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1.  The interaction between the helicase DHX33 and IPS-1 as a novel pathway to sense double-stranded RNA and RNA viruses in myeloid dendritic cells 
In eukaryotes, there are at least 60 members of the DExD/H helicase family, many of which are able to sense viral nucleic acids. By screening all known family members, we identified the helicase DHX33 as a novel double-stranded RNA (dsRNA) sensor in myeloid dendritic cells (mDCs). The knockdown of DHX33 using small heteroduplex RNA (shRNA) blocked the ability of mDCs to produce type I interferon (IFN) in response to poly I:C and reovirus. The HELICc domain of DHX33 was shown to bind poly I:C. The interaction between DHX33 and IPS-1 is mediated by the HELICc region of DHX33 and the C-terminal domain of IPS-1 (also referred to MAVS and VISA). The inhibition of DHX33 expression by RNA interference blocked the poly I:C-induced activation of MAP kinases, NF-κB and IRF3. The interaction between the helicase DHX33 and IPS-1 was independent of RIG-I/MDA5 and may be a novel pathway for sensing poly I:C and RNA viruses in mDCs.
PMCID: PMC4002151  PMID: 24037184
DHX33; helicase; innate immunity; IPS-1; myeloid dendritic cell; viral nucleic acid
2.  A CLDN1-Negative Phenotype Predicts Poor Prognosis in Triple-Negative Breast Cancer 
PLoS ONE  2014;9(11):e112765.
Triple-negative breast cancer (TNBC) is a heterogeneous disease with no definitive prognostic markers. As a major component of tight junctions, claudins (CLDNs) presumably play an important role in carcinogenesis and progression of breast cancer. This study was aimed at determining the relationship between the expression of CLDNs and the clinical outcomes of TNBCs.
Materials and Methods
The surgical specimens of primary breast tumors from a consecutive cohort of 173 TNBC patients were retrospectively collected. The membranous expression of CLDN1, CLDN2, CLDN4, and CLDN7 was measured by immunohistochemistry. Then, the associations between CLDN expression, clinicopathological features, and clinical outcomes were assessed.
Positive CLDN1, CLDN2, CLDN4, and CLDN7 membrane expression was detected in 44.5%, 54.9%, 76.9%, and 73.4% of the cohort specimens, respectively. A lack of CLDN1 expression was related to only lymph node metastasis (P = 0.014). The rate of CLDN4-positive tumors was significantly increased in tumors of a higher grade (P = 0.003). Importantly, negative CLDN1 expression was associated with worse relapse-free survival (RFS) in both lymph node positive (LN+) and negative (LN−) cases (both P<0.001). Similarly it was also associated with shorter overall survival (OS)(P = 0.003 in LN+ cases; P = 0.018 in LN− cases). In the LN+ subgroup, CLDN2-negative cases had a significantly higher risk of recurrence (P = 0.008). Multivariate analysis revealed that negative CLDN1 expression was an independent prognostic factor for high risk of both recurrence and death (HR 5.529, 95% CI 2.664–11.475, P<0.001; HR 3.459, 95% CI 1.555–7.696, P = 0.002). However, neither CLDN4 nor CLDN7 expression was associated with survival.
In TNBC, the CLDN1-negative phenotype predicts a high risk of recurrence and death. The absence of CLDN1 expression is strongly suggested to be an independent adverse prognostic factor in this heterogeneous subtype of breast cancer.
PMCID: PMC4231092  PMID: 25393310
3.  Diagnosis and staging of superficial esophageal precursor based on pre-endoscopic resection system comparable to endoscopic resection 
BMC Cancer  2014;14(1):774.
Endoscopic treatments for early esophageal squamous cell carcinoma and the esophageal neoplasm are two types: endoscopic resection (ER) and ablation. Resection enables evaluation of the lesion in the ER specimens, while ablation cannot. We sought to establish a pre-ER evaluated system with a diagnostic and staging accuracy similar to ER for the development of ablation therapy.
In our study, we collected data pertaining to early esophageal cancer and esophageal neoplasm treated with ER, analyzed the pre- and post-ER data of the lesions and evaluated the diagnostic accuracy of pre-ER system compared with the gold standard.
The diagnostic accuracy rate was 91% based on the pre-ER system compared with the gold standard, and 93% based on the ER diagnosis. The AUC of the pre-ER system was 0.964, while the ER examination was 0.971.
These results suggest that the accuracy of pre-ER system was comparable to ER. The pre-ER system enables prediction of histological diagnosis and stage of the lesions, and the choice of treatment for superficial esophageal neoplasm.
PMCID: PMC4213488  PMID: 25330811
Endoscopic resection (ER); Endoscopic treatment; Superficial esophageal neoplasm; Histological diagnosis
4.  miR-10b is overexpressed in hepatocellular carcinoma and promotes cell proliferation, migration and invasion through RhoC, uPAR and MMPs 
Recently, miR-10b is identified as a miRNA highly expressed in many human cancers, promoting cell migration and invasion. However, the specific function of miR-10b in hepatocellular carcinoma (HCC) is unclear at this point.
The miR-10b expression levels in 60 paired different TNM Stage HCC tumor tissues compared with adjacent non-tumor (ANT) tissues, normal tissue control (8 benign tumor and 7 normal liver tissues), 3 normal liver and 7 HCC cell lines were measured by real-time quantitative RT-PCR and to evaluate their association with HCC clinicopathologic features. Invasion assay, MTT proliferation assay and wound-healing assay were performed to test the invasion and proliferation of HCC cell after transfection. The effect of miR-10b on HCC in vivo was validated by murine xenograft model.
We found that miR-10b expression was increased in human HCC tissues and cell lines compared with normal control, respectively. The expression of miR-10b was correlated with HCC metastatic ability. Overexpression of miR-10b in MHCC-97L cells increased cell motility and invasiveness, whereas inhibition of miR-10b in MHCC-97H cells reduced cell motility and invasiveness in vitro and in vivo. We also showed that HOXD10 was negatively regulated by miR-10b at the posttranscriptional level, via a specific target site within the 3′UTR by luciferase reporter assay. Furthermore, we found that miR-10b induced HCC cell invasion and migration by modulating the HOXD10 target gene RhoC, uPAR, MMP-2 and MMP-9 expression.
Our results suggested that miR-10b was overexpressed in HCC and promoted HCC cell migration and invasion through the HOXD10/ RhoC/ uPAR/ MMPs pathway which may provide a novel bio-target for HCC therapy.
PMCID: PMC4192292  PMID: 25236186
miR-10b; HCC; invasion; migration; RhoC; uPAR; MMPs
5.  Nanotubular surface modification of metallic implants via electrochemical anodization technique 
Due to increased awareness and interest in the biomedical implant field as a result of an aging population, research in the field of implantable devices has grown rapidly in the last few decades. Among the biomedical implants, metallic implant materials have been widely used to replace disordered bony tissues in orthopedic and orthodontic surgeries. The clinical success of implants is closely related to their early osseointegration (ie, the direct structural and functional connection between living bone and the surface of a load-bearing artificial implant), which relies heavily on the surface condition of the implant. Electrochemical techniques for modifying biomedical implants are relatively simple, cost-effective, and appropriate for implants with complex shapes. Recently, metal oxide nanotubular arrays via electrochemical anodization have become an attractive technique to build up on metallic implants to enhance the biocompatibility and bioactivity. This article will thoroughly review the relevance of electrochemical anodization techniques for the modification of metallic implant surfaces in nanoscale, and cover the electrochemical anodization techniques used in the development of the types of nanotubular/nanoporous modification achievable via electrochemical approaches, which hold tremendous potential for bio-implant applications. In vitro and in vivo studies using metallic oxide nanotubes are also presented, revealing the potential of nanotubes in biomedical applications. Finally, an outlook of future growth of research in metallic oxide nanotubular arrays is provided. This article will therefore provide researchers with an in-depth understanding of electrochemical anodization modification and provide guidance regarding the design and tuning of new materials to achieve a desired performance and reliable biocompatibility.
PMCID: PMC4172084  PMID: 25258532
nanotubular arrays; anodization; implant; bioactivity; in vitro; in vivo
6.  Fibroblast α11β1 Integrin Regulates Tensional Homeostasis in Fibroblast/A549 Carcinoma Heterospheroids 
PLoS ONE  2014;9(7):e103173.
We have previously shown that fibroblast expression of α11β1 integrin stimulates A549 carcinoma cell growth in a xenograft tumor model. To understand the molecular mechanisms whereby a collagen receptor on fibroblast can regulate tumor growth we have used a 3D heterospheroid system composed of A549 tumor cells and fibroblasts without (α11+/+) or with a deletion (α11-/-) in integrin α11 gene. Our data show that α11-/-/A549 spheroids are larger than α11+/+/A549 spheroids, and that A549 cell number, cell migration and cell invasion in a collagen I gel are decreased in α11-/-/A549 spheroids. Gene expression profiling of differentially expressed genes in fibroblast/A549 spheroids identified CXCL5 as one molecule down-regulated in A549 cells in the absence of α11 on the fibroblasts. Blocking CXCL5 function with the CXCR2 inhibitor SB225002 reduced cell proliferation and cell migration of A549 cells within spheroids, demonstrating that the fibroblast integrin α11β1 in a 3D heterospheroid context affects carcinoma cell growth and invasion by stimulating autocrine secretion of CXCL5. We furthermore suggest that fibroblast α11β1 in fibroblast/A549 spheroids regulates interstitial fluid pressure by compacting the collagen matrix, in turn implying a role for stromal collagen receptors in regulating tensional hemostasis in tumors. In summary, blocking stromal α11β1 integrin function might thus be a stroma-targeted therapeutic strategy to increase the efficacy of chemotherapy.
PMCID: PMC4116160  PMID: 25076207
7.  PIK3CA Gene Mutations and Overexpression: Implications for Prognostic Biomarker and Therapeutic Target in Chinese Esophageal Squamous Cell Carcinoma 
PLoS ONE  2014;9(7):e103021.
To evaluate PIK3CA gene mutations and PIK3CA expression status in Chinese esophageal squamous cell carcinoma (ESCC) patients, and their correlation with clinicopathological characteristics and clinical outcomes.
Direct sequencing was applied to investigate mutations in exons 9 and 20 of PIK3CA in 406 Chinese ESCC patients. PIK3CA expression was evaluated using immunohistochemistry analysis. The associations of PIK3CA gene mutations and PIK3CA expression with clinicopathological characteristics and clinical outcome were examined.
Thirty somatic point mutations (30/406, 7.4%) were identified in exon 9 whereas no mutations were detected in exon 20. PIK3CA mutations were not correlated with clinicopathological characteristics or clinical outcomes. However in the ESCC patients with family cancer history, PIK3CA mutations were independently correlated with worse overall survival (multivariate hazard ratio (HR) = 10.493, 95% CI: 2.432–45.267, P = 0.002). Compared to normal esophageal tissue, PIK3CA was significantly overexpressed in cancer tissue (P<0.001). PIK3CA overexpression was independently associated with higher risk of local recurrence (multivariate HR  = 1.435, 95% CI: 1.040–1.979, P = 0.028). In female ESCC patients, PIK3CA overexpression was independently correlated with worse overall survival (multivariate HR  = 2.341, 95% CI: 1.073–5.108, P = 0.033).
Our results suggest PIK3CA gene mutation and overexpression could act as biomarkers for individualized molecular targeted therapy for Chinese ESCC patients.
PMCID: PMC4108430  PMID: 25054828
8.  Effects of Biochar on Soil Microbial Biomass after Four Years of Consecutive Application in the North China Plain 
PLoS ONE  2014;9(7):e102062.
The long term effect of biochar application on soil microbial biomass is not well understood. We measured soil microbial biomass carbon (MBC) and nitrogen (MBN) in a field experiment during a winter wheat growing season after four consecutive years of no (CK), 4.5 (B4.5) and 9.0 t biochar ha−1 yr−1 (B9.0) applied. For comparison, a treatment with wheat straw residue incorporation (SR) was also included. Results showed that biochar application increased soil MBC significantly compared to the CK treatment, and that the effect size increased with biochar application rate. The B9.0 treatment showed the same effect on MBC as the SR treatment. Treatments effects on soil MBN were less strong than for MBC. The microbial biomass C∶N ratio was significantly increased by biochar. Biochar might decrease the fraction of biomass N mineralized (KN), which would make the soil MBN for biochar treatments underestimated, and microbial biomass C∶N ratios overestimated. Seasonal fluctuation in MBC was less for biochar amended soils than for CK and SR treatments, suggesting that biochar induced a less extreme environment for microorganisms throughout the season. There was a significant positive correlation between MBC and soil water content (SWC), but there was no significant correlation between MBC and soil temperature. Biochar amendments may therefore reduce temporal variability in environmental conditions for microbial growth in this system thereby reducing temporal fluctuations in C and N dynamics.
PMCID: PMC4098902  PMID: 25025330
9.  Particulate Matter Pollution and Population Exposure Assessment over Mainland China in 2010 with Remote Sensing 
The public is increasingly concerned about particulate matter pollution caused by respirable suspended particles (PM10) and fine particles (PM2.5). In this paper, PM10 and PM2.5 concentration are estimated with remote sensing and individual air quality indexes of PM10 and PM2.5 (IPM10 and IPM2.5) over mainland China in 2010 are calculated. We find that China suffered more serious PM2.5 than PM10 pollution in 2010, and they presented a spatial differentiation. Consequently, a particulate-based air quality index (PAQI) based on a weighting method is proposed to provide a more objective assessment of the particulate pollution. The study demonstrates that, in 2010, most of mainland China faced a lightly polluted situation in PAQI case; there were three areas obviously under moderate pollution (Hubei, Sichuan-Chongqing border region and Ningxia-Inner Mongolia border region). Simultaneously, two indicators are calculated with the combination of population density gridded data to reveal Chinese population exposure to PM2.5. Comparing per capita PM2.5 concentration with population-weighted PM2.5 concentration, the former shows that the high-level regions are distributed in Guangdong, Shanghai, and Tianjin, while the latter are in Hebei, Chongqing, and Shandong. By comparison, the results demonstrate that population-weighted PM2.5 concentration is more in line with the actual situation.
PMCID: PMC4053876  PMID: 24830453
particulate matter pollution; population exposure; air quality assessment; remote sensing
10.  A MicroRNA Signature Predicts Survival in Early Stage Small-Cell Lung Cancer Treated with Surgery and Adjuvant Chemotherapy 
PLoS ONE  2014;9(3):e91388.
Small-cell lung cancer (SCLC) is one of the most aggressive cancers, yet the molecular mechanisms underlying its devastating clinical outcome remain elusive. In this study, we investigated whether microRNA (miRNA) expression profiles can predict the clinical outcomes of SCLC patients. A total of 82 patients with limited SCLC, who were treated with surgical resection and adjuvant chemotherapy, were enrolled in this study. First, we surveyed the expression of 924 miRNAs from 42 SCLC patients to discover survival-relevant miRNAs and develop prognostic models, which were then validated in an independent cohort of 40 cases using quantitative real-time PCR. We found that the miR-150/miR-886-3p signature was significantly correlated with the overall survival (OS) of SCLC patients (p = 0.02) in the training set, and both miRNA expression levels were much lower in the SCLC samples than normal lung samples. The miRNA signature also proved to be a significant predictor of survival in the validation set. Patients with high-risk miRNA signatures had poor overall survival (p = 0.005) and progression-free survival (p = 0.017) compared with those with low-risk scores. These findings retained statistical significance after adjusting for age, gender and smoking status (HR: 0.26, 95%: CI 0.10–0.69, p = 0.007), which suggested it may be an independent predictor of survival. In summary, we developed a prognostic miR-150/miR-886-3p signature and validated expression in an independent dataset of resectable SCLC. These preliminary results indicated that miRNAs may serve as promising molecular prognostic markers and new therapeutic targets for SCLC.
PMCID: PMC3956664  PMID: 24637927
11.  Overexpression of OLC1 Promotes Tumorigenesis of Human Esophageal Squamous Cell Carcinoma 
PLoS ONE  2014;9(3):e90958.
OLC1 was recently identified to be a potential oncogene. However, the role of OLC1 in human esophageal cell carcinoma (ESCC) is unknown. The aim of this study was therefore to evaluate the expression of OLC1 in human ESCC from normal, premalignant, and malignant lesions, and to clarify the mechanisms by which OLC1 contributes to the progression of ESCC.
Experimental Design
Two hundred and fourteen paired ESCC specimens, and an independent set from 28 ESCC patients, were used to analyze the correlation between OLC1 expression and the pathological characteristics of tumors using immunohistochemistry. Stable OLC1-overexpressing and OLC1-interfering esophageal cancer cells were established and a series of experimental methods were used to investigate the biological functions and mechanisms of action of OLC1.
We showed that OLC1 was overexpressed in 145 of 214 (67.8%) of human ESCC specimens, compared with in only 59 of 214 (27.57%) paired adjacent normal tissues (P<0.001). OLC1 overexpression occurred at a rate of 35% (10/28) at the stage of mild/moderate dysplasia, but was significantly upregulated to 66% (22/33) at the stages of severe dysplasia and in situ carcinoma, while 71% positive staining (22/28) was observed in invasive carcinoma tissues compared with normal tissues (P<0.05). We also provided evidence that OLC1 abnormalities significantly altered the cell proliferation and apoptosis induced by cytotoxic agents. OLC1 overexpression suppressed apoptosis, and was associated with attenuated caspase-3 activation and increased Bcl-2 stability.
Our study provides strong evidence suggesting OLC1 abnormalities may contribute to the development of human ESCC and have some important clinical significance.
PMCID: PMC3946619  PMID: 24608342
12.  Severe sepsis: Low expression of the renin-angiotensin system is associated with poor prognosis 
Severe sepsis has a high fatality rate, but no clinical indices for prognosis have been established. In recent years, the renin-angiotensin system (RAS) has received considerable attention. However, clinical data on RAS are inconsistent. Therefore, the aim of the present study was to assess the significance of RAS in the prognosis of sepsis. Blood samples were collected from patients, who met the diagnostic criteria of severe sepsis, on day 1 (D1) and 3 (D3). For each sample, the levels of angiotensin II (AngII), angiotensin-converting enzyme (ACE) and additional indices were measured. Patients were monitored for 28 days. On the D1 of inclusion, the average Acute Physiology and Chronic Health Evaluation II (APACHE II) score was 22.2 and the Sepsis-related Organ Failure Assessment (SOFA) score was 6.1. Logistic regression analysis revealed that mortality-associated variables included the APACHE II score on D1, the SOFA score on D1, high lactic acid levels on D3 and low AngII and ACE levels on D1 and D3. AngII levels (<86.1 ng/ml) on D1 had a sensitivity of 88.2% and specificity of 77.3% for predicting mortality. ACE levels (<39.2 ng/ml) on D1 had a sensitivity of 88.2% and specificity of 72.7% for predicting mortality. These two indices were better than the APACHE II and SOFA scores. Therefore, low expression levels of AngII and ACE are valuable in predicting the mortality of patients with severe sepsis.
PMCID: PMC3991516  PMID: 24940436
severe sepsis; angiotensin II; angiotensin-converting enzyme; mortality; prognosis
13.  The E3 ubiquitin ligase TRIM21 negatively regulates the innate immune response to intracellular double-stranded DNA 
Nature immunology  2012;14(2):172-178.
DDX41 is a sensor of intracellular double-stranded DNA (dsDNA) in myeloid dendritic cells (mDCs) that triggers a type I interferon response via the signaling adaptor STING. We identified the E3 ligase TRIM21 as a DDX41-interacting protein and found that knockdown of or deficiency in TRIM21 resulted in enhanced type I interferon responses to intracellular dsDNA and DNA viruses. Overexpression of TRIM21 resulted in more degradation of DDX41 and less production of interferon-β (IFN-β) in response to intracellular dsDNA. The SPRY-PRY domain of TRIM21 interacted with the DEADc domain of DDX41. Lys9 and Lys115 of DDX41 were the targets of TRIM21-mediated ubiquitination. TRIM21 is therefore an interferon-inducible E3 ligase that induces the Lys48 (K48)-linked ubiquitination and degradation of DDX41 and negatively regulates the innate immune response to intracellular dsDNA.
PMCID: PMC3645272  PMID: 23222971
14.  The interaction between the helicase DHX33 and IPS-1 as a novel pathway to sense double-stranded RNA and RNA viruses in myeloid dendritic cells 
In eukaryotes, there are at least 60 members of the DExD/H helicase family, many of which are able to sense viral nucleic acids. By screening all known family members, we identified the helicase DHX33 as a novel double-stranded RNA (dsRNA) sensor in myeloid dendritic cells (mDCs). The knockdown of DHX33 using small heteroduplex RNA (shRNA) blocked the ability of mDCs to produce type I interferon (IFN) in response to poly I:C and reovirus. The HELICc domain of DHX33 was shown to bind poly I:C. The interaction between DHX33 and IPS-1 is mediated by the HELICc region of DHX33 and the C-terminal domain of IPS-1 (also referred to MAVS and VISA). The inhibition of DHX33 expression by RNA interference blocked the poly I:C-induced activation of MAP kinases, NF-κB and IRF3. The interaction between the helicase DHX33 and IPS-1 was independent of RIG-I/MDA5 and may be a novel pathway for sensing poly I:C and RNA viruses in mDCs.
PMCID: PMC4002151  PMID: 24037184
DHX33; helicase; innate immunity; IPS-1; myeloid dendritic cell; viral nucleic acid
15.  Measuring telomere length for the early detection of precursor lesions of esophageal squamous cell carcinoma 
BMC Cancer  2013;13:578.
Esophageal cancer is the sixth leading cause of cancer death worldwide; current early detection screening tests are inadequate. Esophageal balloon cytology successfully retrieves exfoliated and scraped superficial esophageal epithelial cells, but cytologic reading of these cells has poor sensitivity and specificity for detecting esophageal squamous dysplasia (ESD), the precursor lesion of esophageal squamous cell carcinoma (ESCC). Measuring telomere length, a marker for chromosomal instability, may improve the utility of balloon cytology for detecting ESD and early ESCC.
We examined balloon cytology specimens from 89 asymptomatic cases of ESD (37 low-grade and 52 high-grade) and 92 age- and sex-matched normal controls from an esophageal cancer early detection screening study. All subjects also underwent endoscopy and biopsy, and ESD was diagnosed histopathologically. DNA was extracted from the balloon cytology cells, and telomere length was measured by quantitative PCR. A receiver operating characteristic (ROC) curve was plotted for telomere length as a diagnostic marker for high-grade dysplasia.
Telomere lengths were comparable among the low- and high-grade dysplasia cases and controls, with means of 0.96, 0.96, and 0.92, respectively. The area under the ROC curve was 0.55 for telomere length as a diagnostic marker for high-grade dysplasia. Further adjustment for subject characteristics, including sex, age, smoking, drinking, hypertension, and body mass index did not improve the use of telomere length as a marker for ESD.
Telomere length of esophageal balloon cytology cells was not associated with ESCC precursor lesions. Therefore, telomere length shows little promise as an early detection marker for ESCC in esophageal balloon samples.
PMCID: PMC3882883  PMID: 24308314
Esophageal squamous cell carcinoma; Esophageal squamous dysplasia; Early detection; Screening; Balloon cytology; Telomeres
16.  Long segmental hyperplasia of interstitial cells of Cajal with giant diverticulum formation 
Sporadic gastrointestinal stromal tumors (GISTs) usually form a well-circumscribed mass. In contrast, diffuse interstitial cell of Cajal (ICC) hyperplasia along the Auerbach plexus without a discrete mass may occur in patients with germline mutations in the NF1, c-KIT or PDGFRA genes. However, sporadic, diffuse ICC hyperplasia without c-KIT or PDGFRA mutations has not been reported. We describe herein one such case, forming a giant diverticulum. A 63-year-old woman with no features of Neurofibromatosis 1 (NF1) presented with increasing abdominal pain for more than 30 years. A large, diverticulum-like mass in the ileum was resected. Microscopically, a diffuse proliferation of bland spindle cells was seen extending for 12 cm, replacing the muscularis propria and lined by intact mucosa. The spindle cells were CD117+/CD34+/DOG1+/SMA+/Desmin-/S100-. Mutation analyses did not reveal any mutations in c-KIT or PDGFRA. The lesion had two silent mutations in the NF1 gene. It is rare of the diffuse form of sporadic ICC hyperplasia showing diffuse longitudinal microscopic growth completely replacing the muscularis propria, mimicking diffuse ICC hyperplasia in hereditary GIST syndromes, but without solid components and no c-KIT or PDGFRA gene mutations. This peculiar form of sporadic ICC hyperplasia may be related to intestinal dysmotility in this ileal segment and giant diverticulum formation.
PMCID: PMC3843283  PMID: 24294389
ICC hyperplasia; giant diverticulum; c-KIT; PDGFRA; NF1
17.  HER2 Status in Gastric and Gastroesophageal Junction Cancer Assessed by Local and Central Laboratories: Chinese Results of the HER-EAGLE Study 
PLoS ONE  2013;8(11):e80290.
Trastuzumab has been approved for human epidermal growth factor receptor 2 (HER2)-positive advanced gastric and gastroesophageal junction cancers (GC and GJC) in combination with chemotherapy. The aim of this HER2 early/advanced gastric epidemiology (HER-EAGLE) study was to evaluate the frequency of HER2 over-expression and to evaluate agreement on HER2 status assessment in GC and GJC patients in local laboratories versus a central laboratory in China. Tumor samples from 734 GC or GJC patients who were enrolled at 11 different hospitals in China were examined. HER2 status was assessed by immunohistochemistry (IHC), and followed by dual-color silver-enhanced in Situ hybridization (DSISH) in IHC 2+ cases. Clinicopathologic characteristics were collected from all of the patients. HER2-positive tumors were identified in 12.0% (88/734) of the GC and GJC cases. There were significantly higher rates of HER2 positivity in patients with GJC (GJC: 18.1%, GC: 9.7%, P=0.002), and intestinal-type cancers using the Lauren classification (intestinal: 23.6%, diffuse/mixed: 4.3%, P<0.0001). No significant difference in HER2 positivity was identified between resection and biopsy samples, or between early and advanced disease stages. The agreement between local laboratories and the central laboratory on HER2 status scoring was good (kappa=0.86). The main reason of HER2 status discordance between local and the central laboratories was IHC result mis-interpretation in local laboratories. These results suggest that IHC followed by DSISH testing is an accurate and cost-effective procedure in China.
PMCID: PMC3828190  PMID: 24244671
18.  Nimotuzumab combined with radiotherapy for esophageal cancer: preliminary study of a Phase II clinical trial 
OncoTargets and therapy  2013;6:1589-1596.
To determine the safety and therapeutic effects of nimotuzumab (h-R3) combined with radiotherapy in esophageal cancer.
This Phase II clinical trial involved 42 patients with stage II (inoperable or refused surgery) to stage IV (supraclavicular lymph node metastasis only) esophageal cancers treated between November 2008 and July 2010. All patients had squamous cell carcinomas, and all received three-dimensional conformal radiotherapy and 200 mg nimotuzumab per week during radiotherapy.
There were 9, 25, and 8 patients with stage II, III and IV disease, respectively. All except two patients received 50–70 Gy radiation; 37 patients (88.1%) received more than five nimotuzumab doses. Grade III toxicities (21.4% of all adverse events) included esophagitis and gastrointestinal, dermatological and hematological toxicities. Complete response, partial response, stable disease, and progressive disease were observed in 0, 22 (52.4%), 17 (40.5%) and 3 (7.1%) patients at 1 month after the treatment. The epidermal growth factor receptor (EGFR) overexpression rate was 95.2%. After a median follow-up of 37 months, the median survival time (MST) was 14 months. The 2 year and 3 year overall survival (OS) rates were 33.3% and 26.2%, respectively. The median progression-free survival (PFS) time was 10 months. The 2 year and 3 year PFS rates were 24.5% and 22.1%, respectively. The MST in the 13 patients with (+++) EGFR expression (group A) and 7 patients with (++) EGFR expression (group B) was 15 and 11 months, respectively. The 2 year and 3 year OS rates were 46.2% and 38.5% in group A and 28.6% and 28.6% in group B, respectively (P = 0.405).
Although concurrent chemoradiotherapy was the standard care for locally advanced esophageal cancer, radiotherapy was the choice for those who were refused or could not tolerate chemoradiotherapy. Our study shows that nimotuzumab combined with radiotherapy was well tolerated in patients with esophageal cancer. EGFR overexpression was more common than previously reported. OS was higher after combined therapy than after historical control radiotherapy alone. Further studies are required to confirm the therapeutic efficacy of nimotuzumab in esophageal cancer.
PMCID: PMC3825695  PMID: 24235844
esophageal neoplasms; nimotuzumab; radiotherapy; targeted therapy; treatment outcomes
19.  IL-10 Gene Polymorphisms and Susceptibility to Systemic Lupus Erythematosus: A Meta-Analysis 
PLoS ONE  2013;8(7):e69547.
A number of observational studies have been conducted to investigate the association of the IL-10 gene polymorphisms with systemic lupus erythematosus (SLE) susceptibility. However, their results are conflicting.
We searched published case-control studies on the IL-10 polymorphisms and SLE in PubMed, EMBASE and Chinese Biomedical Literature Database. A meta-analysis was conducted using a fixed-effect or random-effect model based on between-study heterogeneity.
A total of 42 studies with 7948 cases and 11866 controls were included in this meta-analysis. Among Caucasians, the CA27 allele of the IL10.G microsatellites (OR 2.38, 95% CI 1.01–5.62), the G allele of the IL-10 -1082G/A polymorphism (G vs. A: OR 1.21, 95% CI 1.02–1.44; GG vs. AA: OR 1.45, 95% CI 1.16–1.82; GG+GA vs. AA: OR 1.16, 95% CI 1.03–1.29) and its associated haplotype -1082G/−819C/−592C (OR 1.25, 95% CI 1.10–1.42) were associated with increased SLE susceptibility without or with unimportant between-study heterogeneity. Removing studies deviating from Hardy-Weinberg equilibrium (HWE) hardly changed these results. Among Asians, the CA21 allele of the IL-10.G microsatellites (OR 1.28, 95% CI 1.02–1.60) and the -1082G/−819C/−592C haplotype (OR 1.24, 95% CI 1.00–1.53) were associated with increased SLE susceptibility, but with substantial between-study heterogeneity or sensitive to HWE status. Removing studies deviating from HWE also produced statistically significant associations of the IL-10 -1082G/A (GG vs. AA: OR 3.21, 95% CI 1.24–8.28; GG vs. AA+GA: OR 2.85, 95% CI 1.19–6.79) and -592C/A polymorphisms (CC+CA vs. AA: OR 0.69, 95% CI 0.51–0.94) with SLE among Asians.
This meta-analysis showed that the IL10.G microsatellites, the IL-10 -1082G/A and -592C/A polymorphisms and the haplotype -1082G/−819C/−592C are associated with SLE susceptibility. Besides, this is the first time to report an association between the CA27 allele of the IL-10.G microsatellites and SLE among Caucasians. Further studies are needed to confirm these findings.
PMCID: PMC3720721  PMID: 23936042
20.  New intrinsic mechanism on gum-like superelasticity of multifunctional alloys 
Scientific Reports  2013;3:2156.
Ti-Nb-based Gum Metals exhibit extraordinary superelasticity with ultralow elastic modulus, superior strength and ductility, and a peculiar dislocation-free deformation behavior, most of which challenge existing theories of crystal strength. Additionally, this kind of alloys actually displays even more anomalous mechanical properties, such as the non-linear superelastic behavior, accompanied by a pronounced tension-to-compression asymmetry, and large ductility with a low Poisson's ratio. Two main contradictory arguments exist concerning the deformation mechanisms of those alloys, i.e., formation of reversible nanodisturbance and reversible martensitic transformation. Herein we used the in-situ synchrotron high-energy X-ray scattering technique to reveal the novel intrinsic physical origin of all anomalous mechanical properties of the Ti-24Nb-4Zr-8Sn-0.10O alloy, a typical gum-like metal. Our experiments provide direct evidence on two different kinds of interesting, stress-induced, reversible nanoscale martensitic transitions, i.e., the austenitic regions with B2 structure transform to α″ martensite and those with BCC structure transform to δ martensite.
PMCID: PMC3703606  PMID: 23831664
21.  The helicase DDX41 senses intracellular DNA mediated by the adaptor STING in dendritic cells 
Nature immunology  2011;12(10):959-965.
The recognition of pathogenic DNA is important to the initiation of antiviral responses. Here we report the identification of DDX41, a member of the DEXDc family of helicases, as an intracellular DNA sensor in myeloid dendritic cells (mDCs). Knockdown of DDX41 expression by short hairpin RNA blocked the ability of mDCs to mount type I interferon and cytokine responses to DNA and DNA viruses. Overexpression of both DDX41 and the membrane-associated adaptor STING together had a synergistic effect in promoting Ifnb promoter activity. DDX41 bound both DNA and STING and localized together with STING in the cytosol. Knockdown of DDX41 expression blocked activation of the mitogen-activated protein kinase TBK1 and the transcription factors NF-κB and IRF3 by B-form DNA. Our results suggest that DDX41 is an additional DNA sensor that depends on STING to sense pathogenic DNA.
PMCID: PMC3671854  PMID: 21892174
22.  DHX9 Pairs with IPS-1 To Sense Double-Stranded RNA in Myeloid Dendritic Cells 
The innate immune system is equipped with many molecular sensors for microbial DNA/RNA to quickly mount antimicrobial host immune responses. In this paper, we identified DHX9, a DExDc helicase family member, as an important viral dsRNA sensor in myeloid dendritic cells (mDCs). Knockdown of DHX9 expression by small heteroduplex RNA dramatically blocked the ability of mDCs to produce IFN-α/β and proinflammatory cytokines in response to polyinosine-polycytidylic acid, influenza A, and reovirus. DHX9 could specifically bind polyinosine-polycytidylic acid via its double-strand RNA binding motifs. DHX9 interacted with IPS-1 via the HelicC-HA2-DUF and CARD domains of DHX9 and IPS-1, respectively. Knockdown of DHX9 expression in mDCs blocked the activation of NF-κB and IFN regulatory factor 3 by dsRNA. Collectively, these results suggest that DHX9 is an important RNA sensor that is dependent on IPS-1 to sense pathogenic RNA.
PMCID: PMC3656476  PMID: 21957149
23.  Genome Sequencing of Ralstonia solanacearum FQY_4, Isolated from a Bacterial Wilt Nursery Used for Breeding Crop Resistance 
Genome Announcements  2013;1(3):e00125-13.
Ralstonia solanacearum strain FQY_4 was isolated from a bacterial wilt nursery, which is used for breeding crops for Ralstonia resistance in China. Here, we report the complete genome sequence of FQY_4 and its comparison with other published R. solanacearum genomes, especially with the strains GMI1000 and Y45 in the same group.
PMCID: PMC3650430  PMID: 23661471
24.  HER2 expression and relevant clinicopathological features in gastric and gastroesophageal junction adenocarcinoma in a Chinese population 
Diagnostic Pathology  2013;8:76.
With varied immunohistochemistry scoring criteria and patient cohorts, HER2-positivity rates in gastric cancer (GC) and gastroesophageal junction (GEJ) adenocarcinoma have been reported with a wide range. Recently standardized scoring criteria for GC and GEJ cancer has been established and recommended. In this study, the frequency of HER2 expression and the relationship between HER2 expression and clinicopathological features were examined in a large cohort of Chinese GC and GEJ cancer patients.
A total of 1463 patients, including 929 primary GCs and 534 primary GEJ adenocarcinomas, was retrospectively analyzed for HER2 overexpression by immunohistochemistry (IHC). Fluorescence in situ hybridization (FISH) analysis was used in 308 GCs and GEJ adenocarcinoma cases to assess HER2 gene amplification.
HER2 overexpression (3+) was detected in 9.8% of carcinomas and more frequently observed in GEJ cancer cases, in the intestinal type, and in the well or moderately differentiated type (P=0.003, 0.000, and 0.000, respectively). HER2 equivocal (2+) was detected in 14.4% of cases. As for the 308 cases analyzed by FISH, 39 (of 40, 97.5%) IHC 3+ cases, 11 (of 38, 28.9%) IHC 2+ cases, and 3 (of 230, 1.3%) IHC 1+/0 cases showed HER2 gene amplification. A high concordance rate (98.5%) between IHC and FISH was demonstrated.
Approximately 10% of Chinese patients with primary GC and GEJ adenocarcinoma were HER2-positive on IHC. HER2 overexpression was associated with GEJ site, intestinal cancer subtype, and well or moderately differentiated carcinomas.
Virtual slides
The virtual slide(s) for this article can be found here:
PMCID: PMC3655831  PMID: 23656792
HER2; Gastric cancer; Gastroesophageal junction adenocarcinoma; Chineses; Clinicopathological features
25.  Pulmonary metastasis of a papillary thyroid carcinoma and primary lung adenocarcinoma: two coincident carcinomas at the same location 
Diagnostic Pathology  2013;8:26.
Tumor-to-tumor metastasis is a fairly rare phenomenon. The lung cancers are the most common donors, but are exceedingly rare as recipients. Here we report a case of a lung adenocarcinoma acting as the recipient of papillary thyroid carcinoma, with multiple spreading foci of the two cancers in the lung simultaneously. The morphology and immunohistochemisty (Napsin-A, Thyroglobulin) are very important in differential diagnosis of lung primary adenocarcinoma and metastatic papillary thyroid carcinoma.
Virtual Slides
The virtual slide(s) for this article can be found here:
PMCID: PMC3599127  PMID: 23414265
Tumor-to-tumor metastasis; Papillary thyroid carcinoma; Lung adenocarcinoma; Napsin-A; Thyroglobulin

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