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1.  Comparison of Stretta procedure and toupet fundoplication for gastroesophageal reflux disease-related extra-esophageal symptoms 
World Journal of Gastroenterology  2015;21(45):12882-12887.
AIM: To compare the outcomes between the Stretta procedure and laparoscopic toupet fundoplication (LTF) in patients with gastroesophageal reflux disease (GERD)-related extra-esophageal symptoms.
METHODS: From January 2011 to February 2012, a total of 98 patients diagnosed with GERD-related extra-esophageal symptoms who met the inclusion criteria were enrolled in this study. All patients who either underwent the Stretta procedure or LTF treatment have now completed the 3-year follow-up. Primary outcome measures, including frequency and severity of extra-esophageal symptoms, proton pump inhibitor (PPI) use, satisfaction, and postoperative complications, were assessed. The results of the Stretta procedure and LTF therapy were analyzed and compared.
RESULTS: There were 47 patients in the Stretta group and 51 patients in the LTF group. Ninety patients were available at the 3-year follow-up. The total of the frequency and severity scores for every symptom improved in both groups (P < 0.05). Improvement in symptom scores of cough, sputum, and wheezing did not achieve statistical significance between the two groups (P > 0.05). However, the score for globus hysterics was different between the Stretta group and the LTF group (4.9 ± 2.24 vs 3.2 ± 2.63, P < 0.05). After the Stretta procedure and LTF treatment, 29 and 33 patients in each group achieved PPI therapy independence (61.7% vs 64.7%, P = 0.835). The patients in the LTF group were more satisfied with their quality of life than those in the Stretta procedure group (P < 0.05). Most complications resolved without intervention within two weeks; however, two patients in the LTF group still suffered from severe dysphagia 2 wk after the operation, and it improved after bougie dilation treatment in both patients.
CONCLUSION: The Stretta procedure and LTF were both safe and effective for the control of GERD-related extra-esophageal symptoms and the reduction of PPI use.
PMCID: PMC4671044  PMID: 26668513
Gastroesophageal reflux disease; Extra-esophageal symptoms; Laparoscopic Toupet fundoplication; Stretta procedure; Proton pump inhibitor use
2.  Targeting JAK1/STAT3 signaling suppresses tumor progression and metastasis in a peritoneal model of human ovarian cancer 
Molecular cancer therapeutics  2014;13(12):3037-3048.
JAK/STAT3 is one of the major signaling pathways that is aberrantly activated in ovarian cancer and associated with tumor progression and poor prognosis in ovarian cancer patients. In this study, we evaluated the therapeutic potential of targeting JAK/STAT3 signaling in ovarian cancer using a peritoneal dissemination mouse model. We developed this mouse model by injecting a metastatic human ovarian cancer cell line, SKOV3-M-Luc, into the peritoneal cavity of immunodeficient mice. This model displayed a phenotype similar to late stage ovarian cancer, including extensive peritoneal metastasis and ascites production. The constitutive activation of STAT3 in human ovarian cancer cells appeared to be mediated by an autocrine-cytokine loop involving the IL-6 family of cytokines and JAK1 kinase. shRNA-mediated knockdown of JAK1 or STAT3 in ovarian cancer cells led to reduced tumor growth, decreased peritoneal dissemination and diminished ascites production, suggesting a critical role of STAT3 in ovarian cancer progression. Similar results were obtained when a small-molecule inhibitor (JAKi) of the JAK1 kinase was used to treat ovarian cancer in this model. In addition, we found that the expression level of IL-6 was correlated with activation of STAT3 in ovarian cancer cells both in vitro and in vivo, suggesting a potential application of IL-6 as a biomarker. Altogether, our results demonstrate that targeting JAK1/STAT3, using shRNA knockdown or a small molecule inhibitor, effectively suppressed ovarian tumor progression and, therefore, could be a potential novel therapeutic approach for treating advanced ovarian cancer.
PMCID: PMC4321961  PMID: 25319391
JAK1/STAT3; shRNA; peritoneal metastasis; ascites; late stage ovarian cancer
3.  Anti-Glomerular Basement Membrane Disease Combined with IgA Nephropathy Complicated with Reversible Posterior Leukoencephalopathy Syndrome: An Unusual Case 
Patient: Male, 24
Final Diagnosis: Crescentic glomerulonephritis (type I) with IgA nephropathy
Symptoms: Headache • gross hematuria • nocturia • seizures
Medication: Cyclophosphamide
Clinical Procedure: Dignosis to treatment
Specialty: Nephrology
Rare co-existance of disease or pathology
Anti-glomerular basement membrane disease (anti-GBM disease) is an autoimmune glomerulonephritis disease that is characterized by IgG linear deposition along the non-collagen domain of α3 chains of type IV collagen on the GBM. Although anti-GBM disease accompanied with IgA linear deposition along GBMs was discussed previously in some papers, anti-GBM disease combined with IgA granular deposition in the mesangial area, especially complicated with reversible posterior leukoencephalopathy syndrome (RPLS), was rarely reported. RPLS is usually caused by hypertensive encephalopathy, renal decompensation, fluid retention, and adverse effects of immunosuppressive drugs.
Case Report:
A male patient with the chief complaints of headache, gross hematuria, and nocturia was referred to our hospital. Based on renal biopsy, the diagnosis was finally confirmed as anti-GBM disease combined with IgA nephropathy and, the patient received comprehensive treatment, including cyclophosphamide (CTX), which led to symptom improvement. Two days after the third impulse CTX was given, he suddenly experienced headache and dizziness, which eventually developed into a tonic-clonic seizure. RPLS was identified by cranial magnetic resonance imaging (MRI) with reversible neuroimaging. After diazepam and antihypertension management, seizures were controlled. RPLS, a neurological complication, was found in anti-GBM disease with IgA nephropathy during our immunosuppressants therapy for the first time.
It is worth paying more attention to patients with rapidly progressive glomerulonephritis (RPGN), as they might be complicated with RPLS during intravenous administration of CTX and methylprednisolone. We suggest the neuroimaging be examined as soon as the seizure happens.
PMCID: PMC4671450  PMID: 26621456
Anti-Glomerular Basement Membrane Disease; Glomerulonephritis; IGA; Posterior Leukoencephalopathy Syndrome
4.  Comparison the effects of pressurized salt ice packs with water ice packs on patients following total knee arthroplasty 
The aim of this study was to estimate the effects of pressurized salt ice packs (PIP) with water ice packs (WIP) which are used to relieve pain and decrease swelling on patients following total knee arthroplasty (TKA). Sixty-nine patients undergoing primary unilateral TKA were randomly divided into two groups (PIP group and WIP group). We used a visual analog scale (VAS) to score knee pain and the score was recorded. The knee bilateral girth, the slipping times of the ice pack, and the times of wound dressing or bed moist were recorded during cryotherapy. The scores of pain between the two groups were significant difference in 12 h, 24 h, 48 h and 72 h after TKA (P < 0.05). No significant difference was found for the girth measurements of the operative knee on the two levels in 12 h, 24 h and 72 h, respectively. However, there was statistically difference for girth measurements between the two groups in 48 h after TKA (P < 0.05). PIP is a cheap, safe and simple method, which is more effective than WIP on reducing pain and swelling degree of patients. Thus, PIP is recommended in clinical nursing work.
PMCID: PMC4694317  PMID: 26770417
Cryotherapy; total knee arthroplasty; pain; swelling
5.  SLC39A6: a potential target for diagnosis and therapy of esophageal carcinoma 
Esophageal squamous cell carcinoma (ESCC) is a highly lethal cancer, and its underlying molecular mechanisms are poorly understood. Recent large-scale genome-wide association studies in Chinese Han populations have identified an ESCC susceptibility locus within the SLC39A6 gene. Here, we sought to explore the expression and biological function of SLC39A6 in ESCC.
Multiethnic validation of SLC39A6 protein expression was performed in different cohorts of patients from Chinese Han and Kazakh populations in the Xinjiang region by immunohistochemistry. The associations among SLC39A6 expression, clinicopathological parameters, and prognosis outcomes of ESCC were analyzed. And the effects of SLC39A6 silencing by siRNA on cell proliferation, apoptosis, and invasiveness, as well as the proteins involved in epithelial-to-mesenchymal transition (EMT) of esophageal cancer cells, were studied.
SLC39A6 protein expression increased progressively from normal esophageal epithelium (NEE) to low-grade intraepithelial neoplasia to ESCC, and finally reached the highest in high-grade intraepithelial neoplasia from Han ethnic. Similarly, SLC39A6 protein was significantly overexpressed in Kazakh ethnic ESCC compared with that in NEE. Increased expression of SLC39A6 was found to be closely correlated with histological grade and early Tumor-Node-Metastasis stage I/II. High tumorous SLC39A6 expression was significantly correlated with shorter overall survival (OS). Cox regression analysis confirmed that SLC39A6 expression was an independent prognostic factor for poor OS in ESCC. Experimentally, the suppression of SLC39A6 expression promoted ESCC cell apoptosis but abrogated proliferation and invasion, and induced an EMT phenotype that included enhanced expression of E-cadherin, loss of vimentin, and morphological changes in ESCC cells in vitro.
Combined, our findings highlight a tumor-promoting role for SLC39A6 in ESCC, suggesting that SLC39A6 could serve as an early detector of high-risk subjects and prognostic biomarker. The targeting of SLC39A6 might be a potential therapeutic strategy for blocking ESCC.
Electronic supplementary material
The online version of this article (doi:10.1186/s12967-015-0681-z) contains supplementary material, which is available to authorized users.
PMCID: PMC4595240  PMID: 26444413
SLC39A6; ESCC; Precursor lesions; Prognosis
6.  Recql5 protects against lipopolysaccharide/D-galactosamine-induced liver injury in mice 
World Journal of Gastroenterology : WJG  2015;21(36):10375-10384.
AIM: To investigate the effects of Recql5 deficiency on liver injury induced by lipopolysaccharide/D-galactosamine (LPS/D-Gal).
METHODS: Liver injury was induced in wild type (WT) or Recql5-deficient mice using LPS/D-Gal, and assessed by histological, serum transaminases, and mortality analyses. Hepatocellular apoptosis was quantified by transferase dUTP nick end labeling assay and Western blot analysis of cleaved caspase-3. Liver inflammatory chemokine and cytochrome P450 expression was analyzed by quantitative reverse transcription-PCR. Neutrophil infiltration was evaluated by myeloperoxidase activity. Expression and phosphorylation of ERK, JNK, p65, and H2A.X was determined by Western blot. Oxidative stress was evaluated by measuring malondialdehyde production and nitric oxide synthase, superoxide dismutase, glutathione peroxidase, catalase, and glutathione reductase activity.
RESULTS: Following LPS/D-Gal exposure, Recql5-deficient mice exhibited enhanced liver injury, as evidenced by more severe hepatic hemorrhage, higher serum aspartate transaminase and alanine transaminase levels, and lower survival rate. As compared to WT mice, Recql5-deficient mice showed an increased number of apoptotic hepatocytes and higher cleaved caspase-3 levels. Recql5-deficient mice exhibited increased DNA damage, as evidenced by increased γ-H2A.X levels. Inflammatory cytokine levels, neutrophil infiltration, and ERK phosphorylation were also significantly increased in the knockout mice. Additionally, Recql5-deficicent mice exhibited increased malondialdehyde production and elevated inducible nitric oxide synthase, superoxide dismutase, glutathione peroxidase, catalase, and glutathione reductase activity, indicative of enhanced oxidative stress. Moreover, CYP450 expression was significantly downregulated in Recql5-deficient mice after LPS/D-Gal treatment.
CONCLUSION: Recql5 protects the liver against LPS/D-Gal-induced injury through suppression of hepatocyte apoptosis and oxidative stress and modulation of CYP450 expression.
PMCID: PMC4579884  PMID: 26420964
Recql5; Liver injury; Apoptosis; Oxidative stress; CYP450
7.  Inhibition of ERRα suppresses epithelial mesenchymal transition of triple negative breast cancer cells by directly targeting fibronectin 
Oncotarget  2015;6(28):25588-25601.
Triple-negative breast cancer (TNBC) patients have poor prognosis due to the aggressive metastatic behaviors. Our study reveals that expression of estrogen related receptor α (ERRα) is significantly (p < 0.01) positively associated with high grade tumors and lymph node metastasis, while negatively correlated with overall survival (OS), in 138 TNBC patients. Targeted inhibition of ERRα by its inverse agonist XCT-790 or si-RNA obviously inhibits in vitro motility of TNBC cells. While over expression of ERRα triggers the invasion and migration of TNBC cells. Further, si-ERRα and XCT-790 inhibit the epithelial mesenchymal transition (EMT) of TNBC cells with increasing the expression of E-cadherin and decreasing fibronectin (FN) and vimentin. While XCT-790 has no effect on the expression of EMT related transcription factors such as Snail or Slug. Further, inhibitors of MAPK, PI3K/Akt, NF-κB signal molecules, which are activated by XCT-790, can not attenuate the suppression effects of XCT-790 on EMT. Alternatively, luciferase reporter gene assays and ChIP analysis indicate that ERRα can directly bind with FN promoter at ERR response element-3 (ERRE-1), ERRE-3, and ERRE-4, while XCT-790 reduces this bond. In vivo data show that ERRα expression is significantly (p < 0.05) correlated with FN in clinical TNBC patients. In MDA-MB-231 tumor xenograft models, XCT-790 decreases the expression of FN, inhibits the growth and lung metastasis, and suppresses the EMT. Our results demonstrate that ERRα functions as a metastasis stimulator and its targeted inhibition may be a new therapeutic strategy for TNBC treatment.
PMCID: PMC4694852  PMID: 26160845
ERRα; TNBC; EMT; fibronectin
8.  A meta-analysis of the relationship between vitamin D deficiency and obesity 
Previous epidemiologic studies suggested that vitamin D deficiency may be a risk factor of obesity. However, the result is still controversial. This meta-analysis aims to provide a comprehensive summary on the association between vitamin D deficiency and obesity. We systematically searched Pubmed database, Chinese Wanfang Data Knowledge Service Platform, and Chinese National Knowledge Infrastructure (CNKI), for the literatures on the relationship between vitamin D deficiency and obesity published from 2010 to 2015. The effect sizes of overall odds ratio (OR) and 95% confidence interval (CI) were estimated using Stata 11.0. Heterogeneity was evaluated using random-effects model and forest plots. Fifteen studies were eligible for inclusion in the meta-analysis, which included 3867 subjects with obesity and 9342 health subjects. Meta-analysis results showed that the prevalence of vitamin D deficiency was difference between obesity group and control group, and the pooled OR (95% CI) was 3.43 (2.33-5.06). The prevalence of vitamin D deficiency was associated with obesity in Asians and European-American, OR (95% CI) were 3.70 (1.98-6.90) and 3.09 (1.89-5.04), respectively. No publication bias was found in our study. vitamin D deficiency may be associated with obesity, irrespective of areas.
PMCID: PMC4658869  PMID: 26628980
Vitamin D; obesity; meta-analysis
9.  The lncRNA H19 promotes epithelial to mesenchymal transition by functioning as miRNA sponges in colorectal cancer 
Oncotarget  2015;6(26):22513-22525.
Recently, the long non-coding RNA (lncRNA) H19 has been identified as an oncogenic gene in multiple cancer types and elevated expression of H19 was tightly linked to tumorigenesis and cancer progression. However, the molecular basis for this observation has not been characterized in colorectal cancer (CRC) especially during epithelial to mesenchymal transition (EMT) progression. In our studies, H19 was characterized as a novel regulator of EMT in CRC. We found that H19 was highly expressed in mesenchymal-like cancer cells and primary CRC tissues. Stable expression of H19 significantly promotes EMT progression and accelerates in vivo and in vitro tumor growth. Furthermore, by using bioinformatics study and RNA immunoprecipitation combined with luciferase reporter assays, we demonstrated that H19 functioned as a competing endogenous RNA (ceRNA) for miR-138 and miR-200a, antagonized their functions and led to the de-repression of their endogenous targets Vimentin, ZEB1, and ZEB2, all of which were core marker genes for mesenchymal cells. Taken together, these observations imply that the lncRNA H19 modulated the expression of multiple genes involved in EMT by acting as a competing endogenous RNA, which may build up the missing link between the regulatory miRNA network and EMT progression.
PMCID: PMC4673179  PMID: 26068968
miRNA sponges; lncRNA; ceRNA
10.  Effects of electroacupuncture therapy for Bell’s palsy from acute stage: study protocol for a randomized controlled trial 
Trials  2015;16:378.
Although many patients with facial paralysis have obtained benefits or completely recovered after acupuncture or electroacupuncture therapy, it is still difficult to list intuitive evidence besides evaluation using neurological function scales and a few electrophysiologic data. Hence, the aim of this study is to use more intuitive and reliable detection techniques such as facial nerve magnetic resonance imaging (MRI), nerve electromyography, and F waves to observe changes in the anatomic morphology of facial nerves and nerve conduction before and after applying acupuncture or electroacupuncture, and to verify their effectiveness by combining neurological function scales.
A total of 132 patients with Bell’s palsy (grades III and IV in the House-Brackmann [HB] Facial Nerve Grading System) will be randomly divided into electroacupuncture, manual acupuncture, non-acupuncture, and medicine control groups. All the patients will be given electroacupuncture treatment after the acute period, except for patients in the medicine control group. The acupuncture or electroacupuncture treatments will be performed every 2 days until the patients recover or withdraw from the study. The primary outcome is analysis based on facial nerve functional scales (HB scale and Sunnybrook facial grading system), and the secondary outcome is analysis based on MRI, nerve electromyography and F-wave detection. All the patients will undergo MRI within 3 days after Bell’s palsy onset for observation of the signal intensity and facial nerve swelling of the unaffected and affected sides. They will also undergo facial nerve electromyography and F-wave detection within 1 week after onset of Bell’s palsy. Nerve function will be evaluated using the HB scale and Sunnybrook facial grading system at each hospital visit for treatment until the end of the study. The MRI, nerve electromyography, and F-wave detection will be performed again at 1 month after the onset of Bell’s palsy.
Trial registration
Chinese Clinical Trials Register identifier: ChiCTR-IPR-14005730. Registered on 23 December 2014.
PMCID: PMC4548841  PMID: 26303741
Acupuncture; Bell’s palsy; Electromyography; F Wave test; Magnetic resonance imaging
11.  Exogenous hTERT gene transfected endothelial progenitor cells from bone marrow promoted angiogenesis in ischemic myocardium of rats 
Objective: To explore the biological behavior and the revascularizative ability of endothelial progenitor cells (EPCs) transfected with human telomerase reverse transcriptase (hTERT) gene. Methods: EPCs were isolated from mononuclear cells in bone marrow by using the method of density gradient centrifugation, then cultured with differential velocity adherent method, EPCs were transfected by recombinant plasmid carrying GFP report gene EGFP-hTERT. The EPCs secretion and proliferation ability were detected before and after transfection. The expression of EPCs mRNA were detected by RT-PCR before and after transfection. The new capillaries of infarct area were observed. Results: After transgenesis, the proliferation of EPCs were increased, and the secretion of NO, LDH, iNOS by EPCs were significantly increased compared to the non-transgenesis group. After transplanted the transfected EPCs into the ischemic myocardial of rats, revascularization were increased obviously. Conclusion: EPCs maintained the original biological characteristics after transfecting exogenous hTER gene, the proliferation and survival rate were up-regulated significantly, and the revascularization ability of EPCs were significantly strengthen.
PMCID: PMC4613118  PMID: 26550433
Endothelial progenitor cells; human telomerase reverse transcriptase (hTERT); transfection; myocardial infarction
12.  Tumor necrosis factor-α gene 308G/A polymorphism is not associated with esophageal squamous cell carcinoma risk in Kazakh patients 
Background: Esophageal squamous cell carcinoma (ESCC) is a malignant tumor with a strong tendency toward familial aggregation and a higher incidence as well as mortality in Kazakh population. Tumor necrosis factor-alpha (TNF-α) is an important inflammatory cytokine that plays a role in controlling the progression of lung cancer, hepatocellular cancer, breast cancer and gastric cancer. But the association between TNF-α-308G/A and ESCC still remains unclarified. Materials and Methods: Here, we investigated the potential associations between the TNF-α-308G/A and susceptibility to ESCC in 212 cases and 200 controls from a pure ethnic population of Kazakh. DNA extraction and Real-time PCR were performed to detect the TNF-α-308G/A expression levels and odd ratios (ORs) with the corresponding 95% confidence interval (CI) were to evaluate their association with TNF-α-308G/A polymorphism. Results: We found that the frequencies of TNF-α-308G/A in the cases were similar to that of the controls with no differences being statistically significant (χ2=1.23, P>0.05). Using the G allele as the reference genotype, individuals who carried A allele had a significantly increased risk of developing ESCC (OR=2.64, 95% CI=1.31~5.35). Especially, the G/A+A/A genotype are associated with increased risk of metastatic as compared with GG genotype individuals (OR=2.08, 95% CI=1.14-3.80, P=0.02). Conclusions: Our findings suggest that though the TNF-α-308G/A polymorphism may not be correlated with the susceptibility to Kazakh’s ESCC in Xinjiang, patients who carry A allele tend to poorly differentiated and lymph node metastasis.
PMCID: PMC4583911  PMID: 26464679
Tumor necrosis factor; gene polymorphism; esophageal cancer; Kazakh
13.  Age and Gender Differences in Urinary Levels of Eleven Phthalate Metabolites in General Taiwanese Population after a DEHP Episode 
PLoS ONE  2015;10(7):e0133782.
In 2011, the Taiwan FDA disclosed illegal di(2-ethylhexyl phthalate) (DEHP) and dibutyl phthalate (DBP) use in beverage and nutrition supplements. We aim to determine phthalate exposure and other relevant factors in a sample of the general Taiwanese population in order to evaluate actual phthalate exposure levels after this disclosure of DEHP use.
We selected subjects aged 7 years old and older in 2013 from the general Taiwanese population. First morning urine samples from each participant were collected to analyze 11 phthalate metabolites representing 7 parent phthalates using on-line liquid chromatography/ tandem mass spectrometry. An interview questionnaire was applied to obtain participant demographic characteristics, lifestyle, and other relevant factors.
The median levels of metabolites of DEHP, including mono-ethylhexyl phthalate (MEHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), DBP (DnBP and DiBP), including mono-n-butyl phthalate (MnBP) and mono-iso-butyl phthalate (MiBP), and mono-ethyl phthalate (MEP) in urine samples of 290 adults/ 97 minors (<18 years) were 7.9/ 6.1, 12.6/ 17.8, 22.0/ 25.8, 25.4/ 30.8, 18.1/ 23.6, 9.4/ 13.6 and 14.5/ 12.4 μg/g creatinine, respectively. Women (≧18 years) were exposed to significantly higher levels of MEHHP (P=0.011), MECPP (P=0.01), MnBP (P=0.001) and MEP (P<0.001) than men (≧18 years), whereas no gender difference was observed in minors. We found significant higher level of MEP (creatinine-unadjusted) in subject aged between 18 to 40 years old (P<0.001), especially for women. Exposure levels of MEOHP (P<0.001), MECPP (P=0.002) and MnBP (P=0.044) in minors were significantly higher than those of adults. High frequency usage of food preservation film and bags, and personal care products are potential sources of phthalates exposure in general Taiwanese.
Our findings indicated that DEHP and DBP exposure in a sample of the general Taiwanese population varied by age and gender, possibly affected by different lifestyles, and continuing bio-monitoring surveillance is warranted.
PMCID: PMC4514596  PMID: 26207744
14.  Comparison of ArcGIS and SAS Geostatistical Analyst to Estimate Population-Weighted Monthly Temperature for US Counties 
Journal of resources and ecology  2012;3(3):220-229.
Temperature changes are known to have significant impacts on human health. Accurate estimates of population-weighted average monthly air temperature for US counties are needed to evaluate temperature’s association with health behaviours and disease, which are sampled or reported at the county level and measured on a monthly—or 30-day—basis. Most reported temperature estimates were calculated using ArcGIS, relatively few used SAS. We compared the performance of geostatistical models to estimate population-weighted average temperature in each month for counties in 48 states using ArcGIS v9.3 and SAS v 9.2 on a CITGO platform. Monthly average temperature for Jan-Dec 2007 and elevation from 5435 weather stations were used to estimate the temperature at county population centroids. County estimates were produced with elevation as a covariate. Performance of models was assessed by comparing adjusted R2, mean squared error, root mean squared error, and processing time. Prediction accuracy for split validation was above 90% for 11 months in ArcGIS and all 12 months in SAS. Cokriging in SAS achieved higher prediction accuracy and lower estimation bias as compared to cokriging in ArcGIS. County-level estimates produced by both packages were positively correlated (adjusted R2 range=0.95 to 0.99); accuracy and precision improved with elevation as a covariate. Both methods from ArcGIS and SAS are reliable for U.S. county-level temperature estimates; However, ArcGIS’s merits in spatial data pre-processing and processing time may be important considerations for software selection, especially for multi-year or multi-state projects.
PMCID: PMC4497953  PMID: 26167169
temperature estimation; county data; ArcGIS; SAS; cokriging
15.  Magnetic patterning: local manipulation of the intergranular exchange coupling via grain boundary engineering 
Scientific Reports  2015;5:11904.
Magnetic patterning, with designed spatial profile of the desired magnetic properties, has been a rising challenge for developing magnetic devices at nanoscale. Most existing methods rely on locally modifying magnetic anisotropy energy or saturation magnetization, and thus post stringent constraints on the adaptability in diverse applications. We propose an alternative route for magnetic patterning: by manipulating the local intergranular exchange coupling to tune lateral magnetic properties. As demonstration, the grain boundary structure of Co/Pt multilayers is engineered by thermal treatment, where the stress state of the multilayers and thus the intergranular exchange coupling can be modified. With Ag passivation layers on top of the Co/Pt multilayers, we can hinder the stress relaxation and grain boundary modification. Combining the pre-patterned Ag passivation layer with thermal treatment, we can design spatial variations of the magnetic properties by tuning the intergranular exchange coupling, which diversifies the magnetic patterning process and extends its feasibility for varieties of new devices.
PMCID: PMC4496669  PMID: 26156786
16.  Identification of miRNAs that specifically target tumor suppressive KLF6-FL rather than oncogenic KLF6-SV1 isoform 
RNA Biology  2014;11(7):845-854.
The Krüppel like factor 6 (KLF6) gene encodes multiple protein isoforms derived from alternative mRNA splicing, most of which are intimately involved in hepatocarcinogenesis and tumor progression. Recent bioinformatics analysis shows that alternative mRNA splicing of the KLF6 gene produces around 16 alternatively spliced variants with divergent or even opposing functions. Intriguingly, the full-length KLF6 (KLF6-FL) is a tumor suppressor gene frequently inactivated in liver cancer, whereas KLF6 splice variant 1 (KLF6-SV1) is an oncogenic isoform with antagonistic function against KLF6-FL. Compelling evidence indicates that miRNA, the small endogenous non-coding RNA (ncRNA), acts as a vital player in modulating a variety of cellular biological processes through targeting different mRNA regions of protein-coding genes. To identify the potential miRNAs specifically targeting KLF6-FL, we utilized bioinformatics analysis in combination with the luciferase reporter assays and screened out two miRNAs, namely miR-210 and miR-1301, specifically targeted the tumor suppressive KLF6-FL rather than the oncogenic KLF6-SV1. Our in vitro experiments demonstrated that stable expression of KLF6-FL inhibited cell proliferation, migration and angiogenesis while overexpression of miR-1301 promoted cell migration and angiogenesis. Further experiments demonstrated that miR-1301 was highly expressed in liver cancer cell lines as well as clinical specimens and we also identified the potential methylation and histone acetylation for miR-1301 gene. To sum up, our findings unveiled a novel molecular mechanism that specific miRNAs promoted tumorigenesis by targeting the tumor suppressive isoform KLF6-FL rather than its oncogenic isoform KLF6-SV1.
PMCID: PMC4179959  PMID: 24921656
Alternative splicing; KLF6; miRNA
17.  Use of magnetic resonance elastography for assessing liver functional reserve: A clinical study 
AIM: To investigate the value of magnetic resonance elastography (MRE) with regard to assessing liver functional reserve.
METHODS: Data from inpatients diagnosed with a liver tumor at an interventional radiology department from July 2013 to June 2014 were analyzed. A 3.0 Tesla magnetic resonance unit was used to scan 32 patients with confirmed diagnoses of hepatocellular carcinoma (HCC); an MRE sequence was added to the protocol, and the data were reconstructed and analyzed by two attending radiologists. Regions of interest were identified in different slices of the non-tumor liver parenchyma to measure average stiffness. In addition, the indocyanine green (ICG) test was performed no more than 1 wk before or after the magnetic resonance examination for all 32 patients; the ICG retention rate at 15 min (ICGR-15) and the ICG plasma clearance rate (ICG-K) were recorded. Correlational analyses were performed between the liver stiffness values and the ICGR-15 as well as between the liver stiffness values and the ICG-K.
RESULTS: Magnetic resonance imaging, including an MRE sequence and the ICG test, was performed successfully in all 32 enrolled patients. None of the patients developed complications. The mean ± SD of the elasticity values measured by the two attending radiologists were 4.7 ± 2.2 kPa and 4.7 ± 2.1 kPa, respectively. The average liver stiffness value of the non-tumor parenchyma measured using MRE in HCC patients was 4.7 ± 2.2 kPa. The average ICGR-15 was 0.089 ± 0.077, and the average ICG-K was 0.19 ± 0.07. We found that the liver stiffness value of the non-tumor parenchyma was significantly and positively related to the ICGR-15 (r = 0.746, P < 0.01) as well as significantly and negatively related to the ICG-K (r = -0.599, P < 0.01). The ICGR-15 was significantly and negatively related to the ICG-K (r = -0.852, P < 0.01).
CONCLUSION: MRE is accurate and non-invasive; furthermore, it can be used to effectively assess the liver functional reserve of HCC patients.
PMCID: PMC4481448  PMID: 26139999
Magnetic resonance elastography; Liver functional reserve; Indocyanine green clearance test; Liver fibrosis; Hepatocellular carcinoma
18.  Relationship between the concentration of formaldehyde in the air and asthma in children: a meta-analysis 
The aim of our study is to systematically assess the impact of formaldehyde in the air on asthma. Publications from year 1995 to 2014 on asthma were retrieved from PubMed, online Chinese periodical full-text databases of Chongqing VIP, China National Knowledge Index (CNKI) and Wan fang. Meta-Analyst was used to analyze the relationship between the concentration of formaldehyde and asthma in children. After evaluating the quality of the literature, 8 papers were finally included in our study, and the total sample sizes were 718, including the case group 362 and control group 356. The heterogeneous text display P=0.000, I2=0.876, Q=40.451, Meta-analyst finding showed that the pooled weighted mean difference (WMD) in concentration of formaldehyde is 0.021 (95% CI: 0.009-0.033). Children will have a larger probability to get asthma due to the higher level of formaldehyde. Therefore, we should reduce the level of formaldehyde in the air, which can protect our children.
PMCID: PMC4538175  PMID: 26309488
Asthma; formaldehyde; children; meta-analysis
19.  Clinical and Muscle Imaging Findings in 14 Mainland Chinese Patients with Oculopharyngodistal Myopathy 
PLoS ONE  2015;10(6):e0128629.
Oculopharyngodistal myopathy (OPDM) is an extremely rare, adult-onset hereditary muscular disease characterized by progressive external ocular, pharyngeal, and distal muscle weakness and myopathological rimmed vacuole changes. The causative gene is currently unknown; therefore, diagnosis of OPDM is based on clinical and histopathological features and genetic exclusion of similar conditions. Moreover, variable manifestations of this disorder are reported in terms of muscle involvement and severity. We present the clinical profile and magnetic resonance imaging (MRI) changes of lower limb muscles in 14 mainland Chinese patients with OPDM, emphasizing the role of muscle MRI in disease identification and differential diagnosis. The patients came from 10 unrelated families and presented with progressive external ocular, laryngopharyngeal, facial, distal limb muscle weakness that had been present since early adulthood. Serum creatine kinase was mildly to moderately elevated. Electromyography revealed myogenic changes with inconsistent myotonic discharge. The respiratory function test revealed subclinical respiratory muscle involvement. Myopathological findings showed rimmed vacuoles with varying degrees of muscular dystrophic changes. All known genes responsible for distal and myofibrillar myopathies, vacuolar myopathies, and muscular dystrophies were excluded by PCR or targeted next-generation sequencing. Muscle MRI revealed that the distal lower legs had more severe fatty replacement than the thigh muscles. Serious involvement of the soleus and long head of the biceps femoris was observed in all patients, whereas the popliteus, gracilis and short head of biceps femoris were almost completely spared, even in advanced stages. Not only does our study widen the spectrum of OPDM in China, but it also demonstrates that OPDM has a specific pattern of muscle involvement that may provide valuable information for its differential diagnosis and show further evidence supporting the conclusion that OPDM is a unique disease phenotype.
PMCID: PMC4454561  PMID: 26039504
20.  Outcomes of endovascular treatment for patients with TASC II D femoropopliteal occlusive disease: a single center study 
Advances in endovascular technology led to an alternative treatment option for TASC II D (TransAtlantic Inter-Society Consensus II class D) lesions. This study was aimed to evaluate the outcomes of endovascular treatment for TASC II D femoropopliteal lesions.
Endovascular intervention with bare nitinol stent implantation was performed on 58 limbs (53 patients) with TASC II D femoropopliteal lesions from January 2011 to March 2013. Kaplan-Meier curves of primary patency, assisted patency and second patency were performed. Predictive factors of re-stenosis/occlusion were evaluated by univariate methods.
Total 53 patients with mean age of 74.2 ± 8.2 (range, 58.0–91.0 years) and mean lesion length of 314.8 ± 64.3 mm (188.2–400.4 mm) were enrolled. The mean follow-up time was 12.2 ± 6.1 months (5–38 months). Revascularization was successfully on 95 % lesions by bare nitinol stent implantation. Primary patency rates at 1, 2 and 3 years were 63 %, 12 % and 12 %, respectively. Assisted primary patency rates at 1, 2 and 3 years were 77 %, 31 % and 31 %, respectively. Secondary patency rates at 1, 2 and 3 years were 96 %, 63 % and 63 %. During one-year follow-up, no major amputation was occurred. Univariate analysis revealed that number of run-off vessels was a potential predictor of re-stenosis/occlusion.
Endovascular treatment of TASC II D femoropopliteal artery occlusion has a high technical success rate with acceptable one-year patency rate. The long-term outcomes are poor, but endovascular intervention could be a good alternative for patients unsuitable for surgical bypass.
PMCID: PMC4453767  PMID: 26022244
Peripheral artery disease; TASC II D lesions; Endovascular treatment; Patency rate; Risk factor
21.  Integrin β4 in EMT: an implication of renal diseases 
Renal fibrosis is a main cause of chronic renal failure. Epithelial-to-mesenchymal transition (EMT) markers play a role in renal fibrosis. Transforming growth factor-β1 (TGF-β1) has been shown to initiate and complete the whole EMT process. It is now well accepted that loss of E-cadherin, EMT marker α-SMA, and connective tissue growth factor (CTGF) expression are key events in the EMT process. We found that by stimulating human renal proximal tubular epithelial (HK-2) cells with TGF-β1, the expression of E-cadherin was down regulated and the expression of α-SMA and CTGF were up regulated in a dose dependent manner. In our present study we also found that integrin β4 and peroxisome proliferators-activated receptor-γ (PPAR-γ) play roles in EMT process, with TGF-β1 stimulation increasing integrin β4 expression in HK2 cells. Integrin β4 and PPARγ were detected in tubulointerstitial tissues, immunohistochemistry analysis showed enhanced expression of integrin β4 in early stage, with over-expression at later stage. In contrast, the expression of PPARγ showed little increased in early stage, but was dramatically decreased at later stage. This is consistent with TGF-β1 inducing EMT. Our immune-precipitation studies show that integrin β4 disassociation with PPARγ is present in E-cadherin signaling. It suggests that PPARγ has a role in EMT inhibition.
PMCID: PMC4509178  PMID: 26221233
Integrin β4; PPARγ; EMT; renal diseases
22.  The androgen receptor plays a suppressive role in epithelial- mesenchymal transition of human prostate cancer stem progenitor cells 
BMC Biochemistry  2015;16:13.
To investigate the roles of androgen receptor (AR) in epithelial- mesenchymal transition (EMT) in human prostate cancer stem progenitor (S/P) cells isolated from LNCaP cell line.
The S/P cells were obtained from LNCaP cell line through florescence-activated cell sorting (FACS). AR was overexpressed in S/P cells through lentivirus. Western blot assay was used to detect the EMT markers expression, such as E Cadherin, N Cadherin, Vimentin and Snail. MTT assay, soft agar colony formation assay, sphere formation assay and migration assay were used to investigate AR’s roles in EMT of S/P cells. Cell signaling pathways associated with proliferation and apoptosis of S/P cells were detected simultaneously. And S/P cells were treated with in vitro combinatory use of LY 294002 (inhibitor of AKT signaling molecules) with γ-TT and/or 5-AZA.
Our data showed that S/P cells from LNCaP had high EMT markers expression, more tumorigenesis and strong migration ability. And in S/P cells overexpressed with AR, the expression of EMT markers decreased. In addition, these cells had less proliferation ability, tumorigenesis ability, self-renewal and migration ability. At the same time, targeting S/P cells with AKT signaling pathway inhibitor LY29004 andγ-TT and/or 5-AZA could inhibit S/P cell’s proliferation and tumorigenesis.
Our data suggest that AR played a negative role in EMT of PCa S/P cells, by regulating AKT cell signaling pathway, which could be a new strategy to treat castration resistant prostate cancer (CRPC).
PMCID: PMC4430921  PMID: 25943311
Prostatic neoplasms; Stem progenitor cell; Epithelial-mesenchymal transition; Androgen receptor
23.  EphB4 forward signalling regulates lymphatic valve development 
Nature Communications  2015;6:6625.
Bidirectional signalling is regarded as a notable hallmark of the Eph-ephrin signalling system: Eph-dependent forward signalling in Eph-expressing cells and ephrin-dependent reverse signalling in Ephrin-expressing cells. The notion of ephrin-dependent reverse signalling derives from genetic experiments utilizing mice carrying mutations in the intracellular region of ephrinBs. Here we show that EphB4-dependent forward signalling regulates lymphatic valve development, a process previously thought to be regulated by ephrinB2-dependent reverse signalling. We develop antibodies that selectively target EphB4 and ephrinB2. We find that mice bearing genetically altered cytoplasmic region of ephrinB2 have significantly altered EphB4-dependent forward signalling. Selective inhibition of EphB4 using a functional blocking antibody results in defective lymphatic valve development. Furthermore, a chemical genetic approach is used to unequivocally show that the kinase activity of EphB4 is essential for lymphatic valve development.
The bidirectional Eph-ephrin signalling regulates a myriad of developmental programmes. Zhang et al. show that EphB4 forward signalling is crucial for lymphatic valve development, providing new insight into this important developmental process previously thought to be regulated by ephrinB2-dependent reverse signalling.
PMCID: PMC4403310  PMID: 25865237
24.  Amino acid substitutions in the neuraminidase protein of an H9N2 avian influenza virus affect its airborne transmission in chickens 
Veterinary Research  2015;46(1):44.
Cases of H9N2 avian influenza virus (AIV) in poultry are increasing throughout many Eurasian countries, and co-infections with other pathogens have resulted in high morbidity and mortality in poultry. Few studies have investigated the genetic factors of virus airborne transmission which determine the scope of this epidemic. In this study, we used specific-pathogen-free chickens housed in isolators to investigate the airborne transmissibility of five recombinant H9N2 AIV rescued by reverse genetic technology. The results show that airborne transmission of A/Chicken/Shandong/01/2008 (SD01) virus was related to the neuraminidase (NA) gene, and four amino acid mutations (D368E, S370L, E313K and G381D) within the head region of the SD01 NA, reduced virus replication in the respiratory tract of chickens, reduced virus NA activity, and resulted in a loss of airborne transmission ability in chickens. Similarly, reverse mutations of these four amino acids in the NA protein of r01/NASS virus, conferred an airborne transmission ability to the recombinant virus. We conclude that these four NA residues may be significant genetic markers for evaluating potential disease outbreak of H9N2 AIV, and propose that immediate attention should be paid to the airborne transmission of this virus.
Electronic supplementary material
The online version of this article (doi:10.1186/s13567-014-0142-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4404070  PMID: 25928577
25.  IQGAP1 regulates actin cytoskeleton organization in podocytes through interaction with nephrin 
Cellular signalling  2015;27(4):867-877.
Increasing data has shown that the cytoskeletal reorganization of podocytes is involved in the onset of proteinuria and the progression of glomerular disease. Nephrin behaves as a signal sensor of the slit diaphragm to transmit cytoskeletal signals to maintain the unique structure of podocytes. However, the nephrin signaling cascade deserves further study. IQGAP1 is a scaffolding protein with the ability to regulate cytoskeletal organization. It is hypothesized that IQGAP1 contributes to actin reorganization in podocytes through interaction with nephrin. IQGAP1 expression and IQGAP1-nephrin colocalization in glomeruli were progressively decreased and then gradually recovered in line with the development of foot process fusion and proteinuria in puromycin aminonucleoside-injected rats. In cultured human podocytes, puromycin aminonucleoside-induced disruption of F-actin and disorders of migration and spreading were aggravated by IQGAP1 siRNA, and these effects were partially restored by a wild-type IQGAP1 plasmid. Furthermore, the cytoskeletal disorganization stimulated by cytochalasin D in COS7 cells was recovered by cotransfection with wild-type IQGAP1 and nephrin plasmids but was not recovered either by single transfection of the wild-type IQGAP1 plasmid or by cotransfection of mutant IQGAP1 [Δ1443(S → A)] and wild-type nephrin plasmids. Co-immunoprecipitation analysis using lysates of COS7 cells overexpressing nephrin and each derivative-domain molecule of IQGAP1 demonstrated that the poly-proline binding domain and RasGAP domain in the carboxyl terminus of IQGAP1 are the target modules that interact with nephrin. Collectively, these findings showed that activated IQGAP1, as an intracellular partner of nephrin, is involved in actin cytoskeleton organization and functional regulation of podocytes.
PMCID: PMC4356988  PMID: 25652011
Actin cytoskeleton; IQ domain GTPase-activating protein 1; Nephrin; Podocyte

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