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1.  Influence of Preferred Orientation on the Electrical Conductivity of Fluorine-Doped Tin Oxide Films 
Scientific Reports  2014;4:3679.
Current development of high-performance transparent conductive oxide (TCO) films is limited with tradeoff between carrier mobility and concentration since none of them can be improved without sacrificing the other. In this study, we prepare fluorine doped tin oxide (FTO) films by chemical vapor deposition with inclusions of different additives and report that the mobility can be varied from 0.65 to 28.5 cm2 V−1 s−1 without reducing the achieved high carrier concentration of 4 × 1020 cm−3. Such an increase in mobility is shown to be clearly associated with the development of (200) preferred orientation (PO) but concurrent degradation of (110) PO in films. Thus, at a constant high carrier concentration, the electrical conductivity can be improved via carrier mobility simply by PO control. Such a one-step approach avoiding conventional post-deposition treatment is suggested for developing next-generation FTO as well as other TCO films with better than ever conductivities.
PMCID: PMC3890905  PMID: 24419455
3.  Prognostic Value of miR-21 in Various Cancers: An Updating Meta-Analysis 
PLoS ONE  2014;9(7):e102413.
Recently, more and more studies investigated the value of microRNA (miRNA) as a diagnostic or prognostic biomarker in various cancers. MiR-21 was found dysregulated in almost all types of cancers. While the prognostic role of miR-21 in many cancers has been studied, the results were not consistent.
We performed a meta-analysis to investigate the correlation between miR-21 and survival of general cancers by calculating pooled hazard ratios (HR) and 95% confidence intervals (CI).
The pooled results of 63 published studies showed that elevated miR-21 was a predictor for poor survival of general carcinomas, with pooled HR of 1.91 (95%CI: 1.66–2.19) for OS, 1.42 (95% CI: 1.16–1.74) for DFS and 2.2 (95% CI: 1.64–2.96) for RFS/CSS. MiR-21 was also a prognostic biomarker in the patients who received adjuvant therapy, with pooled HR of 2.4 (95%CI: 1.18–4.9) for OS.
Our results showed that miR-21 could act as a significant biomarker in the prognosis of various cancers. Further studies are warranted before the application of the useful biomarker in the clinical.
PMCID: PMC4097394  PMID: 25019505
4.  Interactions between pork consumption, CagA status and IL-1B-31 genotypes in gastric cancer 
AIM: To explore potential interactions among Helicobacter pylori (H. pylori), CagA status, interleukin (IL)-1B-31 genotypes, and non-cardiac gastric cancer (GC) risk.
METHODS: A case-control study of non-cardia GC was performed at 3 hospitals located in Xi’an, China, between September 2008 and July 2010. We included 171 patients with histologically diagnosed primary non-cardia GC and 367 population based controls (matched by sex, age and city of residence). A standardized questionnaire was used to obtain information regarding potential risk factors, including pork consumption. H. pylori CagA status was assessed by enzyme-linked immunosorbent assay, and IL-1B-31 genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism. Multivariate unconditional logistic regression was used to explore potential interactions among the factors.
RESULTS: The CagA appeared to confer an increased risk of GC (OR = 1.81, 95%CI: 1.25-2.61). The main associations with IL-1B-31C allele here were 0.98 (95%CI: 0.59-1.63) for CC vs TT and 0.99 (95%CI: 0.64-1.51) for C Carriers vs TT. However, no associations were observed for CagA or IL-1B-31 genotype status among subjects who reported low pork consumption (P for interaction = 0.11). In contrast, high pork consumption and IL-1B-31C genotypes appeared to synergistically increase GC risk (P for interaction = 0.048) after adjusting for confounding factors, particularly among subjects with CagA (OR = 3.07, 95%CI: 1.17-10.79). We did not observe effect modification of pork consumption by H. pylori CagA status, or between H. pylori CagA status and IL-1B-31 genotypes after adjustment for pork consumption and other factors.
CONCLUSION: These interaction relationships among CagA, IL-1B-31 and pork consumption may have implications for development of the preventive strategies for the early detection of non-cardiac GC.
PMCID: PMC4081686  PMID: 25009387
Gastric cancer; Pork; CagA; interleukin-1B; Interaction; Helicobacter pylori
5.  Abdominal lymphangiomatosis in a 38-year-old female: Case report and literature review 
Lymphangioma is an uncommon benign tumor that develops in the lymphatic system. Abdominal lymphangiomatosis is extremely rare in adult patients, and the clinical symptoms of this condition are complicated and atypical. We report a case of abdominal lymphangiomatosis in a 38-year-old female who presented with intestinal bleeding and protein-losing enteropathy, as well as lesions in the lung and bones. A computed tomography scan revealed multiple small cystic lesions without enhancement. Histological examination revealed microscopic cysts were submucosal, with walls composed of thin fibrous tissue, and D2-40 stained highlight the lining of the lymphatic channels by immunohistochemical method. We make a comparison with the cases reported before, and also discuss the diagnose of diffuse pulmonary lymphangiomatosis and Gorham’s disease.
PMCID: PMC4081712  PMID: 25009412
Lymphangioma; Abdominal lymphangiomatosis; Gastrointestinal bleeding; Diffuse pulmonary lymphangiomatosis; Gorham’s disease
6.  Molecular Epidemiological Characterization and Health Burden of Thalassemia in Jiangxi Province, P. R. China 
PLoS ONE  2014;9(7):e101505.
Thalassemia is the most common inherited disease in southern China. However, this disorder is usually ignored by Jiangxi provincial health system and government due to lack of epidemiological data.
Materials and Methods
A total of 9489 samples from Hakka Han and Gan-speaking Han in three geographical areas of Jiangxi Province were analyzed for both complete blood cell (CBC) count and reverse dot blot (RDB) gene chip for thalassemia.
1182 cases of suspected thalassemia carriers with microcytosis (MCV<82 fL) were found by CBC count, and were tested by RDB gene chip to reveal a total of 594 mutant chromosomes, including 433 α-thalassemia mutant chromosomes and 172 β-thalassemia mutant chromosomes. Our results indicated a higher prevalence of thalassemia with the heterozygote frequency of 9.49% in southern Jiangxi province, whereas the low frequency was found in middle (3.90%) and northern Jiangxi (2.63%).
Based on the epidemiological data, the estimated numbers of pregnancies in Jiangxi province in which the fetus is at risk for β-thalassemia major or intermedia, Bart's hydrops fetalis and Hb H disease are 34 (95% CI, 16 to 58), 79 (95% CI, 50 to 114) and 39 (95% CI, 27 to 58) per year, respectively. We suggested that prevention network of thalassemia should be established, especially in high prevalent southern Jiangxi (Hakka Han), including establishment of thalassemia database collection, hematological analysis laboratories, genetic counselling clinics, prenatal diagnosis centers and neonatal screening centers.
PMCID: PMC4084819  PMID: 25000193
7.  Novel TBX1 loss-of-function mutation causes isolated conotruncal heart defects in Chinese patients without 22q11.2 deletion 
BMC Medical Genetics  2014;15:78.
TBX1 and CRKL haploinsufficiency is thought to cause the cardiac phenotype of the 22q11.2 deletion syndrome. However, few unequivocal mutations of TBX1 and CRKL have been discovered in isolated conotrucal heart defects (CTDs) patients. The aim of the study was to screen the mutation of TBX1 and CRKL in isolated CTDs Chinese patients without 22q11.2 deletion and identify the pathomechanism of the missense mutations.
We enrolled 199 non-22q11.2 deletion patients with CTDs and 139 unrelated healthy controls. Gene sequencing were performed for all of them. The functional data of mutations were obtained by in vitro transfection and luciferase experiments and computer modelling.
Screening of the TBX1 coding sequence identified a de novo missense mutation (c.385G → A; p.E129K) and a known polymorphism (c.928G → A; p.G310S). In vitro experiments demonstrate that the TBX1E129K variant almost lost transactivation activity. The TBX1G310S variant seems to affect the interaction of TBX1 with other factors. Computer molecular dynamics simulations showed the de novo missense mutation is likely to affect TBX1-DNA interaction. No mutation of CRKL gene was found.
These observations suggest that the TBX1 loss-of-function mutation may be involved in the pathogenesis of isolated CTDs. This is the first human missense mutation showing that TBX1 is a candidate causing isolated CTDs in Chinese patients without 22q11.2 deletion.
PMCID: PMC4099205  PMID: 24998776
TBX1 haploinsufficiency; 22q11.2 deletion; Conotruncal heart defects; Molecular dynamics simulation
8.  Inhibition of Smurf2 translation by miR-322/503 modulates TGF-β/Smad2 signaling and intestinal epithelial homeostasis 
Molecular Biology of the Cell  2014;25(8):1234-1243.
Smurf2 is an E3 ubiquitin ligase that regulates TGF-β/Smad signaling and is implicated in a wide variety of cellular responses. miR-322 and miR-503 repress Smurf2 translation and thus modulate TGF-β/Smad2 signaling and intestinal epithelial homeostasis.
Smad ubiquitin regulatory factor 2 (Smurf2) is an E3 ubiquitin ligase that regulates transforming growth factor β (TGF-β)/Smad signaling and is implicated in a wide variety of cellular responses, but the exact mechanisms that control Smurf2 abundance are largely unknown. Here we identify microRNA-322 (miR-322) and miR-503 as novel factors that regulate Smurf2 expression posttranscriptionally. Both miR-322 and miR-503 interact with Smurf2 mRNA via its 3′-untranslated region (UTR) and repress Smurf2 translation but do not affect total Smurf2 mRNA levels. Studies using heterologous reporter constructs reveal a greater repressive effect of miR-322/503 through a single binding site in the Smurf2 3′-UTR, whereas point mutation of this site prevents miR-322/503–induced repression of Smurf2 translation. Increased levels of endogenous Smurf2 via antagonism of miR-322/503 inhibits TGF-β–induced Smad2 activation by increasing degradation of phosphorylated Smad2. Furthermore, the increase in Smurf2 in intestinal epithelial cells (IECs) expressing lower levels of miR-322/503 is associated with increased resistance to apoptosis, which is abolished by Smurf2 silencing. These findings indicate that miR-322/503 represses Smurf2 translation, in turn affecting intestinal epithelial homeostasis by altering TGF-β/Smad2 signaling and IEC apoptosis.
PMCID: PMC3982989  PMID: 24554769
9.  Prognostic Value of PLR in Various Cancers: A Meta-Analysis 
PLoS ONE  2014;9(6):e101119.
Recently, more and more studies investigated the association of inflammation parameters such as the Platelet Lymphocyte Ratio (PLR) and the prognosis of various cancers. However, the prognostic role of PLR in cancer remains controversial.
We conducted a meta-analysis of published studies to evaluate the prognostic value of PLR in various cancers. In order to investigate the association between PLR and overall survival (OS), the hazard ratio (HR) and its 95% confidence interval (CI) were calculated.
A total of 13964 patients from 26 studies were included in the analysis. The summary results showed that elevated PLR was a negative predictor for OS with HR of 1.60 (95%CI: 1.35–1.90; Pheterogeneity <0.001). Subgroup analysis revealed that increased PLR was a negative prognostic marker in patients with gastric cancer (HR = 1.35, 95%CI: 0.80–2.25, Pheterogeneity = 0.011), colorectal cancer (HR = 1.65, 95%CI: 1.33–2.05, Pheterogeneity = 0.995), hepatocellular carcinoma (HR = 3.07, 95% CI: 2.04–4.62, Pheterogeneity = 0.133), ovarian cancer (HR = 1.57, 95%CI: 1.07–2.31, Pheterogeneity = 0.641) and non-small cell lung cancer (NSCLC) (HR = 1.85, 95% CI: 1.42–2.41, Pheterogeneity = 0.451) except for pancreatic cancer (HR = 1.00, 95%CI: 0.92–1.09, Pheterogeneity = 0.388).
The meta-analysis demonstrated that PLR could act as a significant biomarker in the prognosis of various cancers.
PMCID: PMC4072728  PMID: 24968121
10.  Metallothionein III (MT3) is a putative tumor suppressor gene that is frequently inactivated in pediatric acute myeloid leukemia by promoter hypermethylation 
Acute myeloid leukemia (AML) is the second most common form of leukemia in children. Aberrant DNA methylation patterns are a characteristic feature in various tumors, including AML. Metallothionein III (MT3) is a tumor suppresser reported to show promoter hypermethylated in various cancers. However, the expression and molecular function of MT3 in pediatric AML is unclear.
Eleven human leukemia cell lines and 41 pediatric AML samples and 20 NBM/ITP (Norma bone marrow/Idiopathic thrombocytopenic purpura) control samples were analyzed. Transcription levels of MT3 were evaluated by semi-quantitative and real-time PCR. MT3 methylation status was determined by methylation specific PCR (MSP) and bisulfite genomic sequencing (BSG). The molecular mechanism of MT3 was investigated by apoptosis assays and PCR array analysis.
The MT3 promoter was hypermethylated in leukemia cell lines. More CpG’s methylated of MT3 was observed 39.0% pediatric AML samples compared to 10.0% NBM controls. Transcription of MT3 was also significantly decreased in AML samples compared to NBM/ITP controls (P < 0.001); patients with methylated MT3 exhibited lower levels of MT3 expression compared to those with unmethylated MT3 (P = 0.049). After transfection with MT3 lentivirus, proliferation was significantly inhibited in AML cells in a dose-dependent manner (P < 0.05). Annexin V assay showed that apoptosis was significantly upregulated MT3-overexpressing AML cells compared to controls. Real-time PCR array analysis revealed 34 dysregulated genes that may be implicated in MT3 overexpression and apoptosis in AML, including FOXO1.
MT3 may be a putative tumor suppressor gene in pediatric AML. Epigenetic inactivation of MT3 via promoter hypermethylation was observed in both AML cell lines and pediatric AML samples. Overexpression of MT3 may inhibit proliferation and induce apoptosis in AML cells. FOXO1 was dysregulated in MT3-overexpressing cells, offering an insight into the mechanism of MT3-induced apoptosis. However, further research is required to determine the underlying molecular details.
PMCID: PMC4082423  PMID: 24962166
Metallothionein III; Pediatric acute myeloid leukemia; Methylation; Tumor suppressor
11.  Optically-controlled extinction ratio and Q-factor tunable silicon microring resonators based on optical forces 
Scientific Reports  2014;4:5409.
Tunability is a desirable property of microring resonators to facilitate superior performance. Using light to control light, we present an alternative simple approach to tuning the extinction ratio (ER) and Q-factor of silicon microring resonators based on optical forces. We design an opto-mechanical tunable silicon microring resonator consisting of an add-drop microring resonator and a control-light-carrying waveguide (“controlling” waveguide). One of the two bus waveguides of the microring resonator is a deformable nanostring put in parallel with the “controlling” waveguide. The tuning mechanism relies on the optical force induced deflection of suspended nanostring, leading to the change of coupling coefficient of microring and resultant tuning of ER and Q-factor. Two possible geometries, i.e. double-clamped nanostring and cantilever nanostring, are studied in detail for comparison. The obtained results imply a favorable structure with the microring positioned at the end of the cantilever nanostring. It features a wide tuning range of ER from 5.6 to 39.9 dB and Q-factor from 309 to 639 as changing the control power from 0 to 1.4 mW.
PMCID: PMC4067623  PMID: 24958225
12.  Evaluation of the POSSUM, P-POSSUM and E-PASS scores in the surgical treatment of hilar cholangiocarcinoma 
The Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity (POSSUM) model, its Portsmouth (P-POSSUM) modification and the Estimation of physiologic ability and surgical stress (E-PASS) are three surgical risk scoring systems used extensively to predict postoperative morbidity and mortality in general surgery. The aim was to undertake the first study of the predictive value of these models in patients undergoing surgical treatment of hilar cholangiocarcinoma.
A retrospective analysis was performed on data collected prospectively over a 10-year interval from January 2003 to December 2012. The morbidity and mortality risks were calculated using the POSSUM, P-POSSUM and E-PASS equations.
One hundred patients underwent surgical treatment of hilar cholangiocarcinoma. Complications were seen in 52 of 100 patients (52.0%). There were 10 postoperative in-hospital deaths (10.0%). Of 31 preoperative and intraoperative variables studied, operative type (P = 0.000), preoperative serum albumin (P = 0.003) and aspartate aminotransferase (P = 0.029) were found to be factors multivariate associated with postoperative complications. Intraoperative blood loss (P = 0.015), Bismuth-Corlette classification (P = 0.033) and preoperative hemoglobin (P = 0.041) were independent factors multivariate associated with in-hospital death. The POSSUM system predicted morbidity risk effectively with no significant lack of fit (P = 0.488) and an area under the ROC curve (AUC) of 0.843. POSSUM, P-POSSUM and E-PASS scores showed no significant lack of fit in calculating the mortality risk (P >0.05) and all yielded an AUC value exceeding 0.8. POSSUM had significantly more accuracy in predicting morbidity after major and major plus operations (O:E (observed/expected) ratio 0.98 and AUC 0.901) than after minor and moderate operations (O:E ratio 1.13 and AUC 0.759).
POSSUM, P-POSSUM and E-PASS scores effectively predict morbidity and mortality in surgical treatment of hilar cholangiocarcinoma. However, improvements are still needed in the future because none of these scoring systems yielded an AUC value exceeding 0.9 for operations with all different levels of severity. Only POSSUM had more accuracy in predicting postoperative morbidity after operations with higher severity.
Trial registration
This study was undertaken after obtaining approval from the ethics committee of School of Medicine, Shanghai Jiao Tong University with a trial registration number of http://09411960800.
PMCID: PMC4079624  PMID: 24961847
POSSUM; P-POSSUM; E-PASS; Morbidity; Mortality; Hilar cholangiocarcinoma
13.  Calculation of exact p-values when SNPs are tested using multiple genetic models 
BMC Genetics  2014;15:75.
Several methods have been proposed to account for multiple comparisons in genetic association studies. However, investigators typically test each of the SNPs using multiple genetic models. Association testing using the Cochran-Armitage test for trend assuming an additive, dominant, or recessive genetic model, is commonly performed. Thus, each SNP is tested three times. Some investigators report the smallest p-value obtained from the three tests corresponding to the three genetic models, but such an approach inherently leads to inflated type 1 errors. Because of the small number of tests (three) and high correlation (functional dependence) among these tests, the procedures available for accounting for multiple tests are either too conservative or fail to meet the underlying assumptions (e.g., asymptotic multivariate normality or independence among the tests).
We propose a method to calculate the exact p-value for each SNP using different genetic models. We performed simulations, which demonstrated the control of type 1 error and power gains using the proposed approach. We applied the proposed method to compute p-value for a polymorphism eNOS -786T>C which was shown to be associated with breast cancer risk.
Our findings indicate that the proposed method should be used to maximize power and control type 1 errors when analyzing genetic data using additive, dominant, and recessive models.
PMCID: PMC4076502  PMID: 24950707
Genetic association; Multiple testing; Cochran-Armitage trend test; Genetic models; Exact p-value
14.  Epigallocatechin-3-gallate attenuates lipopolysaccharide-induced inflammation in human retinal endothelial cells 
To investigate the mechanism underlying the anti-inflammatory effects of epigallocatechin-3-gallate (EGCG) in lipopolysaccharide (LPS)-stimulated human retinal endothelial cells (HRECs).
HRECs pre-treated with EGCG (0-100 µmol/L) were stimulated with LPS (250 ng/mL). Levels of tumor necrosis factor alpha (TNF-α), vascular endothelial growth factor (VEGF), monocyte chemotactic protein-1 (MCP-1) and nitric oxide (NO) in the supernatants were determined by enzyme-linked immunosorbent assay (ELISA) and Griess assay. The protein expression of phosphorylated extracellular signal-regulated kinase (ERK) 1/2 and p38 mitogen-activated protein kinases (p38) were determined by Western blot analysis.
EGCG pre-treatment significantly inhibited the secretion of TNF-α, VEGF, MCP-1 and NO in LPS-stimulated HRECs. Moreover, EGCG effectively attenuated LPS-induced activation and phosphorylation of ERK1/2 and p38 in HRECs in a dose-dependent manner.
EGCG exhibited inhibitory effects on LPS-induced pro-inflammatory cytokines production by modulating ERK1/2 and p38 pathways in HRECs, suggesting EGCG as a potential candidate for anti-inflammatory intervention.
PMCID: PMC4067650  PMID: 24967182
epigallocatechin-3-gallate; human retinal endothelial cells; inflammatory factors
15.  The significance of Notch ligand expression in the peripheral blood of children with hand, foot and mouth disease (HFMD) 
BMC Infectious Diseases  2014;14:337.
Hand, foot and mouth disease (HFMD), a virus-induced infectious disease that usually affects infants and children, has an increased incidence in China in recent years. This study attempted to investigate the role of the Notch signaling pathway in the pathogenesis of HFMD.
Eighty-two children diagnosed with HFMD were enrolled into this study. The HFMD group was further divided into the uncomplicated HFMD and HFMD with encephalitis groups. The control group included 40 children who underwent elective surgery for treatment of inguinal hernias.
Children with HFMD displayed significantly reduced CD3+, CD3+CD4+ and CD3+CD8+ cell subsets, but substantially enhanced CD3−CD19+ cell subset (p < 0.05 versus control subjects). The expression levels of Notch ligands Dll1 and Dll4 in the peripheral blood of the HFMD group were significantly higher than those in the control group (p < 0.05). There were statistically significant differences in CD3+, CD3+CD4+ and CD3−CD19+ cell subsets, but not in Notch ligand expression, between the uncomplicated HFMD and HFMD with encephalitis groups. Dll4 expression in HFMD subjects correlated negatively with the CD3+ and CD3+CD8+ cell subsets (p < 0.05), but positively with the CD3−CD19+ cell subset (p < 0.05). Furthermore, Dll4 expression in HFMD with encephalitis subjects correlated positively with total white blood cell (WBC) counts and total protein contents in cerebrospinal fluid (CSF) (p < 0.05).
The Notch ligand Dll4 exhibits a strong correlation with the CD3+, CD3+CD8+ and CD3−CD19+ cell subsets in children with HFMD, indicating that the Notch signaling may be involved in the development of HFMD by affecting the number and status of peripheral lymphocytes.
PMCID: PMC4074334  PMID: 24939221
Notch signaling; Subsets of T lymphocytes; Hand; Foot and mouth disease; Children
16.  miRNA-1236 Inhibits HIV-1 Infection of Monocytes by Repressing Translation of Cellular Factor VprBP 
PLoS ONE  2014;9(6):e99535.
Primary monocytes are refractory to HIV-1 infection and become permissive upon differentiation into monocyte-derived dendritic cells (MDDCs) or macrophages. Multiple mechanisms have been proposed to interpret HIV-1 restriction in monocytes. Human cellular miRNAs can modulate HIV-1 infection by targeting either conserved regions of the HIV-1 genome or host gene transcripts. We have recently reported that the translation of host protein pur-alpha is repressed by abundant cellular miRNAs to inhibit HIV-1 infection in monocytes. Here, we report that the transcript of another cellular factor, VprBP [Vpr (HIV-1)-binding protein], was repressed by cellular miRNA-1236, which contributes to HIV-1 restriction in monocytes. Transfection of miR-1236 inhibitors enhanced translation of VprBP in monocytes and significantly promoted viral infection; exogenous input of synthesized miR-1236 mimics into MDDCs suppressed translation of VprBP, and, accordingly, significantly impaired viral infection. Our data emphasize the role of miRNA in modulating differentiation-dependent susceptibility of the host cell to HIV-1 infection. Understanding the modulation of HIV-1 infection by cellular miRNAs may provide key small RNAs or the identification of new important protein targets regulated by miRNAs for the development of antiviral strategies.
PMCID: PMC4059663  PMID: 24932481
17.  Relationship between Apparent Diffusion Coefficient and Tumour Cellularity in Lung Cancer 
PLoS ONE  2014;9(6):e99865.
Background and objective
To prospectively investigate the relationship between the apparent diffusion coefficient (ADC) and cellularity in lung cancer.
Sixty patients histopathologically confirmed with lung cancer (41 men, 19 women) underwent diffusion-weighted magnetic resonance imaging of the chest (with b values of 50 and 1000 s/mm2). The median mean ADC (ADCmean) value and median minimum ADC (ADCmin) value within each primary tumour were calculated and compared with the median nucleo-cytoplasmic ratio (NCR), which was selected to represent the cellularity. The correlation between the NCR and ADCmean/ADCmin was calculated with SPSS 18.0 software.
The mean ADCmean values, ADCmin values and median NCR were (1.07±0.12)×10−3 mm2/s, (0.86±0.14)×10−3 mm2/s, and (14.9±2.6) %, respectively, in adenocarcinoma; (0.88±0.10)×10−3 mm2/s, (0.73±0.12)×10−3 mm2/s, and (20.6±4.4) %, respectively, in squamous cell carcinoma; and (0.89±0.13)×10−3 mm2/s, (0.67±0.13)×10−3 mm2/s, and (18.3±3.5) %, respectively in small cell lung cancer. The NCR of squamous cell carcinoma and small cell lung cancer is greater than that of adenocarcinoma (P<0.01 and P = 0.002, respectively). There was an inverse relationship between ADCmean/NCR and ADCmin/NCR (r = −0.60, P = 0.001 and r = −0.47, P<0.001, respectively).
There is a significant inverse relationship between tumour cellularity and ADC in lung cancer. However, tumour cellularity most likely is not the sole determinant of the ADC.
PMCID: PMC4053522  PMID: 24919055
18.  Astrocytic Toll-Like Receptor 3 Is Associated with Ischemic Preconditioning- Induced Protection against Brain Ischemia in Rodents 
PLoS ONE  2014;9(6):e99526.
Cerebral ischemic preconditioning (IPC) protects brain against ischemic injury. Activation of Toll-like receptor 3 (TLR3) signaling can induce neuroprotective mediators, but whether astrocytic TLR3 signaling is involved in IPC-induced ischemic tolerance is not known.
IPC was modeled in mice with three brief episodes of bilateral carotid occlusion. In vitro, IPC was modeled in astrocytes by 1-h oxygen-glucose deprivation (OGD). Injury and components of the TLR3 signaling pathway were measured after a subsequent protracted ischemic event. A neutralizing antibody against TLR3 was used to evaluate the role of TLR3 signaling in ischemic tolerance.
IPC in vivo reduced brain damage from permanent middle cerebral artery occlusion in mice and increased expression of TLR3 in cortical astrocytes. IPC also reduced damage in isolated astrocytes after 12-h OGD. In astrocytes, IPC or 12-h OGD alone increased TLR3 expression, and 12-h OGD alone increased expression of phosphorylated NFκB (pNFκB). However, IPC or 12-h OGD alone did not alter the expression of Toll/interleukin receptor domain-containing adaptor-inducing IFNβ (TRIF) or phosphorylated interferon regulatory factor 3 (pIRF3). Exposure to IPC before OGD increased TRIF and pIRF3 expression but decreased pNFκB expression. Analysis of cytokines showed that 12-h OGD alone increased IFNβ and IL-6 secretion; 12-h OGD preceded by IPC further increased IFNβ secretion but decreased IL-6 secretion. Preconditioning with TLR3 ligand Poly I:C increased pIRF3 expression and protected astrocytes against ischemic injury; however, cells treated with a neutralizing antibody against TLR3 lacked the IPC- and Poly I:C-induced ischemic protection and augmentation of IFNβ.
The results suggest that IPC-induced ischemic tolerance is mediated by astrocytic TLR3 signaling. This reprogramming of TLR3 signaling by IPC in astrocytes may play an important role in suppression of the post-ischemic inflammatory response and thereby protect against ischemic damage. The mechanism may be via activation of the TLR3/TRIF/IRF3 signaling pathway.
PMCID: PMC4051824  PMID: 24914679
19.  Association of FTO Polymorphisms with Obesity and Metabolic Parameters in Han Chinese Adolescents 
PLoS ONE  2014;9(6):e98984.
Previous studies have suggested that fat mass-and obesity-associated (FTO) gene is associated with body mass index (BMI) and the risk of obesity. This study aims to assess the association of five FTO polymorphisms (rs9939609, rs8050136, rs1558902, rs3751812 and rs6499640) with obesity and relative parameters in Han Chinese adolescents.
We examined a total of 401 adolescents, 223 normal weights (58.7% boys, 41.3% girls), 178 overweight (60.1% boys, 39.9% girls), aging from 14 to 18-years-old, recruited randomly from public schools in the central region of Wuxi, a southern city of China. DNA samples were genotyped for the five polymorphisms by Sequenom Plex MassARRAY. Association of the FTO polymorphisms with BMI, serum fasting plasm glucose (FPG), fasting insulin (FIns), triglyceride (TG) and cholesterol (TC) were investigated.
1) Serum FPG, FIns, TG and TC were statistically significant higher than that in normal control group. 2) We found that BMI was higher in the rs9939609 TA+AA, rs8050136 AC+AA, rs1558902 TA+AA and rs3751812 GT+TT genotypes than in wild TT genotypes (rs9939609: P = 0.038; rs1558902: P = 0.038;), CC genotypes(rs8050136: P = 0.024) and GG genotypes (rs3751812: P = 0.024), which were not significant on adjusting for multiple testing. 3) In case-control studies, five polymorphisms were not significantly associated with overweight (p>0.05), haplotype analyses showed non-haplotype is significantly associated with a higher risk of being overweight (p>0.05). 4) There existed no significant statistical difference about FPG, FIns, TG and TC in genotype model for any SNP.
Our study has conducted a genetic association study of the FTO polymorphisms with BMI, serum fasting plasm glucose (FPG), fasting insulin (FIns), triglyceride (TG) and cholesterol (TC). Our study found BMI of subjects with A allele of FTO rs9939609 is higher than that with T allele. Further studies on other polymorphisms from FTO and increasing the sample size are needed.
PMCID: PMC4049598  PMID: 24911064
20.  Clinicopathologic features and prognostic implications of NOK/STYK1 protein expression in non-small cell lung cancer 
BMC Cancer  2014;14:402.
The expression of novel oncogenic kinase (NOK), a member of the protein tyrosine kinase (PTK) family, has been observed in several human malignancies including non-small cell lung cancer (NSCLC). However, the clinic relevance of NOK expression in NSCLC remains unclear.
In this study, NOK expression in tumor cells was assessed using immunohistochemical methods in 191 patients with resected NSCLC. The association of NOK expression with clinicopathological parameters, including the Ki-67 labeling index (LI), was also evaluated. Kaplan-Meier survival analysis and Cox proportional hazards models were used to estimate the effect of NOK expression on survival.
Data showed that NOK was expressed in 75.4% and 14.1% of cancer lesions and corresponding adjacent non-cancerous tissue, respectively. Out of all the clinicopathological factors analyzed, NOK expression was significantly correlated with the grade of tumor differentiation (P = 0.035), pTNM stage (P = 0.020), lymphatic metastasis (P = 0.005) and high Ki-67 LI (P < 0.001). NOK positive NSCLC patients had a significantly shorter survival time (P = 0.004, Log-rank test) and the prognostic significance of NOK expression was apparent in squamous cell carcinoma patients (P = 0.022). Multivariate analysis indicated that NOK expression may be an independent prognostic factor in NSCLC (hazard ratio [HR], 1.731; P = 0.043).
Our results indicate that NOK expression is of clinical significance and can serve as a prognostic biomarker in NSCLC.
PMCID: PMC4051150  PMID: 24894011
NOK; Oncogene; Lung cancer; NSCLC; Survival; Prognosis; Immunohistochemistry
21.  Postsynaptic potentiation of corticospinal projecting neurons in the anterior cingulate cortex after nerve injury 
Molecular Pain  2014;10:33.
Long-term potentiation (LTP) is the key cellular mechanism for physiological learning and pathological chronic pain. In the anterior cingulate cortex (ACC), postsynaptic recruitment or modification of AMPA receptor (AMPAR) GluA1 contribute to the expression of LTP. Here we report that pyramidal cells in the deep layers of the ACC send direct descending projecting terminals to the dorsal horn of the spinal cord (lamina I-III). After peripheral nerve injury, these projection cells are activated, and postsynaptic excitatory responses of these descending projecting neurons were significantly enhanced. Newly recruited AMPARs contribute to the potentiated synaptic transmission of cingulate neurons. PKA-dependent phosphorylation of GluA1 is important, since enhanced synaptic transmission was abolished in GluA1 phosphorylation site serine-845 mutant mice. Our findings provide strong evidence that peripheral nerve injury induce long-term enhancement of cortical-spinal projecting cells in the ACC. Direct top-down projection system provides rapid and profound modulation of spinal sensory transmission, including painful information. Inhibiting cortical top-down descending facilitation may serve as a novel target for treating neuropathic pain.
PMCID: PMC4060852  PMID: 24890933
22.  Remodeling of rat pulmonary artery induced by chronic smoking exposure 
Journal of Thoracic Disease  2014;6(6):818-828.
To evaluate the dominant role in rat pulmonary artery (PA) remodeling induced by chronic smoking exposure (CSE).
Thirty-five male Sprague-Dawley (SD) rats were exposed to 36 cigarettes per day, 6 days per week, for 1, 3, or 5 months. Another 35 SD rats were sham-exposed during the same period. Hemodynamic measurement, evaluation of the right ventricular hypertrophy index (RVHI) plus right ventricle-to-weight ratio, and hematoxylin eosin staining was performed. Wall thickness, artery radius, luminal area, and total area were measured morphometrically. Western blotting assessed expression of PPAR-γ BMP4, BMPR2, and TRPC1/4/6 in the artery and lung. Store-operated calcium entry (SOCE) and [Ca2+]i were measured using Fura-2 as dye.
Mean right ventricular pressure increased after 3 months of smoking exposure and continued to increase through 5 months. Right ventricular systolic pressure (RVSP) increased after 3 months of exposure and then stabilized. RVHI increased after 5 months; right ventricle-to-weight ratio was elevated after 3 months and further increased after 5 months. Wall thickness-to-radius ratio does-dependently increased after 3 months through 5 months, in parallel with the decreased luminal area/total area ratio after 5 months. Other changes included the development of inflammatory responses, enlargement of the alveolar spaces, and reductions in the endothelial lining of PAs, proliferative smooth muscle cells, fibroblasts, and adventitia. Moreover, BMP4 and TRPC1/4/6 expression increased to varying degrees in the arteries and lungs of smoking-exposed animals, whereas BMPR expression and SOCE increased only in the arteries, and PPAR-γ was downregulated in both the arteries and lungs.
In SD rats, smoking exposure induces pulmonary vascular remodeling. The consequences of increased SOCE include increase in TRPC1/4/6, probably via augmented BMP4 expression, which also contribute to inflammatory responses in the lung. Moreover, interactions between BMP4 and PPAR-γ may play a role in preventing inflammation under normal physiological conditions.
PMCID: PMC4073362  PMID: 24977008
Pulmonary artery hypertension (PAH); smoking; remodeling
23.  Prognostic significance of ERCC1 expression in postoperative patients with gastric cancer 
This study explored the correlation between the expression of excision repair cross-complementation group 1 (ERCC1) and the prognosis of gastric cancer patients.
From January 2005 to December 2008, 605 patients who underwent radical surgery in The First Affiliated Hospital of Nanjing Medical University were enrolled. We conducted the follow-up every 6 months and its contents included a comprehensive medical history, tumor markers and abdominal ultrasound or CT and other imaging findings. Deadline was April 30, 2013 and follow-up time between 51 to 91 months. Survival time is calculated from the date of diagnosis to death or last follow-up date. Immunohistochemistry (IHC) was used to assess the expression of ERCC1 in resected samples. The relationship between ERCC1 expression and survival of patients was investigated. The comparison of count data were analyzed by Chi-square test. Median survival time (MST) and the 5-year survival rate were calculated by life table analysis. The Kaplan-Meier curves were used for survival analysis.
ERCC1 expression was positive in 412 patients (68.1%). There is no significant difference between ERCC1-positive group and ERCC1-negative group in terms of the MST and 5-year survival rate (P=0.455). The MST and 5-year survival rate have no significant difference (P=0.162) between group with chemotherapy and group with no chemotherapy in patients with ERCC1-positive expression. However, the MST and 5-year survival rate in patients with ERCC1-negative expression benefited more from with chemotherapy (P=0.019). The ERCC1-positive patients survived longer than those ERCC1-negative patients (P=0.183) in subgroup with no adjuvant chemotherapy. In the subgroup analysis, ERCC1 expression had no significant relationship with overall survival in patients with stage II or III gastric cancer (P>0.05).
ERCC1 might be a good prognostic factor for the patients of gastric cancer after radical resection. Patients with ERCC1-negative expression could benefit more from adjuvant chemotherapy.
PMCID: PMC4076725  PMID: 25035660
Gastric cancer; excision repair cross-complementation group 1 (ERCC1); prognosis; platinum drugs
24.  Susceptibility-Weighted Imaging for the Noncontrast Evaluation of Hepatocellular Carcinoma: A Prospective Study with Histopathologic Correlation 
PLoS ONE  2014;9(5):e98303.
Specific morphologic features of hepatocellular carcinoma (HCC) on imaging have identifiable pathologic correlates as well as implications for altering surgical management and defining prognosis. In this study, we compared susceptibility-weighted imaging (SWI) to conventional techniques and correlated our findings with histopathology to determine the role of SWI in assessing morphologic features of HCC without using a contrast agent.
86 consecutive patients with suspected HCC were imaged with MRI (including T1, T2, T2*, and SWI) and subsequently CT. 59 histologically-proven HCC lesions were identified in 53 patients. Each lesion on each imaging sequence was evaluated by two radiologists, and classified with respect to lesion morphology, signal intensity relative to surrounding hepatic parenchyma, presence of a pseudocapsule, presence of venous invasion, and internal homogeneity.
Histopathology confirmed pseudocapsules in 41/59 lesions. SWI was able to detect a pseudocapsule in 34/41 lesions; compared to conventional T1/T2 imaging (12/41) and T2* (27/41). Mosaic pattern was identified in 25/59 lesions by histopathology; SWI confirmed this in all 25 lesions, compared to T1/T2 imaging (13/25) or T2* (18/25). Hemorrhage was confirmed by histopathology in 43/59 lesions, and visible on SWI in 41/43 lesions, compared to T1/T2 (7/43) and T2* (38/43). Venous invasion was confirmed by histopathology in 31/59 patients; SWI demonstrated invasion in 28/31 patients, compared to T1/T2 (7/31) and T2* (24/31).
SWI is better at identifying certain morphologic features such as pseudocapsule and hemorrhage than conventional MRI without using a contrast agent in HCC patients.
PMCID: PMC4039503  PMID: 24879409
25.  The Magnolia Bioactive Constituent 4-O-Methylhonokiol Protects against High-Fat Diet-Induced Obesity and Systemic Insulin Resistance in Mice 
Obesity is caused by a combination of both genetic and environmental risks. Disruption in energy balance is one of these risk factors. In the present study, the preventive effect on high-fat diet- (HFD-) induced obesity and insulin resistance in mice by Magnolia bioactive constituent 4-O-methylhonokiol (MH) was compared with Magnolia officinalis extract BL153. C57BL/6J mice were fed by normal diet or by HFD with gavage-administered vehicle, BL153, low-dose MH, and high-dose MH simultaneously for 24 weeks, respectively. Either MH or BL153 slightly inhibited body-weight gain of mice by HFD feeding although the food intake had no obvious difference. Body fat mass and the epididymal white adipose tissue weight were also mildly decreased by MH or BL153. Moreover, MH significantly lowered HFD-induced plasma triglyceride, cholesterol levels and activity of alanine transaminase (ALT), liver weight and hepatic triglyceride level, and ameliorated hepatic steatosis. BL153 only significantly reduced ALT and liver triglyceride level. Concurrently, low-dose MH improved HFD-induced hyperinsulinemia and insulin resistance. Furthermore, the infiltration of mast cells in adipose tissue was decreased in MH or in BL153 treatment. These results suggested that Magnolia bioactive constituent MH might exhibit potential benefits for HFD-induced obesity by improvement of lipid metabolism and insulin resistance.
PMCID: PMC4060163  PMID: 24991305

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