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1.  Aberrant methylation of DACT1 and DACT2 are associated with tumor progression and poor prognosis in esophageal squamous cell carcinoma 
The DACT (Dishevelled-associated antagonist of β-catenin) family of scaffold proteins may play important roles in tumorigenesis. However, the epigenetic changes of DACT1, 2, 3 and their effect on esophageal squamous cell carcinoma (ESCC) have not been investigated so far. The aim of this study was to investigate the promoter methylation and expression of DACT family, in order to elucidate more information on the role of DACT with regard to the progression and prognosis of ESCC.
MSP and BGS methods were respectively applied to examine the methylation status of DACT; RT-PCR, Western blot and immunohistochemistry methods were respectively used to determine the mRNA and protein expression of DACT; MTT, Colony-formation and Wound-healing assay were performed to assess the effect of DACT1 and DACT2 on proliferation and migration of esophageal cancer cells.
Frequent reduced expression of DACT1, DACT2 and DACT3 were found in esophageal cancer cell lines and the expression levels of DACT1 and DACT2 were reversed by 5-Aza-Dc. Decreased mRNA and protein expression of DACT1 and DACT2 were observed in ESCC tumor tissues and were associated with the methylation status of transcription start site (TSS) region. The hypermethylation of CpG islands (CGI) shore region in DACT1 was observed both in tumor and corresponding adjacent tissues but wasn’t related to the transcriptional inhibition of DACT1. The methylation status of TSS region in DACT1 and DACT2 and the protein expression of DACT2 were independently associated with ESCC patients’ prognosis.
The TSS region hypermethylation may be one of the main mechanisms for reduced expression of DACT1 and DACT2 in ESCC. The simultaneous methylation of DACT1 and DACT2 may play important roles in progression of ESCC and may serve as prognostic methylation biomarkers for ESCC patients.
Electronic supplementary material
The online version of this article (doi:10.1186/s12929-016-0308-6) contains supplementary material, which is available to authorized users.
PMCID: PMC5225534  PMID: 28077137
Esophageal squamous cell carcinoma; DACT gene; Methylation; Prognosis
2.  Transcriptome profiling reveals the genetic basis of alkalinity tolerance in wheat 
BMC Genomics  2017;18:24.
Soil alkalinity shows significant constraints to crop productivity; however, much less attention has been paid to analyze the effect of soil alkalinity on plant growth and development. Shanrong No. 4 (SR4) is an alkalinity tolerant bread wheat cultivar selected from an asymmetric somatic hybridization between the bread wheat cultivar Jinan 177 (JN177) and tall wheatgrass (Thinopyrum ponticum), which is a suitable material for studying alkalinity tolerant associate genes.
The growth of SR4 plant seedlings was less inhibited than that of JN177 when exposed to alkalinity stress conditions. The root cytosolic Na+/K+ ratio in alkalinity stressed SR4 was lower than in JN177, while alkalinity stressed SR4 contained higher level of nutrient elements than in JN177. SR4 plant seedlings accumulated less malondialdehyde (MDA) and reactive oxygen species (ROS), it also showed higher activity of ROS scavenging enzymes than JN177 under alkalinity stress. The root intracellular pH decreased in both alkalinity stressed JN177 and SR4, however, it was much lower in SR4 than in JN177 under alkalinity stress. The transcriptomes of SR4 and JN177 seedlings exposed to alkalinity stress were analyzed by digital gene expression tag profiling method. Alkalinity stress conditions up- and down-regulated a large number of genes in the seedling roots that play the functions in the categories of transcription regulation, signal transduction and protein modification.
SR4 expresses a superior tolerance to alkaline stress conditions which is due to its strong absorbing ability for nutrient ions, a strong regulating ability for intracellular and rhizosphere pH and a more active ROS scavenging ability.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-016-3421-8) contains supplementary material, which is available to authorized users.
PMCID: PMC5217398  PMID: 28056779
Alkali tolerance; Digital gene expression; pH; Reactive oxygen species; Wheat
3.  Inhibition of MicroRNA-149-5p Induces Apoptosis of Acute Myeloid Leukemia Cell Line THP-1 by Targeting Fas Ligand (FASLG) 
This study was aimed to reveal the role of miR-149-5p in acute myeloid leukemia (AML) cells apoptosis and the possible mechanism involved.
The expression of miR-149-5p in leukemia cell lines, as well as the blood and bone marrow (BM) samples from leukemia patients, were monitored by reverse-transcription polymerase chain reaction (RT-PCR). AML cell line THP-1 was transfected with miR-149-5p mimic or inhibitor, and then cell apoptosis was determined using the APO Percentage assay kit. The target of miR-149-5p was predicted by using the database, and verified by RT-PCR, Western blot, and Dual-Luciferase reporter assays. Further, small interfering RNA (siRNA) against the target gene was co-transfected with miR-149-5p inhibitor, and then the cell apoptosis and the expression of apoptosis-related proteins were assessed.
MiR-149-5p was significantly up-regulated in leukemia cell lines and samples from leukemia patients (P<0.01 or P<0.001), especially in THP-1 cells and samples from AML patients. Cell apoptosis was significantly decreased by miR-149-5p overexpression (P<0.01) and increased by miR-149-5p suppression (P<0.05). Fas Ligand (FASLG) was a direct target of miR-149-5p, and was negatively regulated by miR-149-5p. More importantly, the inductive effects of miR-149-5p suppression on cell apoptosis were abrogated by si-FASLG (P<0.01). Furthermore, the up-regulative effects of miR-149-5p suppression on the phosphorylated form of Fas-associated via death domain (p-FADD), caspase-8, caspase-2, caspase-3, and the cleaved forms of these caspases were abrogated by si-FASLG.
Inhibition of miR-149-5p can induce apoptosis in THP-1 cells. These inductive effects might be via targeting FASLG and activating FADD and caspases.
PMCID: PMC5207011  PMID: 28013316
Apoptosis; Fas Ligand Protein; Leukemia, Myeloid, Acute; MicroRNAs
4.  Patient-specific structural effects on hemodynamics in the ischemic lower limb artery 
Scientific Reports  2016;6:39225.
Lower limb peripheral artery disease is a prevalent chronic non-communicable disease without obvious symptoms. However, the effect of ischemic lower limb peripheral arteries on hemodynamics remains unclear. In this study, we investigated the variation of the hemodynamics caused by patient-specific structural artery characteristics. Computational fluid dynamic simulations were performed on seven lower limb (including superficial femoral, deep femoral and popliteal) artery models that were reconstructed from magnetic resonance imaging. We found that increased wall shear stress (WSS) was mainly caused by the increasing severity of stenosis, bending, and branching. Our results showed that the increase in the WSS value at a stenosis at the bifurcation was 2.7 Pa. In contrast, the isolated stenosis and branch caused a WSS increase of 0.7 Pa and 0.5 Pa, respectively. The WSS in the narrow popliteal artery was more sensitive to a reduction in radius. Our results also demonstrate that the distribution of the velocity and pressure gradient are highly structurally related. At last, Ultrasound Doppler velocimeter measured result was presented as a validation. In conclusion, the distribution of hemodynamics may serve as a supplement for clinical decision-making to prevent the occurrence of a morbid or mortal ischemic event.
PMCID: PMC5156942  PMID: 27976693
5.  Monitoring Building Deformation with InSAR: Experiments and Validation 
Sensors (Basel, Switzerland)  2016;16(12):2182.
Synthetic Aperture Radar Interferometry (InSAR) techniques are increasingly applied for monitoring land subsidence. The advantages of InSAR include high accuracy and the ability to cover large areas; nevertheless, research validating the use of InSAR on building deformation is limited. In this paper, we test the monitoring capability of the InSAR in experiments using two landmark buildings; the Bohai Building and the China Theater, located in Tianjin, China. They were selected as real examples to compare InSAR and leveling approaches for building deformation. Ten TerraSAR-X images spanning half a year were used in Permanent Scatterer InSAR processing. These extracted InSAR results were processed considering the diversity in both direction and spatial distribution, and were compared with true leveling values in both Ordinary Least Squares (OLS) regression and measurement of error analyses. The detailed experimental results for the Bohai Building and the China Theater showed a high correlation between InSAR results and the leveling values. At the same time, the two Root Mean Square Error (RMSE) indexes had values of approximately 1 mm. These analyses show that a millimeter level of accuracy can be achieved by means of InSAR technique when measuring building deformation. We discuss the differences in accuracy between OLS regression and measurement of error analyses, and compare the accuracy index of leveling in order to propose InSAR accuracy levels appropriate for monitoring buildings deformation. After assessing the advantages and limitations of InSAR techniques in monitoring buildings, further applications are evaluated.
PMCID: PMC5191161  PMID: 27999403
building deformation monitoring; InSAR; accuracy index; validation test; OLS regression analysis; measurement of error analysis
6.  TGF-β1 Induces Polypyrimidine Tract-Binding Protein to Alter Fibroblasts Proliferation and Fibronectin Deposition in Keloid 
Scientific Reports  2016;6:38033.
Human dermal fibrotic disease keloid has been a clinical challenge because of its tumour-like growth and the lack of effective therapy. Dysregulated alternative splicing events have been demonstrated in tumours and fibrosis. In the current study, for the first time, it was demonstrated that the splicing regulator polypyrimidine tract-binding protein (PTB), which plays a pivotal role in tumour proliferation, invasion and metastasis, is overexpressed in keloid tissues and fibroblasts. Additionally, TGF-β1 upregulated the expressions of PTB and its upstream regulator, C-MYC, in keloid fibroblasts. Furthermore, we suppressed PTB using siRNA in keloid fibroblasts and in a keloid xenograft nude mouse model. PTB knockdown significantly slowed the proliferation of keloid fibroblasts and accelerated the regression of transplanted keloid tissues, which was accompanied by a shift in the alternative splicing of USP5 and RTN4. Moreover, when PTB was suppressed, there was a reduction in excessive deposition of FN1 and COL3A1 in transplanted keloid tissues. However, only FN1 was downregulated in keloid fibroblasts that were cultured in media supplemented with TGF-β1. Our study provides evidence for the role of PTB in keloid pathophysiology and offers a novel therapeutic target for keloids. Most importantly, the role TGF-β1 regulation of PTB may provide new insights into the mechanisms underlying inflammatory cytokine-induced fibrosis.
PMCID: PMC5126665  PMID: 27897224
7.  Effect of intensive insulin treatment on plasma levels of lipoprotein-associated phospholipase A2 and secretory phospholipase A2 in patients with newly diagnosed type 2 diabetes 
China has the highest absolute disease burden of diabetes worldwide. For diabetic patients, diabetes-related vascular complications are major causes of morbidity and mortality. The roles of lipoprotein-associated phospholipase A2 (Lp-PLA2) and secretory phospholipase A2 (sPLA2) as inflammatory markers have been recently evaluated in the pathogenesis of both diabetes and atherosclerosis. We aimed to determine the mechanism through which patients with newly diagnosed type 2 diabetes gain long-term vascular benefit from intensive insulin therapy by evaluating the change in Lp-PLA2 and sPLA2 levels after early intensive insulin treatment and its relevance with insulin resistance and pancreatic β-cell function.
In total, 90 patients with newly diagnosed type 2 diabetes mellitus were enrolled. All patients received continuous subcutaneous insulin infusion (CSII) for approximately 2 weeks. Intravenous glucose-tolerance test (IVGTT) and oral glucose-tolerance test (OGTT) were performed, and plasma concentrations of Lp-PLA2 and sPLA2 were measured before and after CSII.
Levels of Lp-PLA2 and sPLA2 were significantly higher in diabetic patients with macroangiopathy than in those without (P < 0.05). After CSII, the sPLA2 level decreased significantly in all diabetic patients (P < 0.05), while the Lp-PLA2 level changed only in those with macroangiopathy (P < 0.05). The area under the curve of insulin in IVGTT and OGTT, the acute insulin response (AIR3–5), early phase of insulin secretion (ΔIns30/ΔG30), modified β-cell function index, and homeostatic model assessment for β-cell function (HOMA-β) increased after treatment even when adjusted for the influence of insulin resistance (IR; P < 0.001). The HOMA-IR was lower after treatment, and the three other indicators adopted to estimate insulin sensitivity (ISIced, IAI, and QUICKI) were higher after treatment (P < 0.05). Correlation analysis showed that the decrease in the Lp-PLA2 and sPLA2 levels was positively correlated with a reduction in HOMA-IR after CSII (P < 0.05). Additionally, multiple linear regression analysis showed that Lp-PLA2 and sPLA2 independently correlated with HOMA-IR (P < 0.05).
Lp-PLA2 and sPLA2 are closely related to insulin resistance and macroangiopathy in diabetic patients. Intensive insulin therapy might help improve IR and protect against diabetic macroangiopathy by influencing the Lp-PLA2 and sPLA2 levels.
Trial registration
ChiCTR-TRC-10001618 2010 September 16.
PMCID: PMC5120429  PMID: 27881128
Type 2 diabetes, newly diagnosed; Intensive insulin treatment; Atherosclerosis; Lp-PLA2; sPLA2
8.  Statin as a Combined Therapy for Advanced-Stage Ovarian Cancer: A Propensity Score Matched Analysis 
BioMed Research International  2016;2016:9125238.
Background. Despite the great achievements in the treatment of advanced-stage ovarian cancer, it is still a severe condition with an unfavorable 5-year survival rate. Statins have been suggested to reduce the risk of several cancers beyond their cholesterol-lowing effects. However, the prognostic significance of statins in patients with advanced-stage ovarian cancer remains controversial. Methods. A retrospective study was performed to evaluate the association between statin intake and overall survival (OS) among patients with advanced-stage ovarian cancer. Patients who underwent cytoreductive surgery followed by courses of intravenous chemotherapy were matched through a propensity score analysis. Results. A total of 60 propensity-matched patients were included. Women in statin group showed a similar OS than the nonstatin counterparts (P = 0.966), whereas residual tumor was significantly associated with better OS (P = 0.013) and was an independent factor that associated with OS (P = 0.002, hazard ratio = 5.460, and 95% confidence interval: 1.894 to 15.742) in multivariable analysis. Conclusions. Our results suggested that statin usage was not associated with improved OS in patients with advanced-stage ovarian cancer undergoing surgery and chemotherapy. Considering the retrospective nature and the relative small sample size of the study, further prospective studies and random control trials are needed.
PMCID: PMC5128698  PMID: 27975064
9.  NANOG reprograms prostate cancer cells to castration resistance via dynamically repressing and engaging the AR/FOXA1 signaling axis 
Cell Discovery  2016;2:16041-.
The pluripotency transcription factor NANOG has been implicated in tumor development, and NANOG-expressing cancer cells manifest stem cell properties that sustain tumor homeostasis, mediate therapy resistance and fuel tumor progression. However, how NANOG converges on somatic circuitry to trigger oncogenic reprogramming remains obscure. We previously reported that inducible NANOG expression propels the emergence of aggressive castration-resistant prostate cancer phenotypes. Here we first show that endogenous NANOG is required for the growth of castration-resistant prostate cancer xenografts. Genome-wide chromatin immunoprecipitation sequencing coupled with biochemical assays unexpectedly reveals that NANOG co-occupies a distinctive proportion of androgen receptor/Forkhead box A1 genomic loci and physically interacts with androgen receptor and Forkhead box A1. Integrative analysis of chromatin immunoprecipitation sequencing and time-resolved RNA sequencing demonstrates that NANOG dynamically alters androgen receptor/Forkhead box A1 signaling leading to both repression of androgen receptor-regulated pro-differentiation genes and induction of genes associated with cell cycle, stem cells, cell motility and castration resistance. Our studies reveal global molecular mechanisms whereby NANOG reprograms prostate cancer cells to a clinically relevant castration-resistant stem cell-like state driven by distinct NANOG-regulated gene clusters that correlate with patient survival. Thus, reprogramming factors such as NANOG may converge on and alter lineage-specific master transcription factors broadly in somatic cancers, thereby facilitating malignant disease progression and providing a novel route for therapeutic resistance.
PMCID: PMC5109294  PMID: 27867534
AR; cancer stem cells; castration resistance; FOXA1; NANOG; prostate cancer
11.  Assessment of the relationship between non‐alcoholic fatty liver disease and diabetic complications 
Non‐alcoholic fatty liver disease (NAFLD) is a metabolic disorder of the liver. The relationship between NAFLD and type 2 diabetes remains largely unknown. The aim of the present study was to determine the incidence of complications arising from the interaction between NAFLD and type 2 diabetes.
Materials and Methods
A total of 212 individuals with type 2 diabetes were included in the study. The presence of NAFLD was determined in individuals using abdominal ultrasonography for the diagnosis of fatty liver disease. Patients were divided into three groups based on the duration of diabetes and NAFLD diagnosis. Type 2 diabetes patients were placed in group A; patients with type 2 diabetes longer than NAFLD were placed in group B; and patients with NAFLD longer than type 2 diabetes were placed in group C. All individuals had undergone electrocardiogram, blood pressure measurements, and thorough medical history and physical examinations (Doppler ultrasound, electrophysiology, fundoscopy, cardiac computed tomography). Laboratory measurements included fasting blood glucose, glycated hemoglobin, oral glucose tolerance test, liver and renal function, lipid profile, and urinary albumin excretion.
Compared with groups A and B, the patients of group C showed a higher prevalence of significant coronary artery disease and hypertension (P < 0.05). Compared with groups A and B, the patients of group C showed a lower prevalence of diabetic retinopathy and diabetic peripheral neuropathy (P < 0.05). There was no significant difference in the prevalence of diabetic nephropathy among the three groups (P > 0.05).
NAFLD combined with type 2 diabetes is associated with the presence of significant coronary artery disease and hypertension.
PMCID: PMC5089952  PMID: 27181828
Diabetic complication; Non‐alcoholic fatty liver disease; Type 2 diabetes
12.  Discovery and structural optimization of 4-(4-(benzyloxy)phenyl)-3,4-dihydropyrimidin-2(1H)-ones as RORc inverse agonists 
Acta Pharmacologica Sinica  2016;37(11):1516-1524.
Retinoic acid receptor-related orphan nuclear receptors (RORs) are orphan nuclear receptors that show constitutive activity in the absence of ligands. Among 3 subtypes of RORs, RORc is a promising therapeutic target for the treatment of Th17-mediated autoimmune diseases. Here, we report novel RORc inverse agonists discovered through structure-based drug design.
Based on the structure of compound 8, a previously described agonist of RORa, a series of 4-(4-(benzyloxy)phenyl)-3,4-dihydropyrimidin-2(1H)-one derivatives were designed and synthesized. The interaction between the compounds and RORc was detected at molecular level using AlphaScreen assay. The compounds were further examined in 293T cells transfected with RORc and luciferase reporter gene. Thermal stability shift assay was used to evaluate the effects of the compounds on protein stability.
A total of 27 derivatives were designed and synthesized. Among them, the compound 22b was identified as the most potent RORc inverse agonist. Its IC50 values were 2.39 μmol/L in AlphaScreen assay, and 0.82 μmol/L in inhibition of the cell-based luciferase reporter activity. Furthermore, the compound 22b displayed a 120-fold selectivity for RORc over other nuclear receptors. Moreover, a molecular docking study showed that the structure-activity relationship was consistent with the binding mode of compound 22b in RORc.
4-(4-(Benzyloxy)phenyl)-3,4-dihydropyrimidin-2(1H)-one derivatives are promising candidates for the treatment of Th17-mediated autoimmune diseases, such as rheumatoid arthritis, psoriasis, and multiple sclerosis.
PMCID: PMC5099407  PMID: 27374490
nuclear receptor; RORc; inverse agonist; SAR; structure-based optimization; autoimmune disease
13.  Population pharmacokinetics of piperaquine in young Ugandan children treated with dihydroartemisinin-piperaquine for uncomplicated malaria 
This prospective trial investigated the population pharmacokinetics of piperaquine, given with dihydroartemisinin to treat uncomplicated malaria in 107 Ugandan children 6 months to 2 years old, an age group previously unstudied. Current weight-based dosing does not adequately address physiological changes in early childhood. Patients were administered standard three-day oral doses and provided 1,282 capillary plasma concentrations from 218 malaria episodes. Less than 30% of treatments achieved 57 ng/mL on day 7. A three-compartment model with first-order absorption described the data well. Age had a statistically significant effect (p<0.005) on clearance/bioavailability in a model that accounts for allometric scaling. Simulations demonstrated that higher doses in all children, but especially in those with lower weight for age, are required for adequate piperaquine exposure, though safety and tolerance will need to be established. These findings support other evidence that both weight and age-specific guidelines for piperaquine dosing in children are urgently needed.
PMCID: PMC5088713  PMID: 25732044
malaria; population pharmacokinetics; piperaquine; antimalarial; pediatrics; children; artemisinin combination therapy; NONMEM
14.  Overexpression of SRC‐3 promotes esophageal squamous cell carcinoma aggressiveness by enhancing cell growth and invasiveness 
Cancer Medicine  2016;5(12):3500-3511.
Steroid receptor coactivator‐3 (SRC‐3), a transcriptional coactivator for nuclear receptors and other transcription factors, plays an important role in the genesis and progression of several cancers. However, studies investigated the role of SRC‐3 in esophageal squamous cell carcinomas (ESCCs) are limited, and the role of SRC‐3 in tumor progression remains unclear. We examined the expression of SRC‐3 in 8 ESCC cell lines and 302 human ESCC tissues by qPCR, Western blot, and immunohistochemistry. In addition, ESCC cell lines were subjected to proliferation and invasion assays, tumorigenicity assay, flow cytometry assay, qPCR, Western blot, and Chromatin Immunoprecipitation assay to investigate the role of SRC‐3 in cancer progression. SRC‐3 was overexpressed in 48% of cases and correlated with poor overall (P = 0.0076) and progression‐free (P = 0.0069) survival of surgically resected ESCC patient. Cox regression analysis revealed that SRC‐3 is an independent prognostic marker. Furthermore, we found that activation of insulin‐like growth factor (IGF)/AKT) was involved in the SRC‐3 on the cell growth and invasiveness in two ESCC cell lines, Eca109 and EC18 cells. SRC‐3 overexpression is clinically and functionally relevant to the progression of human ESCC, and might be a useful molecular target for ESCC prognosis and treatment.
PMCID: PMC5224859  PMID: 27781415
Cell growth; cell invasion; esophageal squamous cell carcinoma; insulin‐like growth factor/AKT; steroid receptor coactivator‐3
15.  Odor composition analysis and odor indicator selection during sewage sludge composting 
On the basis of total temperature increase, normal dehydration, and maturity, the odor compositions of surface and internal piles in a well-run sewage sludge compost plant were analyzed using gas chromatography–mass spectrometry with a liquid nitrogen cooling system and a portable odor detector. Approximately 80 types of substances were detected, including 2 volatile inorganic compounds, 4 sulfur organic compounds, 16 benzenes, 27 alkanes, 15 alkenes, and 19 halogenated compounds. Most pollutants were mainly produced in the mesophilic and pre-thermophilic periods. The sulfur volatile organic compounds contributed significantly to odor and should be controlled primarily. Treatment strategies should be based on the properties of sulfur organic compounds. Hydrogen sulfide, methyl mercaptan, dimethyl disulfide, dimethyl sulfide, ammonia, and carbon disulfide were selected as core indicators. Ammonia, hydrogen sulfide, carbon disulfide, dimethyl disulfide, methyl mercaptan, dimethylbenzene, phenylpropane, and isopentane were designated as concentration indicators. Benzene, m-xylene, p-xylene, dimethylbenzene, dichloromethane, toluene, chlorobenzene, trichloromethane, carbon tetrachloride, and ethylbenzene were selected as health indicators. According to the principle of odor pollution indicator selection, dimethyl disulfide was selected as an odor pollution indicator of sewage sludge composting. Monitoring dimethyl disulfide provides a highly scientific method for modeling and evaluating odor pollution from sewage sludge composting facilities.
Implications: Composting is one of the most important methods for sewage sludge treatment and improving the low organic matter content of many agricultural soils. However, odors are inevitably produced during the composting process. Understanding the production and emission patterns of odors is important for odor control and treatment. Core indicators, concentration indicators, and health indicators provide an index system to odor evaluation. An odor pollution indicator provides theoretical support for further modelling and evaluating odor pollution from sewage sludge composting facilities.
PMCID: PMC5062037  PMID: 27192607
16.  Intrahepatic cholangiocarcinoma prognostic determination using pre-operative serum C-reactive protein levels 
BMC Cancer  2016;16:792.
Serum C-reactive protein (CRP), an acute inflammatory response biomarker, has been recognized as an indicator of malignant disease progression. However, the prognostic significance of CRP levels collected before tumor removal in intrahepatic cholangiocarcinoma requires further investigation.
We sampled the CRP levels in 140 patients with intrahepatic cholangiocarcinoma who underwent hepatectomies with regional lymphadenectomies between 2006 and 2013. A retrospective analysis of the clinicopathological data was performed. We focused on the impact of serum CRP on the patients’ cancer-specific survival and recurrence-free survival rates.
High levels of preoperative serum CRP were significantly associated with well-established clinicopathologic features, including gender, advanced tumor stage, and elevated carcinoembryonic antigen and carbohydrate antigen 19-9 levels (P < 0.05). Univariate analysis demonstrated a significant association between high levels of serum CRP and adverse cancer-specific survival (P = 0.001) and recurrence-free survival (P < 0.001). In patients with stage I/II intrahepatic cholangiocarcinoma, the serum CRP level was a prognostic indicator for cancer-specific survival. In patients with stage I/II or stage III/IV, the serum CRP level was a prognostic indicator for recurrence-free survival (P < 0.05). Additionally, multivariate analysis identified serum CRP level in intrahepatic cholangiocarcinoma as an independent prognostic factor (P < 0.05).
We confirmed a significant association of elevated pre-operative CRP levels with poor clinical outcomes for the tested patients with intrahepatic cholangiocarcinoma. Our results indicate that the serum CRP level may represent a useful factor for patient stratification in intrahepatic cholangiocarcinoma management.
PMCID: PMC5059936  PMID: 27733196
C-reactive protein; Intrahepatic cholangiocarcinoma; Prognosis
17.  Hepatitis B virus infection in Chinese patients with hepatitis C virus infection: prevalence, clinical characteristics, viral interactions and host genotypes: a nationwide cross-sectional study 
BMJ Open  2016;6(10):e012016.
Little is known about hepatitis B virus (HBV) infection in patients with hepatitis C virus (HCV) infection in China. This study aimed to evaluate the prevalence, clinical characteristics, viral interactions and host genotypes of HBV/HCV dual infection compared with HCV monoinfection.
Study design
A cross-sectional study.
Participants and methods
997 patients with HCV from 28 university-affiliated hospitals in China were enrolled in this research. Patients were divided into two subgroups.
The prevalence of HBV infection in patients with HCV was 4.11% (41/997). The age-specific prevalence of HBsAg was 0.70%, 3.97% and 5.85% in groups aged 18–30, 30–50 and >50 years old (p=0.057), respectively. Patients with HBV/HCV dual infection and patients with HCV monoinfection had similar HCV viral loads (5.80±0.89 vs 5.83±1.00 log10 IU/mL, p=0.904). The dominant HCV genotype was 1b in both groups (53.65% vs 56.90%, p=0.493). The protective C allele in IL-28B (rs12979860) was also the dominant allele type in both patient groups (85.36% vs 83.99%, p=0.814). Patients with HBV/HCV dual infection had a higher ratio of liver cirrhosis and hepatic decompensation than patients with HCV monoinfection (39.02% vs 17.69%, p=0.001; 31.70% vs 12.13%, p=0.001).
The HBV burden was moderate in HCV-infected patients in China. Liver cirrhosis was more common in patients with HBV/HCV dual infection, suggesting the need for closer monitoring of dual-infected individuals.
Trial registration number
NCT01293279; Post-results.
PMCID: PMC5073524  PMID: 27733412
Hepatitis; Cirrhosis; Hepatitis B virus (HBV); Hepatitis C virus (HCV)
18.  Electroacupuncture Ameliorates Cerebral Ischemia-Reperfusion Injury by Regulation of Autophagy and Apoptosis 
Background. The therapeutic mechanisms of cerebral ischemia treatment by acupuncture are yet not well addressed. Objective. We investigated the effects of electroacupuncture (EA) at GV26 observing the expression of autophagy-related proteins Beclin-1 and LC3B and proportion of apoptotic cells and Bcl-2 positive cells in MCAO/R model rats. Methods. Sprague-Dawley (SD) male rats were randomly assigned to 7 groups: model groups (M6h, M24h, and M72h), EA treatment groups (T6h, T24h, and T72h), and sham operation group (S). Neurological deficit and cerebral infarction volume were measured to assess the improvement effect, while the expression of Beclin-1 and LC3B and proportion of Tunel-positive and Bcl-2 positive cells were examined to explore EA effect on autophagy and apoptosis. Results. EA significantly decreased neurological deficit scores and the volume of cerebral infarction. Beclin-1 was significantly decreased in T24h, while LC3B-II/LC3B-I ratio markedly reduced in 6th hour. EA groups markedly reduced the number of Tunel positive cells, especially in T24h. Meanwhile, the number of Bcl-2 positive cells obviously increased after EA treatment, especially in T6h and T24h. Conclusions. The alleviation of inadequate autophagy and apoptosis may be a key mechanism involved in the reflex regulation of EA at GV26 to treat cerebral ischemia.
PMCID: PMC5075311  PMID: 27800003
19.  Endobronchial ultrasound versus conventional transbronchial needle aspiration in the diagnosis of mediastinal lymphadenopathy: a meta-analysis 
SpringerPlus  2016;5(1):1716.
Currently, whether endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is superior to conventional TBNA (cTBNA) in the diagnosis of mediastinal lymphadenopathy remains controversial. We undertook a meta-analysis of randomized controlled trials (RCTs) to evaluate the diagnostic yield of EBUS-TBNA versus cTBNA in the diagnosis of mediastinal lymphadenopathy, both in benign and malignant etiologies. Computer-based retrieval was performed on PubMed and EMBASE. The quality was evaluated according to the quality assessment of diagnostic accuracy studies-2, and Meta-Disc was adopted to perform meta-analysis. The pooled sensitivity, specificity, and diagnostic odds ratio (DOR) with 95 % confidence intervals (CIs) were calculated. The summary receiving operating characteristic curve as well as the areas under curve (AUC) was measured. Four studies with a total of 440 patients met the inclusion criteria. Our results showed that the pooled sensitivity was 0.90 (95 % CI 0.85–0.94) and 0.76 (95 % CI 0.68–0.82), pooled specificity was 0.75 (95 % CI 0.60–0.87) and 0.94 (95 % CI 0.86–0.98), DOR was 75.38 (95 % CI 16.38–346.97) and 108.17 (95 % CI 13.84–845.35), and AUC was 0.9339 and 0.9732 for EBUS-TBNA group and cTBNA group, respectively. Although EBUS-TBNA with a higher sensitivity performs better than cTBNA, there is lack of enough evidence regarding EBUS-TBNA being superior to cTBNA in the diagnosis of mediastinal lymphadenopathy. Considering the limitations of methodology and limited data, further robust RCTs are needed to verify the current findings and investigate the optimal choice in patients receiving TBNA.
PMCID: PMC5052246  PMID: 27777852
Transbronchial needle aspiration; Endobronchial ultrasound; Diagnostic yield; Mediastinal lymphadenopathy; Meta-analysis
20.  The Association Between Higher Social Support and Lower Depressive Symptoms Among Aging Services Clients is Attenuated at Higher Levels of Functional Impairment 
Adults seeking services from the Aging Services Provider Network (ASPN) are at risk for depression. ASPN clients also have high prevalence of both functional impairments and social morbidities. Study of the relationships between these factors may inform the development of interventions for depression in this service setting.
We interviewed 373 older adults accessing ASPN services and assessed depression symptom severity, functional impairment (instrumental activities of daily living and activities of daily living), and social support.
Lower social support and greater functional impairment were associated with greater depressive symptoms. At a high level of functional impairment, the inverse associations between indices of social support and depressive symptoms were attenuated.
Results suggest that older adults with more severe functional impairment may benefit somewhat less from increased social support with respect to depression symptom severity.
PMCID: PMC4527957  PMID: 25663607
aging; aging services; social support; social connectedness; functioning; functional impairment; depressive symptoms
21.  Association of insulin resistance with breast, ovarian, endometrial and cervical cancers in non-diabetic women 
American Journal of Cancer Research  2016;6(10):2334-2344.
Hyperinsulinemia and insulin resistance were reported to play a crucial role in diabetes-cancer relationship. This study aimed to explore the associations between insulin resistance and several female cancers in a non-diabetic population. This cross-sectional study was conducted in 121,230 middle-aged and elderly non-diabetic women. Cancer diagnosis was self-reported and further validated by medical records. Insulin resistance was defined as homeostasis model assessment of insulin resistance (HOMA-IR) ≥ 2.50. The prevalence of both premenopausal and postmenopausal breast cancer, postmenopausal ovarian cancer and premenopausal endometrial cancer were higher in insulin-resistant participants than in insulin-sensitive participants (premenopausal breast cancer, 0.45 vs 0.28%; postmenopausal breast cancer, 0.86 vs 0.63%; postmenopausal ovarian cancer, 0.17 vs 0.09%; premenopausal endometrial cancer, 0.43 vs 0.25%, respectively, all P < 0.05). Individuals with insulin resistance had higher odds ratio (OR) of breast cancer, both premenopausal and postmenopausal (OR 1.98, 95% confidence interval (CI) 1.19-3.32; OR 1.29, 95% CI 1.01-1.63), postmenopausal ovarian cancer (OR 2.17, 95% CI 1.10-3.40) as well as total endometrial cancer (OR 1.47, 95% CI 1.02-2.12). Subgroup analysis revealed that the possitive association between insulin resistance and risk of prevalent breast cancer was observed in popualtion with younger age, overweight or obesity, higher education and impaired glucose tolerance (IGR). No relationships were observed for the risk of prevalent cervical cancers with insulin resistance. Non-diabetic women with insulin resistance had higher risk of prevalent breast, ovarian and endomatrial cancer, which suggests special attentions to these female cancer screening and prevention.
PMCID: PMC5088296  PMID: 27822422
Insulin resistance; non-diabetic; breast; ovarian; endometrial and cervical cancers
22.  Bilateral Renal Denervation Ameliorates Isoproterenol-Induced Heart Failure through Downregulation of the Brain Renin-Angiotensin System and Inflammation in Rat 
Heart failure (HF) is characterized by cardiac dysfunction along with autonomic unbalance that is associated with increased renin-angiotensin system (RAS) activity and elevated levels of proinflammatory cytokines (PICs). Renal denervation (RD) has been shown to improve cardiac function in HF, but the protective mechanisms remain unclear. The present study tested the hypothesis that RD ameliorates isoproterenol- (ISO-) induced HF through regulation of brain RAS and PICs. Chronic ISO infusion resulted in remarked decrease in blood pressure (BP) and increase in heart rate and cardiac dysfunction, which was accompanied by increased BP variability and decreased baroreflex sensitivity and HR variability. Most of these adverse effects of ISO on cardiac and autonomic function were reversed by RD. Furthermore, ISO upregulated mRNA and protein expressions of several components of the RAS and PICs in the lamina terminalis and hypothalamic paraventricular nucleus, two forebrain nuclei involved in cardiovascular regulations. RD significantly inhibited the upregulation of these genes. Either intracerebroventricular AT1-R antagonist, irbesartan, or TNF-α inhibitor, etanercept, mimicked the beneficial actions of RD in the ISO-induced HF. The results suggest that the RD restores autonomic balance and ameliorates ISO-induced HF and that the downregulated RAS and PICs in the brain contribute to these beneficial effects of RD.
PMCID: PMC5056308  PMID: 27746855
23.  miR-200c regulates crizotinib-resistant ALK-positive lung cancer cells by reversing epithelial-mesenchymal transition via targeting ZEB1 
Molecular Medicine Reports  2016;14(5):4135-4143.
Crizotinib is an orally administered drug for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive locally advanced or metastatic non-small cell lung cancer (NSCLC). Despite the impressive efficacy of crizotinib in the treatment of ALK-positive lung cancer, acquired resistance eventually develops in the majority of patients. The microRNA (miR)-200c reverses the resistance of lung cancer cells to various chemotherapeutic drugs and molecular targeted drugs, however, whether it can reverse the resistance of crizotinib remains unknown. The present study established a crizotinib resistant cell line (NCI-2228/CRI), which was derived from the parental NCI-2228 cell line by long-term exposure to increasing concentrations of crizotinib. Through overexpression and suppression of miR-200c expression, the characteristics associated with epithelial-mesenchymal transition (EMT), including morphology, EMT marker proteins and cellular mobility, were investigated. Cell viability and invasion assays demonstrated that high expression of miR-200c significantly inhibited the proliferation, migration and invasion of NCI-2228 cells compared with the negative control. A luciferase reporter assay indicated that miR-200c directly targeted the 3′-untranslated region of zinc finger E-box binding homeobox 1. Additionally, reverse transcription-quantitative polymerase chain reaction analysis demonstrated that the mRNA levels of N-cadherin and Vimentin were decreased in NCI-2228 cells transfected with miR-200c mimic compared with negative control cells, whereas the mRNA level of E-cadherin was increased. In addition, EMT was reversed by miR-200c, which suggests that miR-200c may serve a role in mediating the sensitivity of NCI-2228/CRI cells to crizotinib. The present study may therefore contribute to improving the sensitivity of ALK positive lung cancer cells to crizotinib.
PMCID: PMC5101903  PMID: 27666124
lung cancer; microRNA-200c; crizotinib; epithelial to mesenchymal transition
24.  MiR-21-5p Links Epithelial-Mesenchymal Transition Phenotype with Stem-Like Cell Signatures via AKT Signaling in Keloid Keratinocytes 
Scientific Reports  2016;6:28281.
Keloid is the abnormal wound healing puzzled by the aggressive growth and high recurrence rate due to its unrevealed key pathogenic mechanism. MicroRNAs contribute to a series of biological processes including epithelial-mesenchymal transition (EMT) and cells stemness involved in fibrotic disease. Here, using microRNAs microarray analysis we found mir-21-5p was significantly up-regulated in keloid epidermis. To investigate the role of miR-21-5p in keloid pathogenesis, we transfected miR-21-5p mimic or inhibitor in keloid keratinocytes and examined the abilities of cell proliferation, apoptosis, migration and invasion, the expressions of EMT-related markers vimentin and E-cadherin and stem-like cells-associated markers CD44 and ALDH1, and the involvement of PTEN and the signaling of AKT and ERK. Our results demonstrated that up-regulation or knockdown of miR-21-5p significantly increased or decreased the migration, invasion and sphere-forming abilities of keloid keratinocytes, and the phenotype of EMT and cells stemness were enhanced or reduced as well. Furthermore, PTEN and p-AKT were shown to participate in the regulation of miR-21-5p on EMT phenotypes and stemness signatures of keloid keratinocytes, which might account for the invasion and recurrence of keloids. This molecular mechanism of miR-21-5p on keloid keratinocytes linked EMT with cells stemness and implicated novel therapeutic targets for keloids.
PMCID: PMC5011940  PMID: 27596120
25.  Randomized, double-blind, placebo-controlled superiority trial of the Yiqigubiao pill for the treatment of patients with chronic obstructive pulmonary disease at a stable stage 
In traditional Chinese medicine (TCM), the Yiqigubiao pill is commonly used to enhance physical fitness. The current clinical trial was designed to evaluate the efficacy and safety of the Yiqigubiao pill as an adjuvant therapy for patients with stable chronic obstructive pulmonary disease (COPD). The current trial was a randomized, double-blind, placebo-controlled superiority trial. The participants were recruited from outpatients at the Traditional Chinese Medicine Hospital affiliated with Xinjiang Medical University (Ürümqi, China) between February and September 2012. All participants were patients with stable COPD that were randomized to the Yiqigubiao pill (YQGB; n=84) or placebo (Pb; n=87) groups. The occurrences of acute exacerbation (AE) of COPD during the trial were recorded. Lung function value assessments, scoring of life quality and exercise endurance, arterial blood gas analysis and serum inflammatory cytokines level determination were performed prior to and throughout the study. A total of 139 participants completed the intervention and 132 participants completed the study. The interval between the initial intervention and the first AECOPD was greater in the YQGB group compared with the Pb group (P<0.01). The incidence rate of AECOPD was lower in the YQGB group than in the Pb group (P<0.01). Subsequent to the intervention or at the end of the study, the 6-min walking distance difference was longer in the YQGB group compared with the Pb group (P<0.01). The scores reflecting life quality decline became lower in the YQGB group (P<0.01). The serum levels of proinflammatory factors were downregulated to a greater extent in the YQGB group compared with the Pb group. Thus, the Yiqigubiao pill is an efficient and safe adjuvant therapy for the treatment of stable patients with COPD.
PMCID: PMC5038223  PMID: 27698749
Yiqigubiao pill; chronic obstructive pulmonary disease; randomized controlled trial; traditional Chinese medicine; stable stage

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