K/AKT/mTOR, Raf/MAPK, and co-activation of RTKs were evaluated in mesotheliomas. Effects of RTK and downstream inhibitors/shRNAs were assessed by measuring mesothelioma cell viability/growth, apoptosis, activation of signalling intermediates, expression of cell-cycle checkpoints, and cell-cycle alterations.
We demonstrate activation of the PI3K/AKT/p70S6K and RAF/MEK/MAPK pathways in mesothelioma, but not in non-neoplastic mesothelial cells. The AKT activation, but not MAPK activation, was dependent on coordinated activation of RTKs EGFR, MET, and AXL. In addition, PI3K/AKT/mTOR pathway inhibition recapitulated the anti-proliferative effects of concurrent inhibition of EGFR, MET, and AXL. Dual targeting of PI3K/mTOR by BEZ235 or a combination of RAD001 and AKT knockdown had a greater effect on mesothelioma proliferation and viability than inhibition of individual activated RTKs or downstream signalling intermediates. Inhibition of PI3K/AKT was also associated with MDM2-p53 cell-cycle regulation.
These findings show that PI3K/AKT/mTOR is a crucial survival pathway downstream of multiple activated RTKs in mesothelioma, underscoring that PI3K/mTOR is a compelling target for therapeutic intervention.
PMCID: PMC4021537  PMID: 24762959
mesothelioma; tyrosine kinases; PI3K/AKT/mTOR; PI3K/AKT/MDM2
11.  Prediction of Digestible and Metabolizable Energy Content of Rice Bran Fed to Growing Pigs 
Two experiments were conducted to determine the digestible energy (DE) and metabolizable energy (ME) content of 19 rice bran samples and to develop prediction equations for DE and ME based on their chemical composition. The 19 rice bran samples came from different rice varieties, processing methods and regions. The basal diet was formulated using corn and soybean meal (74.43% corn and 22.91% soybean meal and 2.66% vitamins and minerals). The 19 experimental diets based on a mixture of corn, soybean meal and 29.2% of each source of rice bran, respectively. In Exp. 1, 108 growing barrows (32.1±4.2 kg) were allotted to 1 of 18 treatments according to a completely randomized design with 6 pigs per treatment. The treatment 1 was the control group which was fed with basal diet. The treatments 2 to 18 were fed with experimental diets. In Exp. 2, two additional rice bran samples were measured to verify the prediction equations developed in Exp. 1. A control diet and two rice bran diets were fed to 18 growing barrows (34.6±3.5 kg). The control and experimental diets formulations were the same as diets in Exp. 1. The results showed that the DE ranged from 14.48 to 16.85 (mean 15.84) MJ/kg of dry matter while the ME ranged from 12.49 to 15.84 (mean 14.31) MJ/kg of dry matter. The predicted values of DE and ME of the two additional samples in Exp. 2 were very close to the measured values.
PMCID: PMC4412995  PMID: 25656179
Chemical Composition; Digestible and Metabolizable Energy; Growing Pigs; Prediction Equations; Process Method; Rice Bran
12.  Seroprevalence of severe fever with thrombocytopenia syndrome virus in southeastern China and analysis of risk factors 
Epidemiology and Infection  2014;143(4):851-856.
Severe fever with thrombocytopenia syndrome virus (SFTSV) has been prevalent for some time in China and it was first identified in 2010. However, the seroprevalence of SFTSV in the general population in southeastern China and risk factors associated with the infection are currently unclear. Blood samples were collected from seven counties across Zhejiang province and tested for the presence of SFTSV-specific IgG antibodies by ELISA. A total of 1380 blood samples were collected of which 5·51% were seropositive for SFTSV with seroprevalence varying significantly between sites. Seroprevalence of SFTSV in people who were family members of the patient, lived in the same village as the patient, or lived in a different village than the patient varied significantly. There was significant difference in seroprevalence between participants who bred domestic animals and participants who did not. Domestic animals are probably potential reservoir hosts and contact with domestic animals may be a transmission route of SFTSV.
PMCID: PMC4411641  PMID: 24866248
Seroprevalence; severe fever with thrombocytopenia syndrome; risk factor
13.  Prognostic value of magnetic resonance imaging-detected cranial nerve invasion in nasopharyngeal carcinoma 
Liu, X | Liu, L-Z | Mao, Y-P | Chen, L | Tang, L-L | Zhou, G-Q | Sun, Y | Yue, D | Lin, A-H | Li, L | Ma, J
British Journal of Cancer  2014;110(6):1465-1471.
We previously reported that magnetic resonance imaging evidence of cranial nerve invasion was an unfavourable prognostic factor in nasopharyngeal carcinoma. However, the prognostic value of this evidence in nasopharyngeal carcinoma treated with intensity-modulated radiotherapy remains unknown.
We retrospectively analysed 749 nasopharyngeal carcinoma patients who underwent intensity-modulated radiotherapy.
Cranial nerve invasion was observed in 299 (39.9%) patients with T3–4 disease. In T3–4 nasopharyngeal carcinoma, magnetic resonance imaging-detected cranial nerve invasion was associated with inferior 5-year overall survival, distant metastasis-free survival, and locoregional relapse-free survival (P=0.002, 0.003, and 0.012, respectively). Multivariate analyses confirmed that cranial nerve invasion was an independent prognostic factor for distant metastasis-free survival (hazard ratio, 1.927; P=0.019) and locoregional relapse-free survival (hazard ratio, 2.605; P=0.032). Furthermore, the receiver-operating characteristic curves verified that the predictive validity of T classifications was significantly improved when combined with magnetic resonance imaging-detected cranial nerve invasion in terms of death, distant metastasis, and locoregional recurrence (P=0.015, 0.021 and 0.008, respectively).
Magnetic resonance imaging-detected cranial nerve invasion is an independent adverse prognostic factor in nasopharyngeal carcinoma treated with intensity-modulated radiotherapy.
PMCID: PMC3960608  PMID: 24496459
nasopharyngeal neoplasms; perineural invasion; magnetic resonance imaging; prognosis; prognostic factor
14.  HBx mutants differentially affect the activation of hypoxia-inducible factor-1α in hepatocellular carcinoma 
British Journal of Cancer  2013;110(4):1066-1073.
Mutations in HBx gene are frequently found in HBV-associated hepatocellular carcinoma (HCC). Activation of hypoxia-inducible factor-1α (HIF-1α) contributes to HCC development and progression. Wild-type HBx has been demonstrated to activate HIF-1α, but the effect of HBx mutations on HIF-1α has not been elucidated.
HBx mutations were identified by gene sequencing in 101 HCC tissues. Representative HBx mutants were cloned and transfected into HCC cells. Expression and activation of HIF-1α were analysed by western blot and luciferase assays, respectively. The relationship between HBx mutants and HIF-1α expression in HCC tissues was also evaluated.
The dual mutations K130M/V131I enhanced the functionality of HBx as they upregulated the expression and transcriptional activity of HIF-1α. The C-terminal truncations and deletion mutations, however, weakened the ability of HBx to upregulate HIF-1α. Meanwhile, the C-terminus was further found to be essential for the stability and transactivation of HBx. In the HCC tissues, there was a positive association between the HBx mutants and HIF-1α expression.
Different mutations of HBx exert differentiated effects on the functionality of HIF-1α, however, the overall activity of HBx mutants appears to increase the expression and transcriptional activity of HIF-1α.
PMCID: PMC3929872  PMID: 24346287
HBx; HIF-1α; mutation; hepatocellular carcinoma
16.  High levels of LDL-C combined with low levels of HDL-C further increase platelet activation in hypercholesterolemic patients 
High levels of low-density lipoprotein cholesterol (LDL-C) enhance platelet activation, whereas high levels of high-density lipoprotein cholesterol (HDL-C) exert a cardioprotective effect. However, the effects on platelet activation of high levels of LDL-C combined with low levels of HDL-C (HLC) have not yet been reported. We aimed to evaluate the platelet activation marker of HLC patients and investigate the antiplatelet effect of atorvastatin on this population. Forty-eight patients with high levels of LDL-C were enrolled. Among these, 23 had HLC and the other 25 had high levels of LDL-C combined with normal levels of HDL-C (HNC). A total of 35 normocholesterolemic (NOMC) volunteers were included as controls. Whole blood flow cytometry and platelet aggregation measurements were performed on all participants to detect the following platelet activation markers: CD62p (P-selectin), PAC-1 (GPIIb/IIIa), and maximal platelet aggregation (MPAG). A daily dose of 20 mg atorvastatin was administered to patients with high levels of LDL-C, and the above assessments were obtained at baseline and after 1 and 2 months of treatment. The expression of platelets CD62p and PAC-1 was increased in HNC patients compared to NOMC volunteers (P<0.01 and P<0.05). Furthermore, the surface expression of platelets CD62p and PAC-1 was greater among HLC patients than among HNC patients (P<0.01 and P<0.05). Although the expression of CD62p and PAC-1 decreased significantly after atorvastatin treatment, it remained higher in the HLC group than in the HNC group (P<0.05 and P=0.116). The reduction of HDL-C further increased platelet activation in patients with high levels of LDL-C. Platelet activation remained higher among HLC patients regardless of atorvastatin treatment.
PMCID: PMC4321223  PMID: 25466164
Low-density lipoprotein cholesterol; High-density lipoprotein cholesterol; Platelet activation; Statins; PAC-1; CD62p
17.  A combination of STI571 and BCR-ABL1 siRNA with overexpressed p15INK4B induced enhanced proliferation inhibition and apoptosis in chronic myeloid leukemia 
p15INK4B, a cyclin-dependent kinase inhibitor, has been recognized as a tumor suppressor. Loss of or methylation of the p15INK4B gene in chronic myeloid leukemia (CML) cells enhances myeloid progenitor formation from common myeloid progenitors. Therefore, we examined the effects of overexpressed p15INK4B on proliferation and apoptosis of CML cells. Overexpression of p15INK4B inhibited the growth of K562 cells by downregulation of cyclin-dependent kinase 4 (CDK4) and cyclin D1 expression. Overexpression of p15INK4B also induced apoptosis of K562 cells by upregulating Bax expression and downregulating Bcl-2 expression. Overexpression of p15INK4B together with STI571 (imatinib) or BCR-ABL1 small interfering RNA (siRNA) also enhanced growth inhibition and apoptosis induction of K562 cells. The enhanced effect was also mediated by reduction of cyclin D1 and CDK4 and regulation of Bax and Bcl-2. In conclusion, our study may provide new insights into the role of p15INK4B in CML and a potential therapeutic target for overcoming tyrosine kinase inhibitor resistance in CML.
PMCID: PMC4244677  PMID: 25387678
Apoptosis; Chronic myeloid leukemia; p15INK4B; STI571 (Gleevec, imatinib)
18.  Enrichment of c-Met+ tumorigenic stromal cells of giant cell tumor of bone and targeting by cabozantinib 
Cell Death & Disease  2014;5(10):e1471-.
Giant cell tumor of bone (GCTB) is a very rare tumor entity, which is little examined owing to the lack of established cell lines and mouse models and the restriction of available primary cell lines. The stromal cells of GCTB have been made responsible for the aggressive growth and metastasis, emphasizing the presence of a cancer stem cell population. To identify and target such tumor-initiating cells, stromal cells were isolated from eight freshly resected GCTB tissues. Tumorigenic properties were examined by colony and spheroid formation, differentiation, migration, MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, immunohistochemistry, antibody protein array, Alu in situ hybridization, FACS analysis and xenotransplantation into fertilized chicken eggs and mice. A sub-population of the neoplastic stromal cells formed spheroids and colonies, differentiated to osteoblasts, migrated to wounded regions and expressed the metastasis marker CXC-chemokine receptor type 4, indicating self-renewal, invasion and differentiation potential. Compared with adherent-growing cells, markers for pluripotency, stemness and cancer progression, including the CSC surface marker c-Met, were enhanced in spheroidal cells. This c-Met-enriched sub-population formed xenograft tumors in fertilized chicken eggs and mice. Cabozantinib, an inhibitor of c-Met in phase II trials, eliminated CSC features with a higher therapeutic effect than standard chemotherapy. This study identifies a c-Met+ tumorigenic sub-population within stromal GCTB cells and suggests the c-Met inhibitor cabozantinib as a new therapeutic option for targeted elimination of unresectable or recurrent GCTB.
PMCID: PMC4237261  PMID: 25321478
19.  Live Combined Bacillus subtilis and Enterococcus faecium Ameliorate Murine Experimental Colitis by Immunosuppression 
Live combined Bacillus subtilis and Enterococcus faecium ameliorate murine experimental colitis by immunosuppression manifested by downregulation of TLRs, macrophages, Th1, and Th2 but upregulation of Tregs.
PMCID: PMC4170745  PMID: 25276470
20.  Palmoplantar Peeling Secondary to Sirolimus Therapy 
Sirolimus (rapamycin) is an immunosuppressive agent commonly used in transplant recipients. Although sirolimus has less renal toxicity than calcineurin inhibitors, its use has been limited by its side effects. The most common cutaneous pathologies associated with sirolimus are inflammatory acneiform eruptions, lymphedema and aphthous ulcers. We present a novel cutaneous manifestation of sirolimus therapy that limited its use in at least one transplant recipient. Upon commencing sirolimus therapy, four solid organ transplant recipients developed tender, nonpruritic palmoplantar peeling within the first month of therapy. The peeling clinically resembled a mild form of hand-foot syndrome, yet none of the patients had been treated with chemotherapeutics. Desquamation presented on the palms and soles with dry vesicles and minor peeling extending to the dorsal aspects of the hands and feet. Histologically, the lesions were noninflammatory; the epidermis showed subtle separation between keratinocytes, suggesting either spongiosis or a defect in intercellular adhesion. One patient opted to discontinue treatment because of the tenderness associated with the palmoplantar peeling, which resulted in complete resolution within 2 weeks.
PMCID: PMC4148300  PMID: 24224736
Acral; desquamation; palmoplantar; peeling; rapamycin; sirolimus
21.  Initiation of anti-TNF therapy and the risk of optic neuritis; from the Safety Assessment of Biologic ThERapy (SABER) Study 
American journal of ophthalmology  2012;155(1):183-189.e1.
Optic neuritis (ON) cases have been reported in patients using anti-tumor necrosis factor (TNF) alpha therapy. However, no population-based studies have been conducted to assess the risk of this complication associated with anti-TNF drugs.
Cohort study
New users of anti-TNF therapy (etanercept, infliximab, or adalimumab) or non-biologic disease modifying agents (DMARDs) during 2000–2007 from the following data sources: Kaiser Permanente Northern California, Pharmaceutical Assistance Contract for the Elderly, Tennessee Medicaid, and National Medicaid/Medicare.
We used validated algorithms to identify ON cases occurring after onset of new drug exposure. We calculated and compared ON rates between exposure groups.
Main outcome measures
ON incidence rates by medication exposure group
We identified 61,227 eligible inflammatory disease patients with either new anti-TNF or new non-biologic DMARD use. Among this cohort, we found three ON cases among anti-TNF new users, occuring a median 123 days (range, 37–221 days) after anti- TNF start. The crude incidence rate of ON across all disease indications among anti-TNF new users was 10.4 (95% CI 3.3–32.2) cases per 100,000 person-years. In a sensitivity analysis considering current or past anti-TNF or DMARD use, we identified a total of 6 ON cases; 3 among anti-TNF users and 3 among DMARD users. Crude ON rates were similar among anti-TNF and DMARD groups, 4.5 (95% CI 1.4–13.8) and 5.4 (95% CI 1.7–16.6) per 100,000 person-years, respectively.
Optic neuritis is rare among those who initiate anti-TNF therapy and occurs with similar frequency among those with non-biologic DMARD exposure.
PMCID: PMC4142597  PMID: 22967869
shingles; zoster; herpes; biologic therapy; tumor necrosis factor-alpha; rheumatoid arthritis; adverse events; psoriasis
22.  Effect of fibrosis on adverse events in patients with hepatitis C treated with telaprevir 
Data about adverse events are needed to optimise telaprevir-based therapy in a broad spectrum of patients.
To investigate adverse events of telaprevir-based therapy in patients with and without advanced fibrosis or cirrhosis in a real-world setting.
Data on 174 hepatitis C-infected patients initiating telaprevir-based therapy at Mount Sinai and Montefiore medical centres were collected. Biopsy data and FIB-4 scores identified patients with advanced fibrosis. Multivariable fully adjusted models were built to assess the effect of advanced fibrosis on specific adverse events and discontinuation of treatment due to an adverse event.
Patients with (n = 71) and without (n = 103) advanced fibrosis were similar in BMI, ribavirin exposure, gender, prior treatment history, haemoglobin and creatinine, but differed in race. Overall, 47% of patients completed treatment and 40% of patients achieved SVR. Treated patients with and without advanced fibrosis or cirrhosis had similar rates of adverse events; advanced fibrosis, however, was independently associated with ano-rectal discomfort (P = 0.03). Three patients decompensated and had advanced fibrosis. The discontinuation of all treatment medications due to an adverse event was significantly associated with older age (P = 0.01), female gender (P = 0.01) and lower platelets (P = 0.03).
Adverse events were common, but were not significantly related to the presence of advanced fibrosis or cirrhosis. More critical monitoring in older and female patients with low platelets throughout treatment may reduce adverse event-related discontinuations.
PMCID: PMC4141692  PMID: 24266536
23.  Experimental Analyses of the Major Parameters Affecting the Intensity of Outbursts of Coal and Gas 
The Scientific World Journal  2014;2014:185608.
With an increase in mining depth and production, the intensity and frequency of outburst of coal and gas have a tendency to increase. Estimating the intensity of outbursts of coal and gas plays an important role because of its relation with the risk value. In this paper, we described the semiquantitative relations between major parameters and intensity of outburst based on physical experiments. The results showed increment of geostress simulated by horizontal load (from 1.4, 2.4, 3.2, to 3.4 MPa) or vertical load (from 2, 3, 3.6, to 4 MPa) improved the relative intensity rate (3.763–7.403% and 1.273–7.99%); the increment of porosity (from 1.57, 2.51, 3, to 3.6%) improved the relative intensity rate from 3.8 to 13.8%; the increment of gas pressure (from 0, 0.5, 0.65, 0.72, 1, to 1.5 Mpa) induced the relative intensity rate to decrease from 38.22 to 0%; the increment of water content (from 0, 2, 4, to 8%) caused the relative intensity rate to drop from 5.425 to 0.5%. Furthermore, sensitivity and range analysis evaluates coupled factors affecting the relative intensity. In addition, the distinction with initiation of outburst of coal and gas affected by these parameters is discussed by the relative threshold of gas content rate.
PMCID: PMC4139081  PMID: 25162042
24.  The reliability of diagnostic coding and laboratory data to identify tuberculosis and nontuberculous mycobacterial disease among rheumatoid arthritis patients using antitumor necrosis factor therapy 
Anti-tumor necrosis factor alpha (anti-TNF) therapies are associated with severe mycobacterial infections in rheumatoid arthritis patients. We developed and validated electronic record search algorithms for these serious infections.
The study used electronic clinical, microbiologic, and pharmacy records from Kaiser Permanente Northern California (KPNC) and the Portland Veterans Affairs Medical Center (PVAMC). We identified suspect tuberculosis and nontuberculous mycobacteria (NTM) cases using inpatient and outpatient diagnostic codes, culture results, and anti-tuberculous medication dispensings. We manually reviewed records to validate our case-finding algorithms.
We identified 64 tuberculosis and 367 NTM potential cases respectively. For tuberculosis, diagnostic code positive predictive value (PPV) was 54% at KPNC and 9% at PVAMC. Adding medication dispensings improved these to 87% and 46% respectively. Positive tuberculosis cultures had a PPV of 100% with sensitivities of 79% (KPNC) and 55% (PVAMC). For NTM, the PPV of diagnostic codes was 91% (KPNC) and 76% (PVAMC). At KPNC, ≥1 positive NTM culture was sensitive (100%) and specific (PPV, 74%) if non-pathogenic species were excluded; at PVAMC, ≥1 positive NTM culture identified 76% of cases with PPV of 41%. Application of the American Thoracic Society NTM microbiology criteria yielded the highest PPV (100% KPNC, 78% PVAMC).
The sensitivity and predictive value of electronic microbiologic data for tuberculosis and NTM infections is generally high, but varies with different facilities or models of care. Unlike NTM, tuberculosis diagnostic codes have poor PPV, and in the absence of laboratory data, should be combined with anti-tuberculous therapy dispensings for pharmacoepidemiologic research.
PMCID: PMC4094092  PMID: 21351303
tuberculosis; nontuberculous mycobacteria; biologic therapy; tumor necrosis factoralpha; electronic medical records; case-finding
25.  Asparagine synthetase is an independent predictor of surgical survival and a potential therapeutic target in hepatocellular carcinoma 
British Journal of Cancer  2013;109(1):14-23.
Asparagine synthetase (ASNS) is associated with drug resistance in leukaemia, and the function of this enzyme in the context of hepatocellular carcinoma (HCC) is not clear. In this study, the relationship between ASNS expression and clinical outcomes after surgical resection was investigated, and the therapeutic value of ASNS was also evaluated.
The expression of ASNS was evaluated in HCC samples by real-time PCR and immunohistochemistry assays. The correlation between ASNS expression and clinicopathological features was investigated. Potential clinicopathological prognostic factors were examined by univariate and multivariate survival analysis. Asparagine synthetase was overexpressed and knocked down in HCC cell lines to assess the influence of the enzyme on cell proliferation, migration and tumourigenicity. L-asparaginase was used to treat HCC cells with high or low levels of ASNS in vitro and in vivo to examine the therapeutic efficacy.
The expression of ASNS was higher in HCC tumour tissues and was closely correlated with the serum AFP level, tumour size, microscopic vascular invasion, tumour encapsulation, TNM stage and BCLC stage. Patients with low ASNS expression levels had a poor prognosis with respect to overall survival (OS). The multivariate survival analysis indicated that ASNS is an independent prognostic factor for OS. Furthermore, functional studies demonstrated that ASNS significantly inhibits the proliferation, migration and tumourigenicity of HCC cells. The knockdown of ASNS markedly increased sensitivity to L-asparaginase, indicating that cells with different ASNS protein levels have different sensitivities to L-asparaginase.
The expression of ASNS is an independent factor affecting the survival of HCC patients, and low ASNS expression in HCC was correlated with worse surgical outcomes. The ASNS may be a promising therapeutic target for the treatment of HCC.
PMCID: PMC3708586  PMID: 23764751
ASNS; hepatocellular carcinoma; prognosis; predictive biomarker; L-asparaginase

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