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1.  Gene–environment interaction between adiponectin gene polymorphisms and environmental factors on the risk of diabetic retinopathy 
To evaluate whether the adiponectin gene is associated with diabetic retinopathy (DR) risk and interaction with environmental factors modifies the DR risk, and to investigate the relationship between serum adiponectin levels and DR.
Materials and Methods
Four adiponectin polymorphisms were evaluated in 372 DR cases and 145 controls. Differences in environmental factors between cases and controls were evaluated by unconditional logistic regression analysis. The model-free multifactor dimensionality reduction method and traditional multiple regression models were applied to explore interactions between the polymorphisms and environmental factors.
Using the Bonferroni method, we found no significant associations between four adiponectin polymorphisms and DR susceptibility. Multivariate logistic regression found that physical activity played a protective role in the progress of DR, whereas family history of diabetes (odds ratio 1.75) and insulin therapy (odds ratio 1.78) were associated with an increased risk for DR. The interaction between the C-11377 G (rs266729) polymorphism and insulin therapy might be associated with DR risk. Family history of diabetes combined with insulin therapy also increased the risk of DR. No adiponectin gene polymorphisms influenced the serum adiponectin levels. Serum adiponectin levels did not differ between the DR group and non-DR group.
No significant association was identified between four adiponectin polymorphisms and DR susceptibility after stringent Bonferroni correction. The interaction between C-11377G (rs266729) polymorphism and insulin therapy, as well as the interaction between family history of diabetes and insulin therapy, might be associated with DR susceptibility.
PMCID: PMC4296704  PMID: 25621134
Adiponectin; Diabetic retinopathy; Gene–environment interaction
3.  Increased Plasma Levels of FABP4 and PTEN are Associated with More Severe Insulin Resistance in Women with Gestational Diabetes Mellitus 
The aim of this study was to investigate the relationship between plasma fatty acid binding protein 4 (FABP4), phosphatase and tensin homolog (PTEN), and insulin resistance in patients with gestational diabetes mellitus (GDM).
Plasma FABP4 and PTEN were determined by ELISA in GDM patients (GDM group, n=30) and in euglycemic pregnant women (control group, n=30). The clinical features, body mass index (BMI), homeostasis model assessment of insulin resistance (HOMA-IR), and lipid profiles were compared between the 2 groups. The influence of risk factors on insulin resistance, including BMI, lipid profiles, FABP4, and PTEN, were further investigated by multiple-factor stepwise regression analysis.
Higher levels of BMI, ΔBMI, triglyceride (TG), fasting plasma glucose (FPG), 2-hour plasma glucose (2hPG), fasting insulin, HOMA-IR, FABP4, PTEN, and lower level of high-density lipoprotein cholesterol (HDL-C) were found in the GDM patients than in the controls (all P<0.005). The plasma FABP4 was 1.47±0.25 vs. 0.20±0.07 ng/ml in the GDM and control group, respectively (P<0.0001). Plasma PTEN was 6.46±1.57 vs. 4.72±0.82 ng/ml in the GDM and control group, respectively (P<0.0001). There was a positive relation between plasma FABP4 and PTEN when all blood samples, including GDM and control groups, were analyzed (P<0.05). The multiple-factor regression analysis revealed that plasma FABP4, TG, and PTEN were independent risk factors for increased insulin resistance.
GDM patients have more severe insulin resistance compared to euglycemic pregnant women. Higher levels of plasma FABP4 and PTEN are associated with increased insulin resistance and may participate in the pathogenesis of insulin resistance during gestation.
PMCID: PMC4329941  PMID: 25659997
Diabetes, Gestational; Fatty Acid-Binding Proteins; Insulin Resistance; PTEN Phosphohydrolase
4.  Comparative genomics of grass EST libraries reveals previously uncharacterized splicing events in crop plants 
BMC Plant Biology  2015;15:39.
Crop plants such as rice, maize and sorghum play economically-important roles as main sources of food, fuel, and animal feed. However, current genome annotations of crop plants still suffer false-positive predictions; a more comprehensive registry of alternative splicing (AS) events is also in demand. Comparative genomics of crop plants is largely unexplored.
We performed a large-scale comparative analysis (ExonFinder) of the expressed sequence tag (EST) library from nine grass plants against three crop genomes (rice, maize, and sorghum) and identified 2,879 previously-unannotated exons (i.e., novel exons) in the three crops. We validated 81% of the tested exons by RT-PCR-sequencing, supporting the effectiveness of our in silico strategy. Evolutionary analysis reveals that the novel exons, comparing with their flanking annotated ones, are generally under weaker selection pressure at the protein level, but under stronger pressure at the RNA level, suggesting that most of the novel exons also represent novel alternatively spliced variants (ASVs). However, we also observed the consistency of evolutionary rates between certain novel exons and their flanking exons, which provided further evidence of their co-occurrence in the transcripts, suggesting that previously-annotated isoforms might be subject to erroneous predictions. Our validation showed that 54% of the tested genes expressed the newly-identified isoforms that contained the novel exons, rather than the previously-annotated isoforms that excluded them. The consistent results were steadily observed across cultivated (Oryza sativa and O. glaberrima) and wild (O. rufipogon and O. nivara) rice species, asserting the necessity of our curation of the crop genome annotations. Our comparative analyses also inferred the common ancestral transcriptome of grass plants and gain- and loss-of-ASV events.
We have reannotated the rice, maize, and sorghum genomes, and showed that evolutionary rates might serve as an indicator for determining whether the identified exons were alternatively spliced. This study not only presents an effective in silico strategy for the improvement of plant annotations, but also provides further insights into the role of AS events in the evolution and domestication of crop plants. ExonFinder and the novel exons/ASVs identified are publicly accessible at
Electronic supplementary material
The online version of this article (doi:10.1186/s12870-015-0431-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4323234  PMID: 25652661
Crop plants; Alternative splicing; Plant transcriptome evolution; Evolutionary rate; Comparative genomics; Bioinformatics
5.  Meta-Analysis of Anti-Muscarinic Receptor Type 3 Antibodies for the Diagnosis of Sjögren Syndrome 
PLoS ONE  2015;10(1):e0116744.
To conduct a meta-analysis to evaluate the diagnostic value of anti-muscarinic receptor type 3 (M3R) antibodies in Sjögren syndrome (SS).
Two databases, PUBMED and the Cochrane Library, were systematically searched. Approximately 2,000 participants from several studies were included in this research. STATA 11.2 software and Meta-DiSc 1.4 was used to conduct the meta-analysis.
Eleven studies were included in the meta-analysis. The pooled DOR was 13.00 (95% CI, 6.00–26.00). The sensitivity was 0.43 (95% CI, 0.28–0.58) and the specificity was 0.95 (95%CI, 0.91–0.97). The LR+ and LR- were 7.90 (95% CI, 4.70–13.40), 0.61 (95% CI, 0.46–0.79), respectively. The AUC was 0.89 (95% CI, 0.86–0.92).
The anti-M3R antibody had high specificity but relatively low sensitivity for the diagnosis of SS.
PMCID: PMC4309563  PMID: 25629973
6.  Differentiation between mycoplasma and viral community-acquired pneumonia in children with lobe or multi foci infiltration: a retrospective case study 
BMJ Open  2015;5(1):e006766.
To analyse the clinical features, inflammatory markers and radiographs of community-acquired pneumonia (CAP) cases with lobe or multi foci infiltration; with a special focus on factors which allow the differential diagnosis of viral and mycoplasma pneumonia.
Retrospective chart review of CAP cases in a large university teaching hospital.
126 paediatric CAP cases, with lobe or multi foci infiltration, presenting between May 2012 and April 2013. Demographic data, clinical presentation on admission or referral, laboratory tests, prior history, and radiography were collected for each case if available.
Primary and secondary outcome measures
We used univariate and multivariate logistic regression to determine the significant factors which allow the differential diagnosis of viral and mycoplasma CAP with lobe or multi foci infiltration.
There were 71 (56%) male and 55 (44%) female CAP cases with lobar or multi foci infiltration. 70 pneumonia cases were caused by Mycoplasma pneumoniae and 18 by viruses. Univariate analysis of the mycoplasma and viral causes of the CAP revealed that increased respiratory rate, wheeze, male gender and lymphocyte percentage were the factors associated with the differentiation of mycoplasma and viral aetiologies of pneumonia (p<0.05). A stepwise logistic regression analysis was performed to assess independent factors which allow the differential diagnosis of viral and mycoplasma pneumonia. Increased respiratory rate, wheeze, and lymphocyte percentage were reliable independent factors which allow the differential diagnosis of viral and mycoplasma CAP with lobar or multi foci infiltration.
Whether the CAP with lobar or multi foci infiltration was caused by mycoplasma species or viruses could not be inferred from the radiological patterns. Wheeze, lymphocyte percentage and respiratory rate were independent factors which allowed the differential diagnosis of viral and mycoplasma CAP with lobar or multi foci infiltration.
PMCID: PMC4298093  PMID: 25596200
7.  The Transcription Factor ELF4 Suppresses Differentiation of Proliferating CD4+ T Cells to the Th17 Lineage 
Journal of immunology (Baltimore, Md. : 1950)  2013;192(1):10.4049/jimmunol.1301372.
The differentiation of CD4+ T cells into different T helper lineages is driven by cytokine milieu in the priming site and the underlying transcriptional circuitry. Even though many positive regulators have been identified, it is not clear how this process is inhibited at transcriptional level. Here we report that the ETS transcription factor ELF4 suppresses the differentiation of Th17 cells both in vitro and in vivo. Culture of naive Elf4−/− CD4+ T cells in the presence of IL-6 and TGFβ (or IL-6, IL-23, and IL-1β) resulted in increased numbers of IL-17A positive cells compared to wild-type controls. In contrast, the differentiation to Th1, Th2, or Treg was largely unaffected by loss of ELF4. The increased expression of genes involved in Th17 differentiation observed in Elf4−/− CD4+ T cells suggested that ELF4 controls their programming into the Th17 lineage rather than only IL-17A gene expression. Despite normal proliferation of naïve CD4+ T cells, loss of ELF4 lowered the requirement of IL-6 and TGFβ signaling for IL-17A induction in each cell division. ELF4 did not inhibit Th17 differentiation by promoting IL-2 production as proposed for another ETS transcription factor, ETS1. Elf4−/− mice showed increased numbers of Th17 cells in the lamina propria at steady state, in lymph nodes after immunization, and most importantly in the CNS following EAE induction, contributing to the increased disease severity. Collectively, our findings suggest that ELF4 restrains Th17 differentiation in dividing CD4+ T cells by regulating commitment to the Th17 differentiation program.
PMCID: PMC3872250  PMID: 24259505
8.  Complementary Roles of Squamous Cell Carcinoma Antigen and 18F-FDG PET/CT in Suspected Recurrence of Cervical Squamous Cell Cancer 
Journal of Cancer  2015;6(3):287-291.
Purpose: To assess the clinical value of FDG PET/CT and evaluate the complementary roles of serum squamous cell carcinoma antigen (SCCAg) and FDG PET/CT in the diagnosis of suspected recurrent of cervical squamous cell cancer. Methods: Serum SCCAg levels were retrospectively reviewed in patients previously treated for cervical squamous cell carcinoma, who had suspected recurrence of cervical cancer and who had undergone FDG PET/CT scans. The clinical impact of elevated SCCAg (>1.5 ng/ml) and negative SCCAg (≤1.5 ng/ml) levels were analyzed based on the results of PET/CT and final diagnosis. Results: The overall patient-based sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) of PET/CT for the detection of tumor recurrence or malignancy were 100% (86/86), 80.8% (21/26), 95.5% (107/112), 94.5% (86/91) and 100% (21/21), respectively. Of the 112 patients included in this study, recurrence or malignancy was detected by PET/CT in 62 of the 64 patients with elevated SCCAg, compared to 24 of the 48 patients with negative SCCAg levels. The overall patient-based PPV, NPV, sensitivity and accuracy of SCCAg for the detection of tumor recurrence or malignancy were 96.9% (62/64), 50% (24/48), 72.1% (62/86) and 76.8% (86/112), respectively. The five false-positive PET/CT results were all associated with patients with negative SCCAg levels. The PPV of positive PET/CT-associated elevated SCCAg for the detection of tumor recurrence or malignancy was 100% (62/62). The NPV of negative SCCAg-associated negative PET/CT was 100% (19/19). Conclusions: Serum SCCAg evaluation and FDG PET/CT imaging can be complementary techniques in cases of suspected recurrent cervical squamous cancer. Positive PET/CT with elevated SCCAg can predict recurrence. Although PET/CT cannot confidently be deferred due to a negative SCCAg test, the possibility of a false-positive PET/CT in those cases may have diagnostic importance.
PMCID: PMC4317765  PMID: 25663947
Squamous cell carcinoma antigen; Cervical squamous cancer; Recurrence; FDG PET/CT; False positive
9.  Differential gene expression profiling of gastric intraepithelial neoplasia and early-stage adenocarcinoma 
World Journal of Gastroenterology : WJG  2014;20(47):17883-17893.
AIM: To investigate the differentiated whole genome expression profiling of gastric high- and low-grade intraepithelial neoplasia and early-stage adenocarcinoma.
METHODS: Gastric specimens from an upper magnifying chromoendoscopic targeted biopsy were collected from March 2010 to May 2013. Whole genome expression profiling was performed on 19 low-grade intraepithelial neoplasia (LGIN), 20 high-grade intraepithelial neoplasia (HGIN), 19 early-stage adenocarcinoma (EGC), and 19 chronic gastritis tissue samples using Agilent 4 × 44K Whole Human Genome microarrays. Differentially expressed genes between different types of lesions were identified using an unpaired t-test and corrected with the Benjamini and Hochberg false discovery rate algorithm. A gene ontology (GO) enrichment analysis was performed using the GeneSpring software GX 12.6. The differentially expressed gene was verified using a real-time TaqMan® PCR assay with independent tissue samples, including 26 LGIN, 15 HGIN, 14 EGC, and 20 chronic gastritis. The expression of G0S2 were further validated by immunohistochemical staining (IHC) in 24 LGIN, 40 HGIN, 30 EGC and 61 chronic gastritis specimens.
RESULTS: The gene expression patterns of LGIN and HGIN tissues were distinct. There were 2521 significantly differentially expressed transcripts in HGIN, with 951 upregulated and 1570 downregulated. A GO enrichment analysis demonstrated that the most striking overexpressed transcripts in HGIN compared with LGIN were in the category of metabolism, defense response, and nuclear factor κB (NF-κB) cascade. While the vast majority of transcripts had barely altered expression in HGIN and EGC tissues, only 38 transcripts were upregulated in EGC. A GO enrichment analysis revealed that the alterations of the immune response were most prominent in the progression from HGIN to EGC. It is worth noting that, compared with LGIN, 289 transcripts were expressed at higher levels both in HGIN and EGC. A characteristic gene, G0/G1 switch 2 (G0S2) was one of the 289 transcripts and related to metabolism, the immune response, and the NF-κB cascade, and its expression was validated in independent samples through real-time TaqMan® PCR and immunohistochemical staining. In real-time PCR analysis, the expression of G0S2 was elevated both in HGIN and EGC compared with that in LGIN (P < 0.01 and P < 0.001, respectively). In IHC analysis, G0S2 immunoreactivity was detected in the cytoplasmic of neoplastic cells, but was undetectable in chronic gastritis cells. The G0S2 expression in HGIN was higher than that of LGIN (P = 0.012, χ2 = 6.28) and EGC (P = 0.008, χ2 = 6.94).
CONCLUSION: A clear biological distinction between gastric high- and low-grade intraepithelial neoplasia was identified, and provides molecular evidence for clinical application.
PMCID: PMC4273138  PMID: 25548486
Gastric early-stage adenocarcinoma; High-and low-grade intraepithelial neoplasia; G0/G1 switch 2; Whole genome expression microarray; Quantitative real-time PCR; Immunohistochemical staining
10.  Toxicity Assessment of Cadinene Sesquiterpenes from Eupatorium adenophorum in Mice 
This study evaluated toxic efficacy of Eupatorium adenophorum extracts, against the Kunming mice. In acute study, we firstly tested median lethal dose (LD50) in mice of three cadinene sesquiterpenes 2-deoxo-2-(acetyloxy)-9-oxoageraphorone (DAOA), 9-oxo-agerophorone (OA) and 9-oxo-10,11-dehydro-agerophorone (ODA) from Eupatorium adenophorum (Ea). DAOA (215–4640 mg/kg BW, given orally) showed lowest LD50 at 926 mg/kg BW for male mice in contrast with OA (1470 mg/kg BW) and ODA (1470 mg/kg BW). In sub-acute study, repeated doses (75–300 mg/kg BW, for 7 days) of DAOA/OA increased blood parameters, liver and spleen index in dose dependent relationship, along with decrease in thymus index. The blood biochemical and histopathological examination showed that DAOA/OA dose 300 mg/kg BW significantly causes pathological changes of hepatic lobules and hepatocytes, which are consistent with cholestasis and hepatic injury. 75 mg/kg dose of DAOA/OA was found to be approximately/totally safe over the span of 7 days treatment showing no change in all above described parameters. Cadinene sesquiterpenes guarantee low risk to environment as a type of low toxic botanical components, which may find potential application in biopesticides development field.
Graphical Abstract
PMCID: PMC4327999  PMID: 25500813
Eupatorium adenophorum; Sesquiterpenes; Histopathology; Environmental toxicity; Biopesticide
11.  Toxicity Assessment of Cadinene Sesquiterpenes from Eupatorium adenophorum in Mice 
This study evaluated toxic efficacy of Eupatorium adenophorum extracts, against the Kunming mice. In acute study, we firstly tested median lethal dose (LD50) in mice of three cadinene sesquiterpenes 2-deoxo-2-(acetyloxy)-9-oxoageraphorone (DAOA), 9-oxo-agerophorone (OA) and 9-oxo-10,11-dehydro-agerophorone (ODA) from Eupatorium adenophorum (Ea). DAOA (215–4640 mg/kg BW, given orally) showed lowest LD50 at 926 mg/kg BW for male mice in contrast with OA (1470 mg/kg BW) and ODA (1470 mg/kg BW). In sub-acute study, repeated doses (75–300 mg/kg BW, for 7 days) of DAOA/OA increased blood parameters, liver and spleen index in dose dependent relationship, along with decrease in thymus index. The blood biochemical and histopathological examination showed that DAOA/OA dose 300 mg/kg BW significantly causes pathological changes of hepatic lobules and hepatocytes, which are consistent with cholestasis and hepatic injury. 75 mg/kg dose of DAOA/OA was found to be approximately/totally safe over the span of 7 days treatment showing no change in all above described parameters. Cadinene sesquiterpenes guarantee low risk to environment as a type of low toxic botanical components, which may find potential application in biopesticides development field.
Graphical Abstract
PMCID: PMC4327999  PMID: 25500813
Eupatorium adenophorum; Sesquiterpenes; Histopathology; Environmental toxicity; Biopesticide
12.  Reduced NKX2.1 Expression Predicts Poor Prognosis of Gastric Carcinoma 
PLoS ONE  2014;9(12):e114556.
Thyroid transcription factor-1 (NKX2.1/TITF-1) is a member of the thyroid tissue-specific transcription factor family that has been proven to be closely associated with many human diseases. Recently, it was reported that NKX2.1 expression is lost or reduced in some human cancers such as lung cancer and thyroid cancer. However, there was insufficient data to suggest that NKX2.1 functionality could be used as a prognostic factor. Therefore, this study aims to investigate NKX2.1 expression and its prognostic significance in primary gastric carcinoma. Then, we attempted to investigate if NKX2.1 expression was related to the clinicopathological characteristics and prognosis of gastric carcinoma (GC)patients. The expression levels of NKX2.1 were analyzed in tissue samples from 205 gastric carcinoma patients by real-time quantitative PCR (qRT-PCR), Western blotting, and immunohistochemical staining(IHC). Our qRT-PCR results showed that the expression of NKX2.1 mRNA was reduced in tumor tissue samples compared with that in matched adjacent non-tumor tissue samples (P<0.001); this finding was confirmed by Western blot analysis (P<0.001). Our immunohistochemical staining data indicated that NKX2.1 expression was significantly decreased in 87 of 205 (42.4%) gastric carcinoma cases. Kaplan-Meier survival curves revealed that the decreased expression of NKX2.1 was significantly associated with poor prognosis in gastric carcinoma patients (P<0.001). Multivariate Cox analysis identified NKX2.1 expression as an independent prognostic factor for overall survival (P = 0.005). Furthermore, the functions of Nkx2.1 were analyzed with respect to the proliferation, migration, and invasion of GC cell lines. Our data suggest that NKX2.1 may function as a tumor suppressor in primary gastric carcinoma and that its reduced expression independently predicts an unsatisfactory prognosis in gastric carcinoma patients.
PMCID: PMC4257675  PMID: 25478793
13.  Circulating miR-221 Expression Level and Prognosis of Cutaneous Malignant Melanoma 
The aim of this study was to investigate the feasibility of using serum miR-221 as a noninvasive prognostic biomarker for cutaneous malignant melanoma (CMM).
We measured the expression levels of miR-221 in serum samples from 72 CMM patients and 54 healthy controls by real-time quantitative polymerase chain reaction (RT-PCR). The overall survival (OS) and disease-free survival (DFS) were calculated using the Kaplan-Meier method. The differences between the survival curves were tested by using the log-rank test. The COX proportional hazards regression model was used to determine the joint effects of several variables on survival.
The serum miR-221 levels were significantly higher in patients with CMM than in healthy controls (p<0.0001). Patients with high serum miR-221 levels had a significantly lower 5-year OS rate (22.1% vs. 54.6%; P=0.018) and RFS rate (12.5% vs. 45.2%; P=0.008) than those with low serum miR-221 level. In a multivariate Cox model, we found that miR-221 expression was an independent predictor of poor 5-year OS (hazards ratio [HR]=3.189, 95% confidence interval [CI]=1.782–6.777, P=0.007) and 5-year DFS (HR=2.119, CI=1.962–8.552, P=0.01) in CMM patients.
Our data indicate that serum miR-221expression level has prognostic value in patients with CMM.
PMCID: PMC4259523  PMID: 25430553
Melanoma; MicroRNAs; Prognosis
14.  Implantation of INTERTAN™ nail in four patients with intertrochanteric fractures leading to single or comminute fractures: pitfalls and recommendations: a case series 
Intraoperative technical complications are occasionally encountered while implanting INTERTAN™ nails for intertrochanteric fractures. Surgeons need to pay attention to the difficulties they may encounter during the implantation of an INTERTAN™ nail.
Case presentation
We report four cases with intraoperative difficulties during the implantation of INTERTAN™ nails among Han Chinese patients from mainland China. In Case 1, during the operation on a 75-year-old woman, an anatomical specificity of excessive femoral shaft curvation at the coronal and sagittal planes was observed; a relatively smooth implantation was achieved by adjusting the entry point. In Case 2, due to fat obstruction, an INTERTAN™ nail was implanted at an oblique angle in 64-year-old obese woman, which resulted in an iatrogenic fracture of the proximal femur. In Case 3, an iatrogenic fracture of the distal femur developed in an 83-year-old woman because of violent hammering and underestimating of bone fragility. In Case 4, an iatrogenic fracture occurred in a 40-year-old woman around the distal locking slot during the drilling process.
Preoperative evaluation should be considered as an important preparation for the implantation of an INTERTAN™ nail. Full-length anteroposterior and lateral radiographs of the injured femur are necessary to confirm the anatomical specificity. The vertical trajectory as well as sufficient reaming is important in reducing the possibility of iatrogenic fractures, particularly for obese patients. In older patients, violent hammering should be avoided and full reaming is recommended even if the canal seems to be wide enough. For cases where hard fracture reduction is predicted, the strategy of open reduction and fixation with a dynamic hip screw seems to be more rational and should be considered as an alternative method.
PMCID: PMC4275765  PMID: 25416923
Implantation difficulties; Intertrochanteric fracture; Intertain; China; Reaming; Obese; Older
15.  Comparison of clinical features, molecular alterations, and prognosis in morphological subgroups of lung invasive mucinous adenocarcinoma 
OncoTargets and therapy  2014;7:2127-2132.
We performed this analysis to distinguish the differences in two subtypes of lung invasive mucinous adenocarcinoma (IMA) with different kinds of morphological performances, in clinicopathological and molecular features, as well as prognosis.
On the basis of morphological performance, we divided lung IMAs into two subgroups, mucus-in-cell adenocarcinoma (MICA) and mucus-out-of-cell adenocarcinoma (MOCA). We investigated differences in clinicopathological characteristics, recurrence-free survival (RFS), overall survival (OS), and a spectrum of well-identified driver-gene mutations, including EGFR, KRAS, HER2, BRAF, ALK, ROS1, and RET, between the two subgroups.
Of 1,699 lung adenocarcinomas, 148 were identified as IMAs (97 MICAs and 51 MOCAs). The MICA patient group had significantly better RFS than did the MOCA group (39.4 months versus 33.0 months, respectively, log rank P=0.020) and significantly better OS (54.2 months versus 45.1 months, log rank P=0.034). There were no differences in RFS and OS between those with IMAs and those with mucus-negative adenocarcinomas. The frequency of the EGFR gene mutation was significantly higher in MOCAs than in MICAs (P<0.001). In contrast, the KRAS gene had a significantly higher mutational frequency in MICAs (P=0.01). MOCAs also had a significantly higher incidence of lymph-node metastasis (P<0.05).
To our knowledge, this study represents the first comparison of clinical features, molecular alterations, and prognosis in morphological subgroups of lung IMAs. Clinical and pathological features in conjunction with molecular data indicate that IMA should be divided into different subgroups.
PMCID: PMC4242897  PMID: 25429229
lung; invasive mucinous adenocarcinoma; prognosis; driver mutations
16.  RSK promotes G2/M transition through activating phosphorylation of Cdc25A and Cdc25B 
Oncogene  2013;33(18):2385-2394.
Activation of the MAPK cascade in mammalian cell lines positively regulates the G2/M transition. The molecular mechanism underlying this biological phenomenon remains poorly understood. RSK is a key downstream element of the MAPK cascade. Our previous studies established roles of RSK2 in Cdc25C activation during progesterone-induced meiotic maturation of Xenopus oocytes. In this study, we demonstrate that both recombinant RSK and endogenous RSK in Xenopus egg extracts phosphorylate all three isoforms of human Cdc25 at a conserved motif near the catalytic domain. In human HEK293 and PC-3mm2 cell lines, RSK preferentially phosphorylates Cdc25A and Cdc25B in mitotic cells. Phosphorylation of the RSK sites in these Cdc25 isoforms increases their M phase-inducing activities. Inhibition of RSK-mediated phosphorylation of Cdc25 inhibits G2/M transition. Moreover, RSK is likely to be more active in mitotic cells than in interphase cells, as evidenced by the phosphorylation status of T359/S363 in RSK. Together, these findings indicate that RSK promotes G2/M transition in mammalian cells through activating phosphorylation of Cdc25A and Cdc25B.
PMCID: PMC4026278  PMID: 23708659
RSK; Cdc25; activating phosphorylation; mitosis; G2/M transition; cell cycle
17.  Inhibition of Cell Adhesion by an Anti-cadherin 11 Antibody Prevents Bone Metastasis 
Molecular cancer research : MCR  2013;11(11):10.1158/1541-7786.MCR-13-0108.
Cadherin-11 is a member of a superfamily mainly expressed in osteoblasts but not in epithelial cells. However, prostate cancer (PCa) cells with bone metastasis propensity express high levels of cadherin-11 and reduced levels of E-cadherin. Downregulation of cadherin-11 inhibits interaction of PCa cells with osteoblasts in vitro and homing of PCa cells to bone in an animal model of metastasis. These findings raise the possibility that targeting the extracellular domain of cadhein-11 may prevent PCa bone metastasis. To explore this possibility, we generated a panel of monoclonal antibodies (mAbs) against cadherin-11 extracellular domain. From the 21 antibodies obtained, mAbs 2C7 and 1A5 inhibited cadherin-11 mediated cell-cell aggregation in L-cells transfected with cadherin-11 in vitro. Both antibodies were specific to cadherin-11 as they did not recognize E-cadherin or N-cadherin on C4-2B or PC3 cells, respectively. Further, mAb 2C7 inhibited cadherin-11-mediated aggregation between PC3-mm2 cells and MC3T3-E1 osteoblasts. To determine which cadherin domains are critical for PCa and osteoblast interactions, a series of deletion mutants were analyzed. We identified a previously unknown unique motif, aa 343-348, in the cadherin-11 EC3 domain that is recognized by mAb 2C7 and showed that this motif mediated cell-cell adhesion. Consistent with the inhibition of cell-cell aggregation in vitro, application of mAb 2C7 in a prophylactic setting as a single agent effectively prevented dissemination of highly metastatic PC3-mm2 cells to bone in a mouse model of metastasis. These results suggest that targeting the extracellular domain of cadherin-11 may be developed for the prevention of bone metastases.
PMCID: PMC3834228  PMID: 23913163
cadherin-11; prostate cancer; adhesion; bone metastasis; osteoblast
18.  A Three-Dimensional Microdisplacement Sensing System Based on MEMS Bulk-Silicon Technology 
Sensors (Basel, Switzerland)  2014;14(11):20533-20542.
For the dimensional measurement and characterization of microsized and nanosized components, a three-dimensional microdisplacement sensing system was developed using the piezoresistive effect in silicon. The sensor was fabricated using microelectromechanical system bulk-silicon technology, and it was validated using the finite element method. A precise data acquisition circuit with an accuracy of 20 μV was designed to obtain weak voltage signals. By calibration, the sensing system was shown to have a sensitivity of 17.29 mV/μm and 4.59 mV/μm in the axial and lateral directions, respectively; the nonlinearity in these directions was 0.8% and 1.0% full scale, respectively. A full range of 4.6 μm was achieved in the axial direction. Results of a resolution test indicated that the sensing system had a resolution of 5 nm in the axial direction and 10 nm in the lateral direction.
PMCID: PMC4279498  PMID: 25360581
dimensional metrology; piezoresistor; MEMS; microtactile sensor
19.  A Comparative Study of Fast-Track Verus Conventional Surgery in Patients Undergoing Laparoscopic Radical Cystectomy and Ileal Conduit Diversion: Chinese Experience 
Scientific Reports  2014;4:6820.
Fast-track surgery (FTS), which combines various techniques with evidence-based adjustments, is aimed to reduce postoperative morbidity, attenuate surgical stress response, thereby accelerating recovery and shorting length of stay. To further investigate the effectiveness of fast-track surgery, we compared the short-term outcomes of laparoscopic radical cystectomy and ileal conduit diversion for Chinese bladder cancer patients with FTS or with CS in our hospital. Patients with bladder cancer were included and divided into two consecutive groups: CS group and FTS group. Duration to first flatus and regular diet, postoperative hospital days, hospital expense, incidence of complications and postoperative surgical stress response were compared. There was no significant difference between the two groups in age, sex, BMI and postoperative TNM classification. Compared with the CS group, the FTS group had significantly shorter duration to first flatus, time to regular diet, postoperative hospital days and hospital expense, less complications, lower white blood count (WBC) and serum of C-reactive protein (CRP) on postoperative day 5 and 7. Our study indicates that FTS program is safe and efficacious for Chinese patients undergoing laparoscopic radical cystectomy and ileal conduit diversion. It can accelerate recovery, reduce stress action, shorten postoperative hospitals days and reduce hospital expenses.
PMCID: PMC4212226  PMID: 25352195
20.  The IQD Gene Family in Soybean: Structure, Phylogeny, Evolution and Expression 
PLoS ONE  2014;9(10):e110896.
Members of the plant-specific IQ67-domain (IQD) protein family are involved in plant development and the basal defense response. Although systematic characterization of this family has been carried out in Arabidopsis, tomato (Solanum lycopersicum), Brachypodium distachyon and rice (Oryza sativa), systematic analysis and expression profiling of this gene family in soybean (Glycine max) have not previously been reported. In this study, we identified and structurally characterized IQD genes in the soybean genome. A complete set of 67 soybean IQD genes (GmIQD1–67) was identified using Blast search tools, and the genes were clustered into four subfamilies (IQD I–IV) based on phylogeny. These soybean IQD genes are distributed unevenly across all 20 chromosomes, with 30 segmental duplication events, suggesting that segmental duplication has played a major role in the expansion of the soybean IQD gene family. Analysis of the Ka/Ks ratios showed that the duplicated genes of the GmIQD family primarily underwent purifying selection. Microsynteny was detected in most pairs: genes in clade 1–3 might be present in genome regions that were inverted, expanded or contracted after the divergence; most gene pairs in clade 4 showed high conservation with little rearrangement among these gene-residing regions. Of the soybean IQD genes examined, six were most highly expressed in young leaves, six in flowers, one in roots and two in nodules. Our qRT-PCR analysis of 24 soybean IQD III genes confirmed that these genes are regulated by MeJA stress. Our findings present a comprehensive overview of the soybean IQD gene family and provide insights into the evolution of this family. In addition, this work lays a solid foundation for further experiments aimed at determining the biological functions of soybean IQD genes in growth and development.
PMCID: PMC4208818  PMID: 25343341
21.  Genetic Association Study of TNFAIP3, IFIH1, IRF5 Polymorphisms with Polymyositis/Dermatomyositis in Chinese Han Population 
PLoS ONE  2014;9(10):e110044.
Single-nucleotide polymorphisms (SNPs) in the TNFAIP3, IFIH1, and IRF5 genes have been associated with several auto-inflammation diseases, while the susceptibility between these genes and idiopathic inflammatory myopathies (IIMs) were not reported. This study aimed to investigate whether TNFAIP3, IFIH1, and IRF5 gene polymorphisms confer susceptibility for the IIMs in Chinese Han population.
A large case–control study of Chinese subjects with polymyositis (PM) (n = 298) and dermatomyositis (DM) (n = 530) was accomplished. 968 healthy and ethnically matched controls were available for comparison. Six SNPs in the TNFAIP3 region (rs2230926 and rs5029939), the IFIH1 gene (rs1990760 and rs3747517) and the IRF5 region (rs4728142 and rs729302) were assessed and genotyped using the Sequenom MassArray iPLEX platform.
Our study indicated a strong allele association was observed in PM/DM and PM patients for rs2230926 (OR: 1.61, 95%CI: 1.20–2.16, Pc = 7.5×10−3; OR: 1.88, 95%CI: 1.30–2.74, Pc = 4.0×10−3, respectively) and rs5029939 (OR: 1.64, 95%CI: 1.21–2.21, Pc = 6.0×10−3; OR: 1.88, 95%CI: 1.28–2.76, Pc = 5.5×10−3,respectively). And rs2230926 and rs5029939 were significantly associated with interstitial lung disease (ILD) in PM/DM and PM patients (Pc = 0.04 and Pc = 0.016; Pc = 0.02 and Pc = 0.03, respectively). In addition, rs4728142 allele and genotype had significant association with PM/DM patients (Pc = 0.026 and Pc = 0.048, respectively). Further analysis with three logistic regression genetic models revealed statistically significant difference in the genotypic distribution in the PM/DM, PM or DM patients when the additive and dominant models were used.
This was the first study to reveal TNFAIP3 and IRF5 polymorphisms were associated with PM/DM patients or these patients with ILD, indicating that TNFAIP3 and IRF5 might be the susceptibility gene for PM/DM patients in Chinese Han population.
PMCID: PMC4206287  PMID: 25337792
22.  Molecular Epidemiology of Human Rhinovirus in Children with Acute Respiratory Diseases in Chongqing, China 
Scientific Reports  2014;4:6686.
Human rhinovirus-C (HRV-C) has been increasingly detected in patients with acute respiratory diseases (ARDs). Prolonged surveillance was performed on children with ARD to investigate the molecular epidemiology and clinical characteristics of HRV in Chongqing, China. Nasopharyngeal aspirates (NPA) were collected from hospitalized children with ARD during 2009–2012. HRV-C was genotyped by sequencing the VP4/VP2 coding region. Among the 1,567 NPAs obtained, 223 (14.2%) were HRV positive, and 75.3% of these 223 NPAs were co-infected with other viruses. HRV-A (54.7%) and HRV-C (39.9%) accounted for the majority of HRV infections. Logistic regression models demonstrated significant associations between HRV-A, HRV-C, and asthma attacks, as well as between HRV-C and wheezing. A phylogenetic tree showed that HRV-C2 was the predominant type of HRV-C, followed by HRV-C43, HRV-C1, and HRV-C17. Three novel genotypes were proposed on the basis of a low identity with the known HRVs. Our results showed that HRV-A and HRV-C were the predominant types of HRV infection, and HRV-C showed a high genetic variation in Chongqing, China. HRV infection was associated with asthma attacks and wheezing; furthermore, HRV infections played a minor role in causing severe pneumonia. This knowledge provides information for the prevention and control of HRV associated with ARDs.
PMCID: PMC4202208  PMID: 25328042
23.  The Association between Bile Salt Export Pump Single-Nucleotide Polymorphisms and Primary Biliary Cirrhosis Susceptibility and Ursodeoxycholic Acid Response 
Disease Markers  2014;2014:350690.
Background. Primary biliary cirrhosis (PBC) is a chronic and progressive cholestasis liver disease. Bile salt export pump (BSEP) is the predominant bile salt efflux system of hepatocytes. BSEP gene has been attached great importance in the susceptibility of PBC and the response rate of ursodeoxycholic acid (UDCA) treatment of PBC patients. Methods. In this study, TaqMan assay was used to genotype four variants of BSEP, and the Barcelona criteria were used for evaluating the response rate of UDCA treatment. Results. Variant A allele of BSEP rs473351 (dominant model, OR = 2.063; 95% CI, 1.254–3.393; P = 0.004) was highly associated with PBC susceptibility. On the contrary, variant A allele of BSEP rs2287618 (dominant model, OR = 0.617; 95% CI, 0.411–0.928; P = 0.020) provided a protective role and Barcelona evaluation criterion indicated that the frequency of variant allele at BSEP rs2287618 was significantly decreased in UDCA-responsive PBC patients (P = 0.021). Conclusion. These results suggested that BSEP rs473351 was closely associated with the susceptibility of PBC and if people with BSEP rs2287618 were diagnosed as PBC, the UDCA treatment was not satisfactory. Larger studies with mixed ethnicity subjects and stratified by clinical and subclinical characteristics are needed to validate our findings.
PMCID: PMC4216684  PMID: 25392597
24.  Genotypes and Transmitted Drug Resistance among Treatment-Naive HIV-1-Infected Patients in a Northwestern Province, China: Trends from 2003 to 2013 
PLoS ONE  2014;9(10):e109821.
Transmitted drug resistance (TDR) reduces the efficacy of initial antiretroviral treatment and has become a public health concern. Little information is available regarding the genetic diversity of HIV-1 and the prevalence of TDR among treatment-naïve patients in a northwestern province of China since the implementation of national free antiretroviral therapy (ART).
Blood samples from 372 HIV-1 treatment-naive patients were collected between 2003 and 2013 in Shaanxi province. Viral RNA was extracted for nested PCR, and phylogenetic reconstruction and recombination analyses were performed to characterize patterns of the HIV-1 subtypes. Genotypic drug resistance testing was performed using an in-house assay to determine trends in the prevalence of HIV-1 transmitted drug resistance.
Multiple genotypes were identified among the patients in Shaanxi, including B (25.0%), C (0.3%), G (0.3%), and CRF01_AE (39.2%), CRF07_BC (32.7%), CRF08_BC (0.8%), CRF55_01B (1.1%), and URFs (0.6%). The subtypes were associated with the transmission routes (χ2 = 77.113, p<0.01). In this study, a low baseline CD4+ T cell count and a high viral load were found among CRF01_AE-infected patients compared with patients who were infected with non-CRF01_AE (p<0.01) through sexual transmission; however, the CRF01_AE subtype was not associated with a low baseline CD4+ T cell count or a high viral load in Chinese patients infected through blood transmission (p = 0.249). The overall TDR rate in this population was 4.4% between 2003 and 2013. A univariate logistic regression model revealed that a low CD4 T cell count (≤100 cells/µL) was associated with the development of drug-resistant strains.
Our work revealed diverse HIV-1 subtype distributions in Shaanxi province. We identified a low and stable TDR time trend among ART-naive patients. These findings enhance our understanding of HIV-1 genetic diversity and provide some guidelines for the improvement and implementation of a comprehensive public health strategy of HIV-1 TDR prevention.
PMCID: PMC4198111  PMID: 25333965
25.  Overexpression of Wip1 Is Associated with Biologic Behavior in Human Clear Cell Renal Cell Carcinoma 
PLoS ONE  2014;9(10):e110218.
Wild-type p53-induced phosphatase (Wip1 or PPM1D) has been reported to be aberrantly expressed in various cancers and correlated with the malignant behavior of cancer cells. However, the function of Wip1 in RCC remains unclear. The present study investigated its abnormal expression and dysfunctions in clear cell renal cell carcinoma (ccRCC) in vitro. With the combination of immunohistochemistry, western blotting, immunofluorescence, qRT-PCR, and cell proliferation, migration and invasion assays, we found that levels of Wip1 mRNA and protein were dramatically increased in human ccRCC tissues (P<0.001 for both), and upregulation of Wip1 was significantly associated with depth of invasion (P<0.001), Distant metastasis (P = 0.001), lymph node status (P<0.001) and Fuhrman grade (P<0.001). Wip1 knockdown inhibited the proliferation, migration and invasion of 786-O and RLC-310 cells, whereas Wip1 overexpression promoted the growth and aggressive phenotype of 786-O and RLC-310 cells in vitro. The uni- and multivariate analyses indicated that expression of Wip1 was an independent predictor for survival of ccRCC patients (P = 0.003, P = 0.027 respectively). Wip1- negative patients had a higher tumor-free/overall survival rate than patients with high Wip1 expression (P = 0.001, P = 0.002 respectively). Overexpression of Wip1 is useful in the prediction of survival in ccRCC patients.
PMCID: PMC4198297  PMID: 25334029

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