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1.  Loss of stromal caveolin-1 expression in colorectal cancer predicts poor survival 
AIM: To investigate the clinicopathological significance and prognostic value of caveolin-1 (CAV-1) in both tumor and stromal cells in colorectal cancer (CRC).
METHODS: A total of 178 patients with CRC were included in this study. The correlation between CAV-1 expression and clinicopathologic features and survival was studied.
RESULTS: CAV-1 expression was detected in tumor and stromal cells. The expression of stromal CAV-1 was closely associated with histological type (P = 0.022), pathologic tumor-node-metastasis stage (P = 0.047), pathologic N stage (P = 0.035) and recurrence (P = 0.000). However, tumor cell CAV-1 did not show any correlation with clinical parameters. Additionally, the loss of stromal CAV-1 expression was associated with shorter disease-free survival (P = 0.000) and overall survival (P = 0.000). Multivariate analysis revealed that the loss of stromal CAV-1 expression was an independent prognostic factor for both overall survival (P = 0.014) and disease-free survival (P = 0.006).
CONCLUSION: The loss of stromal CAV-1 expression in CRC was associated with poor prognosis and could be a prognostic factor for CRC patients.
PMCID: PMC4306157  PMID: 25632186
CAV-1; Stroma; Colorectal cancer; Prognosis
2.  Electrical Stimulation over Bilateral Occipito-Temporal Regions Reduces N170 in the Right Hemisphere and the Composite Face Effect 
PLoS ONE  2014;9(12):e115772.
Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that can modulate cortical excitability. Although the clinical value of tDCS has been advocated, the potential of tDCS in cognitive rehabilitation of face processing deficits is less understood. Face processing has been associated with the occipito-temporal cortex (OT). The present study investigated whether face processing in healthy adults can be modulated by applying tDCS over the OT. Experiment 1 investigated whether tDCS can affect N170, a face-sensitive ERP component, with a face orientation judgment task. The N170 in the right hemisphere was reduced in active stimulation conditions compared with the sham stimulation condition for both upright faces and inverted faces. Experiment 2 further demonstrated that tDCS can modulate the composite face effect, a type of holistic processing that reflects the obligatory attention to all parts of a face. The composite face effect was reduced in active stimulation conditions compared with the sham stimulation condition. Additionally, the current polarity did not modulate the effect of tDCS in the two experiments. The present study demonstrates that N170 can be causally manipulated by stimulating the OT with weak currents. Furthermore, our study provides evidence that obligatory attention to all parts of a face can be affected by the commonly used tDCS parameter setting.
PMCID: PMC4274090  PMID: 25531112
3.  Small sphincterotomy combined with endoscopic papillary large balloon dilation vs sphincterotomy alone for removal of common bile duct stones 
World Journal of Gastroenterology : WJG  2014;20(47):17962-17969.
AIM: To evaluate the efficacy and safety of endoscopic papillary large diameter balloon dilation (EPLBD) following limited endoscopic sphincterotomy (EST) and EST alone for removal of large common bile duct (CBD) stones.
METHODS: We retrospectively compared EST + EPLBD (group A, n = 64) with EST alone (group B, n = 89) for the treatment of large or multiple bile duct stones. The success rate of stone clearance, procedure-related complications and incidents, frequency of mechanical lithotripsy use, and recurrent stones were recorded.
RESULTS: There was no statistically significant difference between the two groups regarding periampullary diverticula (35.9% vs 34.8%, P > 0.05), pre-cut sphincterotomy (6.3% vs 6.7%, P > 0.05), size (12.1 ± 2.0 mm vs 12.9 ± 2.6 mm, P > 0.05) and number (2.2 ± 1.9 vs 2.4 ± 2.1, P > 0.05) of stones or the diameters of CBD (15.1 ± 3.3 mm vs 15.4 ± 3.6 mm, P > 0.05). The rates of overall stone removal and stone removal in the first session were not significantly different between the two groups [62/64 (96.9%) vs 84/89 (94.4%), P > 0.05; and 58/64 (90.6%) vs 79/89 (88.8%), P > 0.05, respectively]. The rates of post-endoscopic retrograde cholangiopancreatography pancreatitis and hyperamylasemia were not significantly different between the two groups [3/64 (4.7%) vs 4/89 (4.5%), P > 0.05; 7/64 (10.9%) vs 9/89 (10.1%), P > 0.05, respectively]. There were no cases of perforation, acute cholangitis, or cholecystitis in the two groups. The rate of bleeding and the recurrence of CBD stones were significantly lower in group A than in group B [1/64 (1.6%) vs 5/89 (5.6%), P < 0.05; 1/64 (1.6%) vs 6/89 (6.7%), P < 0.05, respectively].
CONCLUSION: EST + EPLBD is an effective and safe endoscopic approach for removing large or multiple CBD stones.
PMCID: PMC4273147  PMID: 25548495
Choledocholithiasis; Endoscopic retrograde cholangiopancreatography; Endoscopic papillary balloon dilation; Endoscopic sphincterotomy
4.  Reduced Expression of PTPRD Correlates with Poor Prognosis in Gastric Adenocarcinoma 
PLoS ONE  2014;9(11):e113754.
PTPRD, encoding protein tyrosine phosphatases receptor type D, is located at chromosome 9p23–24.1, a loci frequently lost in many types of tumors. Recently, PTPRD has been proposed to function as a tumor suppressor gene. The current study aimed to investigate PTPRD expression and its prognostic significance in primary gastric adenocarcinoma.
Methods and Results
Quantitative real time reverse transcription PCR (qRT-PCR) and western blotting were used to examine PTPRD expression in paired gastric tumourous and paracancerous tissues. Compared with the matched normal gastric mucosa tissues, both the mRNA (P = 0.0138) and protein (P = 0.0093) expression of PTPRD in fresh surgical specimens were significantly reduced. Clinicopathological and prognostic roles of PTPRD in gastric adenocarcinoma were investigated using immunohistochemistry with 513 paraffin-embedded gastric adenocarcinoma tissue blocks. Statistical analysis revealed that reduced PTPRD expression was significantly associated with T stage (P = 0.004), TNM stage (P<0.001) and tumor size (P = 0.003). Furthermore, Kaplan-Meier survival analysis revealed that low expression of PTPRD significantly correlated with poor survival of gastric cancer patients (P<0.001). Cox regression analysis confirmed PTPRD expression as independent predictor of the overall survival of gastric cancer patients. The MTT assay determined the effects of PTPRD on cell proliferation of MGC803 and GES1 cell lines. Restoring PTPRD expression in MGC803 cells significantly inhibited their growth rate. Silencing PTPRD expression by siRNA treatment in GES1 significantly enhanced cell proliferation compared with mock siRNA treatment. Methylation analysis of PTPRD promoter CpG island in 3 primary GC samples showed one case with partial methylation.
These results indicated that PTPRD is a candidate tumour suppressor in gastric cancer. Thus, PTPRD may play an important role in gastric tumorigenesis and serve as a valuable prognostic marker of gastric adenocarcinoma.
PMCID: PMC4239117  PMID: 25412184
5.  SnoVectors for nuclear expression of RNA 
Nucleic Acids Research  2014;43(1):e5.
Many long noncoding RNAs (lncRNAs) are constrained to the nucleus to exert their functions. However, commonly used vectors that were designed to express mRNAs have not been optimized for the study of nuclear RNAs. We reported recently that sno-lncRNAs are not capped or polyadenylated but rather are terminated on each end by snoRNAs and their associated proteins. These RNAs are processed from introns and are strictly confined to the nucleus. Here we have used these features to design expression vectors that can stably express virtually any sequence of interest and constrain its accumulation to the nucleus. Further, these RNAs appear to retain normal nuclear associations and function. SnoVectors should be useful in conditions where nuclear RNA function is studied or where export to the cytoplasm needs to be avoided.
PMCID: PMC4288147  PMID: 25378317
6.  CT features of retroperitoneal solitary fibrous tumor: report of three cases and review of the literature 
CT findings in three cases with solitary fibrous tumors (SFTs) confirmed by histopathology and immunohistochemistry were reviewed retrospectively, and compared with pathological results. The three tumors were large, well-defined, and smooth contour masses and SFT consisted of solid components of two different densities. On enhanced CT scans, tumors were strongly enhancing, the multiple vascular shadows were seen within the tumor in the arterial phase. There is progressive enhancement from the arterial to the venous phase, and the tumor capsule can be observed. Histologically, the tumors are composed of spindle cells within a background of collagen stroma, and showed a wide range of growth patterns, alternating hypercellular (tumor cell-rich) and hypocellular (collagen-rich) areas. The diagnosis is confirmed by characteristic positive immunohistochemical staining for CD34.
PMCID: PMC4282173  PMID: 25351104
Retroperitoneum; Solitary fibrous tumors; Tomography; X-ray computed
7.  Octreotide attenuates liver fibrosis by inhibiting hepatic heme oxygenase-1 expression 
Molecular Medicine Reports  2014;11(1):83-90.
The aim of the present study was to investigate the effects of octreotide treatment on hepatic heme oxygenase-1 (HO-1) expression, together with the influence of altered hepatic HO-1 expression levels on hepatic function and fibrosis in bile duct-ligated rats. The rats were divided randomly into sham, cirrhotic, cobalt protoporphyrin and octreotide treatment groups. The expression levels of hepatic HO-1 mRNA were measured by reverse-transcription polymerase chain reaction, while the protein expression was determined by western blotting and immunohistochemical analysis. Hematoxylin and eosin, and Van Gieson’s staining, along with determination of the hydroxyproline content in the liver, were performed to determine the degree of liver fibrosis. The serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL) and carboxyhemoglobin (COHb) in arterial blood, and the mean arterial pressure and portal vein pressure were also measured. As compared with the sham group, hepatic HO-1 mRNA and protein expression levels, serum levels of ALT, AST and TBIL, COHb in arterial blood, hydroxyproline and collagen type I content were all significantly increased in the cirrhotic group. As compared with the cirrhotic group, the octreotide-treated group exhibited significantly reduced hepatic HO-1 expression levels, serum levels of ALT, AST and TBIL, COHb in arterial blood and the extent of hepatic fibrosis, whereas the cobalt protoporphyrin group exhibited significantly increased hepatic HO-1 expression levels, as well as aggravated hepatic function and fibrosis (P<0.05). In conclusion, octreotide inhibited hepatic HO-1 overexpression in cirrhotic rats, reduced hepatic HO-1 expression levels to relieve liver injury and attenuated liver fibrosis.
PMCID: PMC4237075  PMID: 25338529
heme oxygenase-1; carbon monoxide; octreotide; bile duct ligation; liver fibrosis
8.  MCL1 and BCL-xL Levels in Solid Tumors Are Predictive of Dinaciclib-Induced Apoptosis 
PLoS ONE  2014;9(10):e108371.
Dinaciclib is a potent CDK1, 2, 5 and 9 inhibitor being developed for the treatment of cancer. Additional understanding of antitumor mechanisms and identification of predictive biomarkers are important for its clinical development. Here we demonstrate that while dinaciclib can effectively block cell cycle progression, in vitro and in vivo studies, coupled with mouse and human pharmacokinetics, support a model whereby induction of apoptosis is a main mechanism of dinaciclib's antitumor effect and relevant to the clinical duration of exposure. This was further underscored by kinetics of dinaciclib-induced downregulation of the antiapoptotic BCL2 family member MCL1 and correlation of sensitivity with the MCL1-to-BCL-xL mRNA ratio or MCL1 amplification in solid tumor models in vitro and in vivo. This MCL1-dependent apoptotic mechanism was additionally supported by synergy with the BCL2, BCL-xL and BCL-w inhibitor navitoclax (ABT-263). These results provide the rationale for investigating MCL1 and BCL-xL as predictive biomarkers for dinaciclib antitumor response and testing combinations with BCL2 family member inhibitors.
PMCID: PMC4188521  PMID: 25289887
9.  Effect of Pioglitazone on In-Stent Restenosis after Coronary Drug-Eluting Stent Implantation: A Meta-Analysis of Randomized Controlled Trials 
PLoS ONE  2014;9(10):e109614.
In-stent restenosis (ISR) remains a common life-threatening complication and some studies have shown that pioglitazone can reduce the incidence of ISR in patients with drug-eluting stents (DES) implantation. We conducted a meta-analysis to assess the effect of pioglitazone in preventing ISR after DES implantation.
Randomized controlled trials (RCTs) investigating the effects of pioglitazone for ISR after DES implantation were identified by systematic searches of multiple online databases and manual searches of related reference lists of identified trials through May 2014. The primary endpoint was the rate of ISR. Secondary endpoints included minimum lumen diameter, percentage stenosis of stented vessels, late loss, in-stent neointimal volume, target vessel revascularization (TVR), target lesion revascularization, myocardial infarction, stent thrombosis and death.
Five studies, comprising 255 pioglitazone-treated patients and 245 controls, were identified in the current meta-analysis. Pioglitazone did not significantly reduce the rate of ISR (P = 0.20) with low heterogeneity (I2 = 13.3%, P = 0.32). For the secondary outcomes, pioglitazone did not substantially affect the pooled estimates of these endpoints except late loss (P = 0.01) and TVR (P = 0.04).
The limited evidence indicates that pioglitazone does not demonstrate markedly beneficial effect in patients subjected to coronary DES implantation. However, the results should be interpreted with care given the small sample size. Further large-scale RCTs are needed.
PMCID: PMC4184901  PMID: 25279761
10.  Endocannabinoids and Inflammatory Response in Periodontal Ligament Cells 
PLoS ONE  2014;9(9):e107407.
Endocannabinoids are associated with multiple regulatory functions in several tissues. The main endocannabinoids, anandamide (AEA) and 2-arachidonylglycerol (2-AG), have been detected in the gingival crevicular fluid of periodontitis patients, but the association between periodontal disease or human periodontal ligament cells (hPdLCs) and endocannabinoids still remain unclear. The aim of the present study was to examine the effects of AEA and 2-AG on the proliferation/viability and cytokine/chemokine production of hPdLCs in the presence/absence of Porphyromonas gingivalis lipopolysaccharide (P. gingivalis LPS). The proliferation/viability of hPdLCs was measured using 3,4,5-dimethylthiazol-2-yl-2,5-diphenyl tetrazolium bromide (MTT)-assay. Interleukin-6 (IL-6), interleukin-8 (IL-8), and monocyte chemotactic protein-1 (MCP-1) levels were examined at gene expression and protein level by real-time PCR and ELISA, respectively. AEA and 2-AG did not reveal any significant effects on proliferation/viability of hPdLCs in the absence of P. gingivalis LPS. However, hPdLCs viability was significantly increased by 10–20 µM AEA in the presence of P. gingivalis LPS (1 µg/ml). In the absence of P. gingivalis LPS, AEA and 2-AG did not exhibit any significant effect on the expression of IL-8 and MCP-1 expression in hPdLCs, whereas IL-6 expression was slightly enhanced by 10 µM 2-AG and not affected by AEA. In P.gingivalis LPS stimulated hPdLCs, 10 µM AEA down-regulated gene-expression and protein production of IL-6, IL-8, and MCP-1. In contrast, 10 µM 2-AG had an opposite effect and induced a significant up-regulation of gene and protein expression of IL-6 and IL-8 (P<0.05) as well as gene-expression of MCP-1 in P. gingivalis LPS stimulated hPdLCs. Our data suggest that AEA appears to have an anti-inflammatory and immune suppressive effect on hPdLCs’ host response to P.gingivalis LPS, whereas 2-AG appears to promote detrimental inflammatory processes. In conclusion, AEA and 2-AG might play an important role in the modulation of periodontal inflammation.
PMCID: PMC4165771  PMID: 25226300
11.  Surgical Outcomes and Prognostic Factors of T4 Gastric Cancer Patients without Distant Metastasis 
PLoS ONE  2014;9(9):e107061.
To evaluate surgical outcomes and prognostic factors for T4 gastric cancer treated with curative resection.
Between January 1994 and December 2008, 94 patients diagnosed with histological T4 gastric carcinoma and treated with curative resection were recruited. Patient characteristics, surgical complications, survival, and prognostic factors were analyzed.
Postoperative morbidity and mortality were 18.1% and 2.1%, respectively. Multivariate analysis indicated lymph node metastasis (hazard ratio, 2.496; 95% confidence interval, 1.218–5.115; p = 0.012) was independent prognostic factor.
For patients with T4 gastric cancer, lymph node metastasis was associated with poorer survival. Neoadjuvant chemotherapy or aggressive adjuvant chemotherapy after radical resection was strongly recommended for these patients.
PMCID: PMC4161379  PMID: 25211331
12.  Comparative analysis of human and mouse immunoglobulin variable heavy regions from IMGT/LIGM-DB with IMGT/HighV-QUEST 
Immunoglobulin (IG) complementarity determining region (CDR) includes VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3. Of these, VH CDR3 plays a dominant role in recognizing and binding antigens. Three major mechanisms are involved in the formation of the VH repertoire: germline gene rearrangement, junctional diversity and somatic hypermutation. Features of the generation mechanisms of VH repertoire in humans and mice share similarities while VH CDR3 amino acid (AA) composition differs. Previous studies have mainly focused on germline gene rearrangement and the composition and structure of the CDR3 AA in humans and mice. However the number of AA changes due to somatic hypermutation and analysis of the junctional mechanism have been ignored.
Here we analyzed 9,340 human and 6,657 murine unique productive sequences of immunoglobulin (IG) variable heavy (VH) domains derived from IMGT/LIGM-DB database to understand how VH CDR3 AA compositions significantly differed between human and mouse. These sequences were identified and analyzed by IMGT/HighV-QUEST (, including gene usage, number of AA changes due to somatic hypermutation, AA length distribution of VH CDR3, AA composition, and junctional diversity.
Analyses of human and murine IG repertoires showed significant differences. A higher number of AA changes due to somatic hypermutation and more abundant N-region addition were found in human compared to mouse, which might be an important factor leading to differences in VH CDR3 amino acid composition.
These findings are a benchmark for understanding VH repertoires and can be used to characterize the VH repertoire during immune responses. The study will allow standardized comparison for high throughput results obtained by IMGT/HighV-QUEST, the reference portal for NGS repertoire.
PMCID: PMC4085081  PMID: 24992938
Immunoglobulin; VH CDR3; IMGT/HighV-QUEST; IMGT/LIGM-DB; VH repertoire
13.  The Effect of XPD Polymorphisms on Digestive Tract Cancers Risk: A Meta-Analysis 
PLoS ONE  2014;9(5):e96301.
The Xeroderma pigmento-sum group D gene (XPD) plays a key role in nucleotide excision repair. Single nucleotide polymorphisms (SNP) located in its functional region may alter DNA repair capacity phenotype and cancer risk. Many studies have demonstrated that XPD polymorphisms are significantly associated with digestive tract cancers risk, but the results are inconsistent. We conducted a comprehensive meta-analysis to assess the association between XPD Lys751Gln polymorphism and digestive tract cancers risk. The digestive tract cancers that our study referred to, includes oral cancer, esophageal cancer, gastric cancer and colorectal cancer.
We searched PubMed and EmBase up to December 31, 2012 to identify eligible studies. A total of 37 case-control studies including 9027 cases and 16072 controls were involved in this meta-analysis. Statistical analyses were performed with Stata software (version 11.0, USA). Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the association.
The results showed that XPD Lys751Gln polymorphism was associated with the increased risk of digestive tract cancers (homozygote comparison (GlnGln vs. LysLys): OR = 1.12, 95% CI = 1.01–1.24, P = 0.029, P heterogeneity = 0.133). We found no statistical evidence for a significantly increased digestive tract cancers risk in the other genetic models. In the subgroup analysis, we also found the homozygote comparison increased the susceptibility of Asian population (OR = 1.28, 95% CI = 1.01–1.63, P = 0.045, P heterogeneity = 0.287). Stratified by cancer type and source of control, no significantly increased cancer risk was found in these subgroups. Additionally, risk estimates from hospital-based studies and esophageal studies were heterogeneous.
Our meta-analysis suggested that the XPD 751Gln/Gln genotype was a low-penetrate risk factor for developing digestive tract cancers, especially in Asian populations.
PMCID: PMC4008560  PMID: 24787743
14.  Apolipoprotein E Gene Polymorphism and Risk for Coronary Heart Disease in the Chinese Population: A Meta-Analysis of 61 Studies Including 6634 Cases and 6393 Controls 
PLoS ONE  2014;9(4):e95463.
Numerous studies have evaluated the association between the apolipoprotein E (apoE) gene polymorphisms in coronary heart disease (CHD). However, the results remain uncertain. We carried out a meta-analysis to derive a more comprehensive estimation of the association in Chinese population.
Case-control studies in Chinese and English publications were identified by searching databases of PubMed, EMBASE, Web of Science, CNKI, CBM, Wanfang, VIP and hand searching of relevant journals and the reference lists of retrieved articles. Odds ratio (OR) and 95% confidence interval (CI) were applied to assess the strength of the associations. Subgroup analysis and sensitivity analysis were performed to explore the between-study heterogeneity.
We finally identified 61 relevant studies which comprised 6634 case-patients and 6393 controls. The pooled OR for ε4 carriers was 96% higher than the ε3/3 genotype for CHD (OR, 1.96; 95% CI, 1.70 to 2.24; P<0.001). However, there was no evidence of statistically significant association between ε2 carriers and risk of CHD (OR, 1.02; 95% CI, 0.91 to 1.13; P = 0.729). In the subgroup analysis, different endpoints may partially account for the heterogeneity. No publication bias was found.
Our meta-analysis suggests that the apoE ε4 allele may be a risk factor for CHD in the Chinese population, however, ε2 allele has no significant association.
PMCID: PMC3995769  PMID: 24755673
15.  Surgical techniques and results of the pulmonary artery reconstruction for patients with central non-small cell lung cancer 
It is difficult to achieve a margin-negative resection (R0) for non-small cell lung cancer (NSCLC) patients with infiltration of the pulmonary artery. We report our experience of the pulmonary artery reconstruction with regard to long-term survival.
Clinical records of 118 patients with NSCLC who underwent partial or circumferential pulmonary artery resection during a 21-year period were reviewed retrospectively. Techniques and survival outcomes were analyzed.
We performed 22 pulmonary artery sleeve resections, 51 reconstructions by autologous pericardial patch, 36 tangential resections, 3 left main pulmonary artery (PA) angioplasties during pneumonectomy without cardiopulmonary bypass, and 6 by only preserving the apical and anterior (1st) branch of pulmonary arterial trunk. In 41 patients, bronchial sleeve resection was associated; in 7 cases, superior vena cava reconstruction was also required. Thirty-one patients received induction therapy. Thirteen patients had stage IB disease, 41 stage II, 53 IIIA, and 11 IIIB. Ninety-three patients had squamous cell carcinoma, 22 adenocarcinoma, 2 mixed and 1 large cell carcinoma. Negative vascular margins were achieved in all. 5 positive bronchial margins were due to limited lung function. The analysis of 118 cases yielded follow-up data in 94 cases. The mean follow-up was 70 months (range 1–156 months). There was no in hospital death, and the overall 5-year survival was 50.2%. Five-year survivals for stages I and II versus III were 63.9% versus 37.0% (p = 0.0059). Multivariate analysis yielded non-squamous cell carcinoma, stage III and patch pulmonary arterioplasty as negative prognosis factors. PA reconstruction associated with bronchial sleeve resection was the positive prognostic factor.
Pulmonary artery resection and reconstruction is feasible and safe, with favorable long-term survival. Our results support this technique as an effective alternative to selected patients with infiltration of the pulmonary artery, such as stage I and II and those who proved down-staged from stage III. Accurate preoperative evaluation, precise and suitable surgical techniques are crucial to achieve good results. Only preserving the anterior and apical pulmonary arteries and reconstruction of the main pulmonary artery by using the artery conduit technique without cardiopulmonary bypass in association with left pneumonectomy can be performed successfully. Postoperative anticoagulation is unnecessary.
PMCID: PMC4222057  PMID: 24289720
Lung cancer; Pulmonary artery; Reconstruction; Surgery
16.  The Osteogenic Potential of Mesoporous Bioglasses/Silk and Non-Mesoporous Bioglasses/Silk Scaffolds in Ovariectomized Rats: In vitro and In vivo Evaluation 
PLoS ONE  2013;8(11):e81014.
Silk-based scaffolds have been introduced to bone tissue regeneration for years, however, their local therapeutic efficency in bone metabolic disease condition has been seldom reported. According to our previous report, mesoporous bioactive glass (MBG)/silk scaffolds exhibits superior in vitro bioactivity and in vivo osteogenic properties compared to non-mesoporous bioactive glass (BG)/silk scaffolds, but no information could be found about their efficiency in osteoporotic (OVX) environment. This study investigated a biomaterial-based approach for improving MSCs behavior in vitro, and accelerating OVX defect healing by using 3D BG/silk and MBG/silk scaffolds, and pure silk scaffolds as control. The results of SEM, CCK-8 assay and quantitative ALP activity showed that MBG/silk scaffolds can improve attachment, proliferation and osteogenic differentiation of both O-MSCs and sham control. In vivo therapeutic efficiency was evaluated by μCT analysis, hematoxylin and eosin staining, safranin O staining and tartrate-resistant acid phosphatase, indicating accelerated bone formation with compatible scaffold degradation and reduced osteoclastic response of defect healing in OVX rats after 2 and 4 weeks treatment, with a rank order of MBG/silk > BG/silk > silk group. Immunohistochemical markers of COL I, OPN, BSP and OCN also revealed that MBG/silk scaffolds can better induce accelerated collagen and non-collagen matrix production. The findings of this study suggest that MBG/silk scaffolds provide a better environment for cell attachment, proliferation and differentiation, and act as potential substitute for treating local osteoporotic defects.
PMCID: PMC3827187  PMID: 24265840
17.  Novel and Convenient Method to Evaluate the Character of Solitary Pulmonary Nodule-Comparison of Three Mathematical Prediction Models and Further Stratification of Risk Factors 
PLoS ONE  2013;8(10):e78271.
To study risk factors that affect the evaluation of malignancy in patients with solitary pulmonary nodules (SPN) and verify different predictive models for malignant probability of SPN.
Retrospectively analyzed 107 cases of SPN with definite post-operative histological diagnosis whom underwent surgical procedures in China-Japan Friendship Hospital from November of 2010 to February of 2013. Age, gender, smoking history, malignancy history of patients, imaging features of the nodule including maximum diameter, position, spiculation, lobulation, calcification and serum level of CEA and Cyfra21-1 were assessed as potential risk factors. Univariate analysis model was used to establish statistical correlation between risk factors and post-operative histological diagnosis. Receiver operating characteristic (ROC) curves were drawn using different predictive models for malignant probability of SPN to get areas under the curves (AUC values), sensitivity, specificity, positive predictive values, negative predictive values for each model, respectively. The predictive effectiveness of each model was statistically assessed subsequently.
In 107 patients, 78 cases were malignant (72.9%), 29 cases were benign (27.1%). Statistical significant difference was found between benign and malignant group in age, maximum diameter, serum level of Cyfra21-1, spiculation, lobulation and calcification of the nodules. The AUC values were 0.786±0.053 (Mayo model), 0.682±0.060 (VA model) and 0.810±0.051 (Peking University People’s Hospital model), respectively.
Serum level of Cyfra21-1, patient’s age, maximum diameter of the nodule, spiculation, lobulation and calcification of the nodule are independent risk factors associated with the malignant probability of SPN. Peking University People’s Hospital model is of high accuracy and clinical value for patients with SPN. Adding serum index (e.g. Cyfra21-1) into the prediction models as a new risk factor and adjusting the weight of age in the models might improve the accuracy of prediction for SPN.
PMCID: PMC3812137  PMID: 24205175
18.  Correction: Hypoxia-Inducible Factor-1α Polymorphisms and Risk of Cancer Metastasis: A Meta-Analysis 
PLoS ONE  2013;8(10):10.1371/annotation/938850a0-b05c-4557-becc-9d91d3d90742.
PMCID: PMC3792166
19.  Hypoxia-Inducible Factor-1α Polymorphisms and Risk of Cancer Metastasis: A Meta-Analysis 
PLoS ONE  2013;8(8):e70961.
HIF-1α is a major regulator in tumor progression and metastasis which responds to hypoxia. Many studies have demonstrated that hypoxia-inducible factor1-α (HIF-1α) polymorphisms are significantly associated with cancer metastasis, but the results are inconsistent. We conducted a comprehensive meta-analysis to estimate the associations between HIF-1α C1772 T polymorphism and cancer metastasis.
Comprehensive searches were conducted on PubMed and EMBASE database. Fifteen studies were included in the meta-analysis. We used the OR and 95%CI to assess the associations between HIF-1α C1772T polymorphism and cancer metastasis. Heterogeneity and publication bias were also assessed by Q test, I 2, and funnel plot.
Totally, fifteen studies including 1239 cases with metastasis-positive (M+) and 2711 cases with metastasis-negative (M−) were performed in this meta-analysis. The results showed that HIF-1a C1772T polymorphism was associated with the increased risk of cancer metastasis (T allele vs. C allele, OR  = 1.36, 95% CI  = 1.12–1.64; TT+ TC vs. CC, OR  = 1.39, 95% CI  = 1.13–1.71; TT vs. TC+ CC, OR  = 1.93, 95% CI  = 0.86–4.36). In the subgroup analyses, the significant associations remained significant among Asians, Caucasians and other cancers in the dominant model. Publication bias was not observed in the analysis.
Our results indicate that the HIF-1αC1772T polymorphism T allele may increase the risk of cancer metastasis, which might be a potential risk factor of cancer progress.
PMCID: PMC3756035  PMID: 24015181
20.  New proposal for the serum ascites albumin gradient cut-off value in Chinese ascitic patients 
Diagnostic Pathology  2013;8:143.
Serum ascites albumin gradient (SAAG) has been recognized as a reliable marker in the differential diagnosis of ascites. The etiological background of cirrhosis is rather different between western countries and eastern countries. The threshold of SAAG in Chinese ascitic patients has not been evaluated yet. The aim of this study was to define a new reasonable threshold of SAAG in Chinese ascitic patients.
Adult patients with ascites admitted to the Shanghai Changzheng Hospital from Jan 2004 to Jun 2010 were retrospectively analyzed. The diagnostic criteria for cirrhotic ascites are clinical manifestations, radiological features and esophageal-gastric varicosis, or histopathology. Serum was detected by chemical method using a commercial kit. We used receiver operating characteristic (ROC) analysis to achieve maximal sensitivity and specificity of SAAG.
The mean value of SAAG in portal-hypertension-related ascites was significantly higher than that in the non-portal-hypertension-related ascites (21.15 ± 4.38 g/L vs 7.48 ± 3.64 g/L, P = 0.002). The SAAG cut-off value under 12.50 g/L predicted portal hypertension ascites with the sensitivity of 99.20%, specificity of 95.10% and accuracy of 97.65%.
SAAG is useful to distinguish portal-hypertension-related ascites and non-portal-hypertension-related ascites, and 12.50 g/L might present as a more reasonable threshold in Chinese ascitic patients.
Virtual slides
The virtual slide(s) for this article can be found here:
PMCID: PMC3846365  PMID: 23971938
Ascites; Cirrhosis; Portal hypertension; SAAG
21.  Severe intraoperative complications during VATS Lobectomy compared with thoracotomy lobectomy for early stage non-small cell lung cancer 
Journal of Thoracic Disease  2013;5(4):513-517.
Video-assisted thoracic surgery (VATS) lobectomy has been proved to have shorter hospital stay, less perioperative complications and less pain compared with lobectomy by thoracotomy, but severe intraoperative complications during VATS lobectomy is rare reported. We compared intraoperative safety between VATS lobectomy and lobectomy by thoracotomy.
659 patients with postoperative stage I and IIa non-small cell lung cancer (NSCLC) who underwent lobectomy in China-Japan Friendship Hospital from February 2008 to June 2012 were analyzed retrospectively, in which 277 were performed by thoracotomy, 357 performed by VATS, and 25 performed by VATS converted to open. Outcomes were analyzed to compare the incidence of significant bleeding, with conversion cases were included into VATS group.
Ten severe intraoperative complications were identified in 10 patients (6 in VATS, 4 in open), with no intraoperative deaths. The incidence of severe intraoperative complications was similar between VATS group and thoracotomy group [1.57% (6/382) vs. 1.44% (4/277), P=1.0]. Most severe intraoperative complications were related to the injury of major pulmonary vessels (9/10), and most of these complications occurred during upper lobectomy (8/10). There was no statistically significant difference in blood loss (242.85±220.47 vs. 240.43±144.36, P=0.865), and operative time (198.00±75.24 vs. 208.05±61.97, P=0.061) between the open and VATS groups, respectively, but blood loss and operative time are significant different after elimination of conversion cases (214.34±151.85 vs. 240.43±144.36, P<0.01; 193.24±72.64 vs. 208.05±61.97, P<0.01).
Our preliminary study demonstrated that the incidence of severe intraoperative complication during VATS lobectomy was low and similar to open lobectomy. The severe intraoperative complications during VATS lobectomy are manageable and the surgeons need to take proper caution in performing VATS lobectomy.
PMCID: PMC3755690  PMID: 23991310
Lung cancer surgery; lobectomy; bleeding; surgery complications
22.  Age at Menarche and Risk of Colorectal Cancer: A Meta-Analysis 
PLoS ONE  2013;8(6):e65645.
Various observational studies have focused on the relationship between menarcheal age and the risk of colorectal cancer (CRC). However, the association is still controversial because of inconsistent results. Therefore, we performed a meta-analysis to assess this issue from epidemiological studies.
After a literature search in MEDLINE, EMBASE, and Web of Science for studies of menarcheal age and CRC risk published through the end of January 2013, we pooled the relative risks (RRs) from included studies using a fixed- or random-effects model and performed heterogeneity and publication bias analyses. All statistical tests were two-sided.
Eleven case-control and 11 cohort studies were eligible for inclusion in our analysis. The random-effects pooled RR for oldest versus youngest menarcheal age was 0.95 [95% confidence intervals (CIs) = 0.85–1.06], with significant heterogeneity (Q = 61.03, P<0.001, I2 = 65.6%). When separately analyzed, case-control (RR = 0.95, 95% CI = 0.75–1.21) and cohort studies (RR = 0.97, 95% CI = 0.90–1.04) yielded similar results. Moreover, similar results were also observed among the subgroup analyses by study quality, population, exposure assessment, anatomic cancer site, subsite of colon cancer, and several potential important confounders and risk factors. There was no evidence of publication bias and significant heterogeneity between subgroups detected by meta-regression analyses.
Findings from this meta-analysis demonstrated that menarcheal age was not associated with the risk of CRC in humans. Further studies are warranted to stratify results by the subsite of colon cancer and menopause status in the future.
PMCID: PMC3675201  PMID: 23762403
23.  Molecular and Functional Characterizations of the Association and Interactions between Nucleophosmin-Anaplastic Lymphoma Kinase and Type I Insulin-Like Growth Factor Receptor1,2 
Neoplasia (New York, N.Y.)  2013;15(6):669-683.
Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) is aberrantly expressed in a subset of T cell lymphoma that commonly affects children and young adults. NPM-ALK possesses significant oncogenic potential that was previously documented using in vitro and in vivo experimental models. The exact mechanisms by which NPM-ALK induces its effects are poorly understood. We have recently demonstrated that NPM-ALK is physically associated with type I insulin-like growth factor receptor (IGF-IR). A positive feedback loop appears to exist between NPM-ALK and IGF-IR through which these two kinases interact to potentiate their effects. We have also found that a single mutation of the Tyr644 or Tyr664 residue of the C terminus of NPM-ALK to phenylalanine decreases significantly, but does not completely abolish, the association between NPM-ALK and IGF-IR. The purpose of this study was to determine whether the dual mutation of Tyr644 and Tyr664 abrogates the association and interactions between NPM-ALK and IGF-IR. We also examined the impact of this dual mutation on the oncogenic potential of NPM-ALK. Our results show that NPM-ALKY644,664F completely lacks association with IGF-IR. Importantly, we found that the dual mutation of Tyr644 and Tyr664 diminishes the oncogenic effects of NPM-ALK, including its ability to induce anchorage-independent colony formation and to sustain cellular transformation, proliferation, and migration. Furthermore, the association between NPM-ALK and IGF-IR through Tyr644 and Tyr664 appears to contribute to maintaining the stability of NPM-ALK protein. Our results provide novel insights into the mechanisms by which NPM-ALK induces its oncogenic effects through interactions with IGF-IR in this aggressive lymphoma.
PMCID: PMC3664999  PMID: 23730215
24.  Inhibiting heme oxygenase-1 attenuates rat liver fibrosis by removing iron accumulation 
AIM: To investigate the effects of the heme oxygenase (HO)-1/carbon monoxide system on iron deposition and portal pressure in rats with hepatic fibrosis induced by bile duct ligation (BDL).
METHODS: Male Sprague-Dawley rats were divided randomly into a Sham group, BDL group, Fe group, deferoxamine (DFX) group, zinc protoporphyrin (ZnPP) group and cobalt protoporphyrin (CoPP) group. The levels of HO-1 were detected using different methods. The serum carboxyhemoglobin (COHb), iron, and portal vein pressure (PVP) were also quantified. The plasma and mRNA levels of hepcidin were measured. Hepatic fibrosis and its main pathway were assessed using Van Gieson’s stain, hydroxyproline, transforming growth factor-β1 (TGF-β1), nuclear factor-E2-related factor 2 (Nrf2), matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinase-1 (TIMP-1).
RESULTS: Serum COHb and protein and mRNA expression levels of HO-1 and Nrf2 were increased in the BDL group compared with the Sham group and were much higher in the CoPP group. The ZnPP group showed lower expression of HO-1 and Nrf2 and lower COHb. The levels of iron and PVP were enhanced in the BDL group but were lower in the ZnPP and DFX groups and were higher in the CoPP and Fe groups. Hepcidin levels were higher, whereas superoxide dismutase levels were increased and malonaldehyde levels were decreased in the ZnPP and DFX groups. The ZnPP group also showed inhibited TGF-β1 expression and regulated TIMP-1/MMP-2 expression, as well as obviously attenuated liver fibrosis.
CONCLUSION: Reducing hepatic iron deposition and CO levels by inhibiting HO-1 activity though the Nrf2/Keap pathway could be helpful in improving hepatic fibrosis and regulating PVP.
PMCID: PMC3660817  PMID: 23704825
Heme oxygenase-1; Hepcidin; Iron accumulation; Oxidative stress; Portal vein pressure; Carboxyhemoglobin; Bile duct ligation
25.  Controlled variations in stimulus similarity during learning determine visual discrimination capacity in freely moving mice 
Scientific Reports  2013;3:1048.
The mouse is receiving growing interest as a model organism for studying visual perception. However, little is known about how discrimination and learning interact to produce visual conditioned responses. Here, we adapted a two-alternative forced-choice visual discrimination task for mice and examined how training with equiprobable stimuli of varying similarity influenced conditioned response and discrimination performance as a function of learning. Our results indicate that the slope of the gradients in similarity during training determined the learning rate, the maximum performance and the threshold for successful discrimination. Moreover, the learning process obeyed an inverse relationship between discrimination performance and discriminative resolution, implying that sensitivity within a similarity range cannot be improved without sacrificing performance in another. Our study demonstrates how the interplay between discrimination and learning controls visual discrimination capacity and introduces a new training protocol with quantitative measures to study perceptual learning and visually-guided behavior in freely moving mice.
PMCID: PMC3541512  PMID: 23308341

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