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1.  Further evidence for the existence of major susceptibility of nasopharyngeal carcinoma in the region near HLA-A locus in Southern Chinese 
Nasopharyngeal carcinoma (NPC) is a multi-factorial malignancy closely associated with environmental factors, genetic factors and Epstein-Barr virus infection. Human leukocyte antigen (HLA) complex, specially the region near HLA-A locus, was regarded as a major candidate region bearing NPC genetic susceptibility loci in many previous studies including two recent genome-wide association (GWA) studies. To provide further evidence for the NPC susceptibility in the region near HLA-A locus based on other previous studies, we carried out a two-stage hospital-based case control association study including 535 sporadic NPC patients and 525 cancer-free control subjects from Guangdong, a high prevalence area of NPC in China.
38 tag SNPs were initially selected by Heploview from the segment around HLA-A locus (from D6S211 to D6S510) and genotyped on GenomeLab SNPstream platform in 206 cases and 180 controls in the stage 1. Subsequently, the stage 1 significant SNPs and 17 additional SNPs were examined on another platform (Sequenom iPlex Assay) in another independent set of study population including 329 cases and 345 controls.
Totally eight SNPs from the segment from D6S211 to D6S510 within HLA complex were found to be significantly associated with NPC. Two of the most significant SNPs (rs9260734 and rs2517716) located near to HLA-A and HCG9 respectively were in strong LD with some other SNPs of this region reported by two previous GWA studies. Meanwhile, Meanwhile, novel independent susceptibility loci (rs9404952, Pcombined = 6.6 × 10-5, OR combined = 1.45) was found to be close to HLA-G.
Therefore, our present study supports that the segment from D6S211 to D6S510 in HLA complex region might contain NPC susceptibility loci which indeed needs to be fully investigated in the future.
PMCID: PMC3383544  PMID: 22440091
Nasopharyngeal carcinoma; Single nucleotide polymorphism; Human leukocyte antigen (HLA)
2.  A visual method for direct selection of high-producing Pichia pastoris clones 
BMC Biotechnology  2011;11:23.
The methylotrophic yeast, Pichia pastoris, offers the possibility to generate a high amount of recombinant proteins in a fast and easy way to use expression system. Being a single-celled microorganism, P. pastoris is easy to manipulate and grows rapidly on inexpensive media at high cell densities. A simple and direct method for the selection of high-producing clones can dramatically enhance the whole production process along with significant decrease in production costs.
A visual method for rapid selection of high-producing clones based on mannanase reporter system was developed. The study explained that it was possible to use mannanase activity as a measure of the expression level of the protein of interest. High-producing target protein clones were directly selected based on the size of hydrolysis holes in the selected plate. As an example, the target gene (9elp-hal18) was expressed and purified in Pichia pastoris using this technology.
A novel methodology is proposed for obtaining the high-producing clones of proteins of interest, based on the mannanase reporter system. This system may be adapted to other microorganisms, such as Saccharomyces cerevisiae for the selection of clones.
PMCID: PMC3071314  PMID: 21418613
3.  Tumor expressed PTHrP facilitates prostate cancer-induced osteoblastic lesions 
Expression of parathyroid hormone-related protein (PTHrP) correlates with prostate cancer skeletal progression; however, the impact of prostate cancer-derived PTHrP on the microenvironment and osteoblastic lesions in skeletal metastasis has not been completely elucidated. In this study, PTHrP overexpressing prostate cancer clones were stably established by transfection of full length rat PTHrP cDNA. Expression and secretion of PTHrP were verified by western blotting and IRMA assay. PTHrP overexpressing prostate cancer cells had higher growth rates in vitro, and generated larger tumors when inoculated subcutaneously into athymic mice. The impact of tumor-derived PTHrP on bone was investigated using a vossicle co-implant model. Histology revealed increased bone mass adjacent to PTHrP overexpressing tumor foci, with increased osteoblastogenesis, osteoclastogenesis and angiogenesis. In vitro analysis demonstrated pro-osteoclastic and pro-osteoblastic effects of PTHrP. PTHrP enhanced proliferation of bone marrow stromal cells and early osteoblast differentiation. PTHrP exerted a pro-angiogenic effect indirectly, as it increased angiogenesis but only in the presence of bone marrow stromal cells. These data suggest PTHrP plays a role in tumorigenesis in prostate cancer, and that PTHrP is a key mediator for communication and interactions between prostate cancer and the bone microenvironment. Prostate cancer-derived PTHrP is actively involved in osteoblastic skeletal progression.
PMCID: PMC3979464  PMID: 18729185
parathyroid hormone-related protein; PTHrP; skeletal metastasis; prostate carcinoma; angiogenesis
4.  Transcription factor ERG is a specific and sensitive diagnostic marker for hepatic angiosarcoma 
AIM: To investigate the expression of ERG, CD34, CD31 (PECAM-1, platelet/endothelial cell adhesion molecule 1) and factor VIII-related antigen (FVIIIRAg) in the diagnosis of hepatic angiosarcoma patients.
METHODS: Patient samples were collected from January 1986 to December 2012 from the People’s Liberation Army General Hospital in Beijing, China. We obtained twenty-four samples of hepatic angiosarcoma (HAS) that were confirmed by two pathologist. The samples were the result of three autopsy cases, eight biopsy cases and 13 patients who underwent surgical tumor removal. The HAS cases accounted for 2.23% (24/1075) of all hepatic vascular tumors at the hospital during the same time period. Patient histories including age, gender, clinical manifestations, medical treatments, laboratory tests, radiological images, histological observations and outcomes for each case were analyzed in detail. All samples were evaluated histologically with hematoxylin and eosin staining. Using immunohistochemistry, the expression and localization of ERG was examined in all HAS specimens and compared to the known endothelial markers CD34, CD31 and FVIIIRAg. The endothelial markers were also evaluated in a panel of non-HAS tumors.
RESULTS: This cohort of 24 HAS cases is, to the best of our knowledge, currently the largest cohort in the world in the publicly available literature. Hepatic angiosarcoma tissue samples were obtained from 14 males and 10 females with a mean age of 50.6 years (range: 7-86 years). The patients presented with the following clinical manifestations: abdominal pain (16/24), back pain (3/24), heart palpitations (1/20), cough (1/24) or no clinical symptoms (3/24). Tumors were predominantly localized in the right hepatic lobe (15/24) or left hepatic lobe (6/24), or a diffuse growth on the right and left hepatic lobes (3/24). Eleven patients underwent surgical resection (45.8%), two patients received a liver transplant (8.3%), eight patients received interventional therapy (33.3%) and three patients received no treatment (lesions discovered at autopsy, 12.5%). Postoperative follow-up of patients revealed that 87.5% (21/24) of patients had died and three cases were not able to be tracked. In all cases, the mean survival time was 12.1 mo. While 100% of the HAS samples were positive for ERG expression, expression of the other markers was more variable. CD31 was expressed in 79.2% (19/24) of samples, CD34 was expressed in 87.5% (21/24) of samples and FVIIIRAg was expressed in 41.7% (10/24) of samples.
CONCLUSION: ERG is a more sensitive and specific diagnostic marker for hepatic angiosarcoma in comparison to CD31, CD34 and FVIIIRAg.
PMCID: PMC3974537
Liver; Angiosarcoma; ERG; Immunohistochemistry; Diagnosis
5.  Role of Toll-Like Receptor 4 in Colorectal Carcinogenesis: A Meta-Analysis 
PLoS ONE  2014;9(4):e93904.
This meta-analysis was performed to evaluate the role of toll-like receptor 4 (TLR-4) in colorectal carcinogenesis.
The PubMed, CISCOM, CINAHL, Web of Science, Google Scholar, EBSCO, Cochrane Library, and CBM databases were searched from inception through November 1st, 2013 without language restrictions. Odds ratios (ORs) or standardized mean differences (SMD) with their 95% confidence intervals (CI) were calculated.
Fourteen case-control studies met the inclusion criteria for this meta-analysis. A total of 1,209 colorectal cancer (CRC) cases and 1,218 healthy controls were involved in this meta-analysis. Two common polymorphisms (299 A>G and 399 C>T) in the TLR-4 gene, TLR-4 mRNA and protein expression were assessed. Our meta-analysis results revealed that the TLR-4 399 C>T polymorphism might increase the risk of CRC (allele model: OR = 1.77, 95%CI = 1.32∼2.36, P<0.001; dominant model: OR = 1.83, 95%CI = 1.32∼2.52, P<0.001; respectively). However, we found no correlation between the TLR-4 299 A>G polymorphism and CRC risk (all P>0.05). A subgroup analysis by ethnicity suggested that TLR-4 genetic polymorphisms were associated with an increased risk of CRC among Asians (allele model: OR = 1.50, 95%CI = 1.19∼1.88, P = 0.001; dominant model: OR = 1.49, 95%CI = 1.16∼1.92, P = 0.002; respectively), but not among Caucasians and Africans (all P>0.05). Furthermore, our results showed that TLR-4 mRNA and protein levels in CRC patients were higher than those in healthy controls (TLR-4 mRNA: SMD  = 2.51, 95%CI  = 0.98∼4.05, P = 0.001; TLR-4 protein: OR  = 4.75, 95%CI  = 1.16∼19.36, P = 0.030; respectively).
Our findings provide empirical evidence that TLR-4 may play an important role in colorectal carcinogenesis. Thus, TLR-4 is a promising potential biomarker for the early diagnosis of CRC.
PMCID: PMC3976338  PMID: 24705379
6.  Laparoscopic hepaticoplasty using gallbladder as a subcutaneous tunnel for hepatolithiasis 
AIM: To investigate the feasibility, efficacy and safety of laparoscopic hepaticoplasty using gallbladder as subcutaneous tunnel and sphincter-of-Oddi preservation for hepatolithiasis.
METHODS: From January 2010 to July 2013, six patients with hepatolithiasis were treated at our institution. All the patients underwent laparoscopic surgery. The procedures included common hepatic duct exploration, stone clearance by fiberoptic choledochoscopy, hilar bile duct hepaticoplasty with preservation of the sphincter of Oddi, anastomosis between the hilar bile duct and neck of the gallbladder, and establishment of a subcutaneous tunnel with the gallbladder. Two patients underwent left lateral hepatectomy simultaneously. Clinical data including operation time, intraoperative blood loss, operative morbidity, hospital mortality, stone clearance, and recurrence rate were analyzed.
RESULTS: All patients successfully completed laparoscopic surgery. The mean length of hospital stay was 4.5 ± 0.9 d (range: 3-6 d). The mean blood loss of the hepatectomy was 450 mL (range: 200-700 mL), and the blood loss of the other four was 137 ± 151 mL (range: 50-400 mL). The mean operative time was 318 ± 68 min (range: 236-450 min). The operative morbidity and hospital mortality were zero. The immediate stone clearance rate was 100%. All patients were followed up for an average of 17 mo (range: 7-36 mo). One of the six patients had abdominal mass with pain, and subcutaneous tunnel cholangiography showed severe gallbladder-biliary anastomotic stricture at 4 mo postoperatively. There was no stone recurrence and no cholangitis during follow-up.
CONCLUSION: Laparoscopic hepaticoplasty using gallbladder with a subcutaneous tunnel and preserving the sphincter of Oddi is feasible, safe and effective for hepatholithiasis.
PMCID: PMC3964406
Hepatolithiasis; Laparoscopy; Hepaticoplasty; Minimally invasive surgery; Subcutaneous tunnel
7.  Alpha, Beta and Gamma Diversity Differ in Response to Precipitation in the Inner Mongolia Grassland 
PLoS ONE  2014;9(3):e93518.
Understanding the distribution pattern and maintenance mechanism of species diversity along environmental gradients is essential for developing biodiversity conservation strategies under environmental change. We have surveyed the species diversity at 192 vegetation sites across different steppe zones in Inner Mongolia, China. We analysed the total species diversity (γ diversity) and its composition (α diversity and β diversity) of different steppe types, and their changes along a precipitation gradient. Our results showed that (i) β diversity contributed more than α diversity to the total (γ) diversity in the Inner Mongolia grassland; the contribution of β diversity increased with precipitation, thus the species-rich (meadow steppe) grassland had greater contribution of β diversity than species-poor (desert steppe) grassland. (ii) All α, β and γ species diversity increased significantly (P<0.05) with precipitation, but their sensitivity to precipitation (diversity change per mm precipitation increase) was different between the steppe types. The sensitivity of α diversity of different steppe community types was negatively (P<0.05) correlated with mean annual precipitation, whereas the sensitivity of β and γ diversity showed no trend along the precipitation gradient (P>0.10). (iii) The α diversity increased logarithmically, while β diversity increased exponentially, with γ diversity. Our results suggest that for local species diversity patterns, the site species pool is more important in lower precipitation areas, while local ecological processes are more important in high precipitation areas. In addition, for β diversity maintenance niche processes and diffusion processes are more important in low and high precipitation areas, respectively. Our results imply that a policy of “multiple small reserves” is better than one of a “single large reserve” for conserving species diversity of a steppe ecosystem, and indicate an urgent need to develop management strategies for climate-sensitive desert steppe ecosystem.
PMCID: PMC3968148  PMID: 24675900
8.  Ubiquitination and Degradation of Ribonucleotide Reductase M1 by the Polycomb Group Proteins RNF2 and Bmi1 and Cellular Response to Gemcitabine 
PLoS ONE  2014;9(3):e91186.
Ribonucleotide reductase M1 (RRM1) is required for mammalian deoxyribonucleotide (dNTP) metabolism. It is the primary target of the antimetabolite drug gemcitabine, which is among the most efficacious and most widely used cancer therapeutics. Gemcitabine directly binds to RRM1 and irreversibly inactivates ribonucleotide reductase. Intra-tumoral RRM1 levels are predictive of gemcitabine’s therapeutic efficacy. The mechanisms that regulate intracellular RRM1 levels are largely unknown. Here, we identified the E3 ubiquitin-protein ligases RNF2 and Bmi1 to associate with RRM1 with subsequent poly-ubiquitination at either position 48 or 63 of ubiquitin. The lysine residues 224 and 548 of RRM1 were identified as major ubiquitination sites. We show that ubiquitinated RRM1 undergoes proteasome-mediated degradation and that targeted post-transcriptional silencing of RNF2 and Bmi1 results in increased RRM1 levels and resistance to gemcitabine. Immunohistochemical analyses of 187 early-stage lung cancer tumor specimens revealed a statistically significant co-expression of RRM1 and Bmi1. We were unable to identify suitable reagents for in situ quantification of RNF2. Our findings suggest that Bmi1 and possibly RNF2 may be attractive biomarkers of gemcitabine resistance in the context of RRM1 expression. They also provide novel information for the rational design of gemcitabine-proteasome inhibitor combination therapies, which so far have been unsuccessful if given to patients without taking the molecular context into account.
PMCID: PMC3948819  PMID: 24614341
9.  A Systematic In Silico Mining of the Mechanistic Implications and Therapeutic Potentials of Estrogen Receptor (ER)-α in Breast Cancer 
PLoS ONE  2014;9(3):e91894.
Estrogen receptor (ER)-α has long been a potential target in ER-α-positive breast cancer therapeutics. In this study, we integrated ER-α-related bioinformatic data at different levels to systematically explore the mechanistic and therapeutic implications of ER-α. Firstly, we identified ER-α-interacting proteins and target genes of ER-α-regulating microRNAs (miRNAs), and analyzed their functional gene ontology (GO) annotations of those ER-α-associated proteins. In addition, we predicted ten consensus miRNAs that could target ER-α, and screened candidate traditional Chinese medicine (TCM) compounds that might hit diverse conformations of ER-α ligand binding domain (LBD). These findings may help to uncover the mechanistic implications of ER-α in breast cancer at a systematic level, and provide clues of miRNAs- and small molecule modulators- based strategies for future ER-α-positive breast cancer therapeutics.
PMCID: PMC3948898  PMID: 24614816
10.  Significance of red cell distribution width measurement for the patients with isolated coronary artery ectasia 
Red cell distribution width (RDW) has been recognized as a novel marker for several cardiovascular diseases. The aim of this study was to evaluate the association between RDW levels and the presence of isolated coronary artery ectasia (CAE).
We studied 414 subjects including 113 patients with isolated CAE (Group A), 144 patients with coronary artery disease (CAD, group B) and 157 angiographically normal controls (group C). Baseline clinical characteristics and laboratory findings including RDW were compared among three groups.
The levels of RDW were significantly higher in group A and B compared with that in group C (12.97 ± 1.4 and 12.88 ± 1.0 vs 12.34 ± 0.9, p = 0.020) while no difference was found between CAE and CAD (p = 0.17). Additionally, the levels of CRP were also higher in patients with CAE and CAD compared with normal controls (0.26 ± 0.14 mg/L, 0.31 ± 0.27 mg/L vs 0.20 ± 0.06 mg/L, p = 0.04). The multivariate analysis indicated that RDW and CRP were the independent variables most strongly associated with the presence of isolated CAE and CAD. There was a positive correlation between levels of RDW and CRP in patients with isolated CAE (γ=0.532, p = 0.001).
Our data suggested that RDW may be a useful marker and independent predictor for the presence of isolated CAE.
PMCID: PMC3975450  PMID: 24606910
Red cell distribution width; Coronary artery ectasia; Coronary artery disease; C-reactive protein
11.  Fenamates block gap junction coupling and potentiate BKCa channels in guinea pig arteriolar cells 
European journal of pharmacology  2013;703(0):74-82.
We determined the actions of the fenamates, flufenamic acid (FFA) and niflumic acid (NFA), on gap junction-mediated intercellular coupling between vascular smooth muscle cells (VSMC) in situ of acutely isolated arteriole segments from the three vascular beds: the spiral modiolar artery (SMA), anterior inferior cerebellar artery (AICA) and mesenteric artery (MA), and on non-junctional membrane channels in dispersed VSMCs. Conventional whole-cell recording methods were used. FFA reversibly suppressed the input conductance (Ginput) or increased the input resistance (Rinput) in a concentration dependent manner, with slightly different IC50s for the SMA, AICA and MA segments (26, 33 and 56 μM respectively, P>0.05). Complete electrical isolation of the recorded VSMC was normally reached at ≥300 μM. NFA had a similar effect on gap junction among VSMCs with an IC50 of 40, 48 and 62 μM in SMA, AICA and MA segments, respectively. In dispersed VSMCs, FFA and NFA increased outward rectifier K+-current mediated by the big conductance calcium-activated potassium channel (BKCa) in a concentration-dependent manner, with a similar EC50 of ~300 μM for both FFA and NFA in the three vessels. Iberiotoxin, a selective blocker of the BKCa, suppressed the enhancement of the BKCa by FFA and NFA. The KV blocker 4-AP had no effect on the fenamates-induced K+-current enhancement. We conclude that FFA and NFA blocked the vascular gap junction mediated electrical couplings uniformly in arterioles of the three vascular beds, and complete electrical isolation of the recorded VSMC is obtained at ≧300 μM; FFA and NFA also activate BKCa channels in the arteriolar smooth muscle cells in addition to their known inhibitory effects on chloride channels.
PMCID: PMC3615131  PMID: 23420003
flufenamic acid; niflumic acid; gap junction; potassium channel; arteriole; electrical coupling
12.  Relation of Leukocytes and Its Subsets Counts with the Severity of Stable Coronary Artery Disease in Patients with Diabetic Mellitus 
PLoS ONE  2014;9(3):e90663.
Both coronary artery disease (CAD) and diabetes mellitus (DM) are associated with inflammation. However, whether and which leukocytes can predict the presence and extent of CAD in patients with DM has not been investigated. The aim of the present study was to examine the association of leukocyte and its subsets counts with the severity of CAD in patients with DM.
Methods and Findings
Three hundred and seventy-three diabetic patients who were scheduled for coronary angiography due to typical stable angina pectoris were enrolled in this study. They were classified into the three groups according to tertiles of Gensini score (GS, low group <8, n = 143; intermediate group 8∼28, n = 109; high group >28, n = 121). The relationship between the leukocyte and its subsets counts with the severity of CAD were evaluated. The data indicated that there were significant correlations between leukocyte and neutrophil counts with GS (r = 0.154 and 0.156, respectively, all P<0.003 for Pearson's correlation). Similarly, area under the receivers operating characteristic curve of leukocyte and neutrophil counts were 0.61 and 0.60 respectively (95%CI: 0.55–0.67, all P = 0.001) for predicting high GS. Multivariate logistic regression analysis demonstrated that leukocyte count was an independent predictor for high GS patients with DM (OR = 1.20, 95%CI 1.03–1.39, P = 0.023) after adjusting for conventional risk factors of CAD.
Compared with its subsets, leukocyte count appeared to be an independent predictor for the severity of CAD and the optimal cut-off value for predicting high GS (>28 points) was 5.0×109 cells/L in diabetic patients.
PMCID: PMC3944194  PMID: 24599246
13.  Reduced Intensity Conditioning, Combined Transplantation of Haploidentical Hematopoietic Stem Cells and Mesenchymal Stem Cells in Patients with Severe Aplastic Anemia 
PLoS ONE  2014;9(3):e89666.
We examined if transplantation of combined haploidentical hematopoietic stem cells (HSC) and mesenchymal stem cells (MSC) affected graft failure and graft-versus-host disease (GVHD) in patients with severe aplastic anemia (SAA). Patients with SAA-I (N = 17) received haploidentical HSCT plus MSC infusion. Stem cell grafts used a combination of granulocyte colony-stimulating factor (G-CSF)-primed bone marrow and G-CSF-mobilized peripheral blood stem cells of haploidentical donors and the culture-expanded third-party donor-derived umbilical cord MSCs (UC-MSCs), respectively. Reduced intensity conditioning consisted of fludarabine (30 mg/m2·d)+cyclosphamide (500 mg/m2·d)+anti-human thymocyte IgG. Transplant recipients also received cyclosporin A, mycophenolatemofetil, and CD25 monoclonal antibody. A total of 16 patients achieved hematopoietic reconstitution. The median mononuclear cell and CD34 count was 9.3×108/kg and 4.5×106/kg. Median time to ANC was >0.5×109/L and PLT count >20×109/L were 12 and 14 days, respectively. Grade III-IV acute GVHD was seen in 23.5% of the cases, while moderate and severe chronic GVHD were seen in 14.2% of the cases. The 3-month and 6-month survival rates for all patients were 88.2% and 76.5%, respectively; mean survival time was 56.5 months. Combined transplantation of haploidentical HSCs and MSCs on SAA without an HLA-identical sibling donor was safe, effectively reduced the incidence of severe GVHD, and improved patient survival.
PMCID: PMC3940616  PMID: 24594618
14.  Pure Mucinous Breast Carcinoma: A Favorable Subtype 
Breast Care  2013;8(1):56-59.
Pure mucinous breast carcinoma is a relatively rare subtype of breast malignancy. This study is to investigate the clinical and pathologic features of pure mucinous breast carcinoma.
Patients and Methods
A retrospective review of our database of patients who presented with breast cancer was performed. The medical records of 1,060 patients with invasive breast cancer who underwent surgery were reviewed.
28 patients with pure mucinous breast cancer were identified. The mean age was 55.28 ± 15.73 years. 17 patients underwent modified radical mastectomy; 11 underwent breast-conserving therapy. The tumor size was T1 in 19 patients, T2 in 8 patients, and T3 in 1 patient. None of the patients had lymph node metastasis. There was no distant metastasis. 18 were stage I, and 10 were stage II. Estrogen receptor, progesterone receptor, HER-2, and P53 were positive in 96, 93, 0, and 28%, respectively. Median follow-up was 42 months (range 1–84 months). 1 patient had local recurrence. The overall survival rate was 100%.
Pure mucinous breast carcinoma has a favorable prognosis. Less invasive treatment might be optional. Larger data samples with longer follow-up would be necessary to gain a better understanding of this disease.
PMCID: PMC3971816  PMID: 24715844
Breast cancer; Mucinous carcinoma; Prognosis
15.  The Status of Rheumatoid Factor and Anti-Cyclic Citrullinated Peptide Antibody Are Not Associated with the Effect of Anti-TNFα Agent Treatment in Patients with Rheumatoid Arthritis: A Meta-Analysis 
PLoS ONE  2014;9(2):e89442.
This meta-analysis was conducted to investigate whether the status of rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibody are associated with the clinical response to anti-tumor necrosis factor (TNF) alpha treatment in rheumatoid arthritis (RA).
A systemic literature review was performed using the MEDLINE, SCOPUS, Cochrane Library, ISI Web of Knowledge, and Clinical Trials Register databases, and Hayden's criteria of quality assessment for prognostic studies were used to evaluate all of the studies. The correlation between the RF and anti-CCP antibody status with the treatment effect of anti-TNFα agents was analyzed separately using the Mantel Haenszel method. A fixed-effects model was used when there was no significant heterogeneity; otherwise, a random-effects model was applied. Publication bias was assessed using Egger's linear regression and a funnel plot.
A total of 14 studies involving 5561 RA patients meeting the inclusion criteria were included. The overall analysis showed that the pooled relative risk for the predictive effects of the RF and anti-CCP antibody status on patient response to anti-TNFα agents was 0.98 (95% CI: 0.91–1.05, p = 0.54) and 0.88 (95% CI: 0.76–1.03, p = 0.11), respectively, with I2 values of 43% (p = 0.05) and 67% (p<0.01), respectively. Subgroup analyses of different anti-TNFα treatments (infliximab vs. etanercept vs. adalimumab vs. golimumab), response criteria (DAS28 vs. ACR20 vs. EULAR response), follow-up period (≥6 vs. <6 months), and ethnic group did not reveal a significant association for the status of RF and anti-CCP.
Neither the RF nor anti-CCP antibody status in RA patients is associated with a clinical response to anti-TNFα treatment.
PMCID: PMC3937352  PMID: 24586782
16.  Enhanced surveillance of acute flaccid paralysis following importation of wild poliovirus in Xinjiang Uygur Autonomous Region, China 
BMC Infectious Diseases  2014;14:113.
After being polio free for more than 10 years, an outbreak occurred in China in 2011 in Xinjiang Uygur Autonomous Region (Xinjiang) following the importation of wild poliovirus (WPV) originating from neighboring Pakistan.
To strengthen acute flaccid paralysis (AFP) surveillance in Xinjiang, “zero case daily reporting” and retrospective searching of AFP cases were initiated after the confirmation of the WPV outbreak. To pinpoint all the polio cases in time, AFP surveillance system was expanded to include persons of all ages in the entire population in Xinjiang.
Totally, 578 AFP cases were reported in 2011 in Xinjiang, including 21 WPV cases, 23 clinical compatible polio cases and 534 non-polio AFP cases. Of the 44 polio cases, 27 (61.4%) cases were reported among adults aged 15–53 years. Strengthening AFP surveillance resulted in an increase in the number of non-polio AFP cases in 2011 (148 children < 15 years) compared with 76 cases < 15 years in 2010. The AFP surveillance system in Xinjiang was sensitive enough to detect polio cases, with the AFP incidence of 3.28/100,000 among children < 15 years of age.
Incorporating adult cases into the AFP surveillance system is of potential value to understand the overall characteristics of the epidemic and to guide emergency responses, especially in countries facing WPV outbreak following long-term polio free status. The AFP surveillance system in Xinjiang was satisfactory despite limitations in biological sample collection.
PMCID: PMC3941572  PMID: 24576083
Acute flaccid paralysis; Wild poliovirus; Clinical compatible polio cases; China
17.  Pharmacist Interventions for Prophylactic Antibiotic Use in Urological Inpatients Undergoing Clean or Clean-Contaminated Operations in a Chinese Hospital 
PLoS ONE  2014;9(2):e88971.
To evaluate the impact and cost-benefit value of pharmacist interventions for prophylactic antibiotic use in surgical patients undergoing clean or clean-contaminated operations.
A pre-to-post intervention study was performed in the Department of Urological Surgery of a tertiary hospital. Patients admitted from January through June 2011, undergoing clean or clean-contaminated surgery, served as the pre-intervention group; patients admitted from January through June 2012 formed the post-intervention group. Pharmacist interventions were performed for the surgeries in the post-intervention group. The criteria for the rational use of antibiotic prophylaxis were established by the hospital administration. The pharmacist interventions included real-time monitoring of medical records and controlling of the prescriptions of prophylactic antibiotics against the criteria. The pre- and post-intervention groups were then compared to evaluate the outcomes of the pharmacist interventions. A cost-benefit analysis was performed to determine the economic effects of implementing the pharmacist intervention on preoperative antibiotic prophylaxis.
After the pharmacist intervention, a significant decrease was found in the rate of no indications for prophylactic antibiotic use (p = 0.004), the rate of broad-spectrum antibiotic use (p<0.001), the rate of drug replacement (p<0.001) and the rate of prolonged duration of prophylaxis (p<0.001). Significant reductions were observed in the mean antibiotic cost (p<0.001), the mean duration of antibiotic prophylaxis (p<0.001) and the mean number of antibiotics used (p<0.001). A significant increase was observed in the rate of correct choice of antibiotics (p<0.001). The ratio of the net mean cost savings for antibiotics to the mean cost of pharmacist time was approximately 18.79∶1.
Real-time interventions provided by a clinical pharmacist promoted rational use of prophylactic antibiotics, with a significant reduction in antibiotic costs, thus leading to favorable economic outcomes.
PMCID: PMC3934870  PMID: 24586465
18.  Estrogen receptor α-coupled Bmi1 regulation pathway in breast cancer and its clinical implications 
BMC Cancer  2014;14:122.
Bmi1 has been identified as an important regulator in breast cancer, but its relationship with other signaling molecules such as ERα and HER2 is undetermined.
The expression of Bmi1 and its correlation with ERα, PR, Ki-67, HER2, p16INK4a, cyclin D1 and pRB was evaluated by immunohistochemistry in a collection of 92 cases of breast cancer and statistically analyzed. Stimulation of Bmi1 expression by ERα or 17β-estradiol (E2) was analyzed in cell lines including MCF-7, MDA-MB-231, ERα-restored MDA-MB-231 and ERα-knockdown MCF-7 cells. Luciferase reporter and chromatin immunoprecipitation assays were also performed.
Immunostaining revealed strong correlation of Bmi1 and ERα expression status in breast cancer. Expression of Bmi1 was stimulated by 17β-estradiol in ERα-positive MCF-7 cells but not in ERα-negative MDA-MB-231 cells, while the expression of Bmi1 did not alter expression of ERα. As expected, stimulation of Bmi1 expression could also be achieved in ERα-restored MDA-MB-231 cells, and at the same time depletion of ERα decreased expression of Bmi1. The proximal promoter region of Bmi1 was transcriptionally activated with co-transfection of ERα in luciferase assays, and the interaction of the Bmi1 promoter with ERα was confirmed by chromatin immunoprecipitation. Moreover, in breast cancer tissues activation of the ERα-coupled Bmi1 pathway generally correlated with high levels of cyclin D1, while loss of its activity resulted in aberrant expression of p16INK4a and a high Ki-67 index, which implied a more aggressive phenotype of breast cancer.
Expression of Bmi1 is influenced by ERα, and the activity of the ERα-coupled Bmi1 signature impacts p16INK4a and cyclin D1 status and thus correlates with the tumor molecular subtype and biologic behavior. This demonstrates the important role which is played by ERα-coupled Bmi1 in human breast cancer.
PMCID: PMC3939403  PMID: 24559156
Bmi1; Estrogen receptor α; p16INK4a; Cyclin D1; Breast cancer
19.  Formation of Arbitrary Patterns in Ultraviolet Cured Polymer Film via Electrohydrodynamic Patterning 
The Scientific World Journal  2014;2014:840497.
Electrohydrodynamic patterning of arbitrary patterns is achieved by optimizing the critical parameters (applied voltage and spacer height). The applied voltage has a great influence on the fidelity of L-shaped line structures with different sizes. The L-shaped line structures with high fidelity are obtained by using the moderate applied voltage. The spacer height has a great influence on the fidelity of square structures with different sizes. The square structures with high fidelity are obtained by using the low height spacer. The multi-field coupling transient finite element simulation demonstrates that the lack of polymer owing to the high height spacer leads to the formation of defects.
PMCID: PMC3956517  PMID: 24723831
20.  Temporal Patterning of Neural Progenitors in Drosophila 
Drosophila has recently become a powerful model system to understand the mechanisms of temporal patterning of neural progenitors called neuroblasts (NBs). Two different temporal sequences of transcription factors (TFs) have been found to be sequentially expressed in NBs of two different systems: the Hunchback, Krüppel, Pdm1/Pdm2, Castor, and Grainyhead sequence in the Drosophila ventral nerve cord; and the Homothorax, Klumpfuss, Eyeless, Sloppy-paired, Dichaete, and Tailless sequence that patterns medulla NBs. In addition, the intermediate neural progenitors of type II NB lineages are patterned by a different sequence: Dichaete, Grainyhead, and Eyeless. These three examples suggest that temporal patterning of neural precursors by sequences of TFs is a common theme to generate neural diversity. Cross-regulations, including negative feedback regulation and positive feedforward regulation among the temporal factors, can facilitate the progression of the sequence. However, there are many remaining questions to understand the mechanism of temporal transitions. The temporal sequence progression is intimately linked to the progressive restriction of NB competence, and eventually determines the end of neurogenesis. Temporal identity has to be integrated with spatial identity information, as well as with the Notch-dependent binary fate choices, in order to generate specific neuron fates.
PMCID: PMC3927947  PMID: 23962839
21.  Promotion of minTBP-1-PRGDN on the attachment, proliferation and collagen I synthesis of human keratocyte on titanium 
To investigate the influence of minTBP-1-PRGDN on the attachment, proliferation and collagen I synthesis of human keratocyte on titanium (Ti) surface.
The chimeric peptide RKLPDAPRGDN (minTBP-1-PRGDN) was synthesized by connecting RKLPDA (minTBP-1) to the N-terminal of PRGDN, the influence of minTBP-1-PRGDN on the attachment, proliferation and collagen I synthesis of human keratocyte on Ti surface were tested using PRGDN and minTBP-1as controls. The keratocytes attached to the surface of Ti were either stained with FITC-labeled phalloidin and viewed with fluorescence microscope or quantified with alamar Blue method. The proliferation of keratocytes on Ti were quantified with 3-(4,5-dim- ethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide up-taking methods. The secretion of type I collagen were determined using an ELISA kit.
The results showed that minTBP-1-PRGDN at a concentration of 100ng/mL was the most potent peptide to enhance the attachment of human keratocytes to the surface of Ti (1.40±0.03 folds, P=0.003), to promote the proliferation (1.26±0.05 folds, P=0.014) and the synthesis of type I collagen (1.530±0.128, P=0.008). MinTBP-1 at the same concentration could only promote the attachment (1.13±0.04 folds, P=0.020) and proliferation(1.15±0.06 folds, P=0.021), while PRGDN had no significant influence (P>0.05).
Our data shows that the novel chimeric peptide minTBP-1-PRGDN could promote the attachment, proliferation and type I collagen synthesis of human keratocytes on the surface of Ti.
PMCID: PMC3949453  PMID: 24634858
minTBP-1-PRGDN; titanium; cell attachment; proliferation; type I collagen
22.  A case of ulcerative colitis presenting as pyoderma gangrenosum and lung nodule 
Pyoderma gangrenosum is a phenomenon of cutaneous ulceration where etiology is not well understood. About half of the cases have an associated extracutanoeus manifestation or associated systemic diseases. Most commonly associated systemic disorders include inflammatory bowel disease, hematologic malignancies, autoimmune arthritis, and vasculitis. We are reporting a case where pyoderma gangrenosum has presenting features for ulcerative colitis.
PMCID: PMC3937560  PMID: 24596646
ulcerative colitis; pyoderma gangrenosum; lung nodule
23.  Emodin As an Effective Agent in Targeting Cancer Stem-Like Side Population Cells of Gallbladder Carcinoma 
Stem Cells and Development  2012;22(4):554-566.
Side population (SP) cells are previously identified from bone marrow based on their capacity to efflux of the fluorescent dye Hoechst 33342. Recent studies demonstrate that SP cells isolated from various cancer cell lines and primary tumors possess stem-cell-like properties. Thus, targeting tumor SP cells may provide new strategies for treatment in clinic. We previously showed that 1,3,8-trihydroxy-6-methylanthraquinone (emodin), a reactive oxygen species (ROS) generator, enhanced sensitivity of gallbladder cancer SGC-996 cells to cisplatin (CDDP) via generation of ROS and downregulation of multidrug-resistance-associated protein 1 (MRP1). To determine whether emodin also acts effectively on cancer stem cells of gallbladder carcinoma, we use SP cells as a model of cancer stem-cell-like cells. Here, we found that emodin, via ROS-related mechanism and suppressing the function of ATP-binding cassette super-family G member (ABCG2), which is known to be associated with Hoechst dye efflux activity of SP cells, not only reduced the ratio, inhibited clone formation, and eliminated sphere formation of SP cells effectively, but also promoted obviously the intracellular accumulation of doxorubicin, the main substrate of the efflux pump ABCG2. In addition, emodin could sensitize CDDP, via inhibition of expression of ABCG2, to overcome chemoresistance of SP cells. Importantly, similar to the experiment in vitro, emodin/CDDP co-treatment in vivo suppressed the tumor growth derived from SP cells through downregulating ABCG2 expression. Our results suggest that emodin is an effective agent targeting cancer stem-like SP cells of gallbladder carcinoma, either alone or acts as a chemotherapy enhancer.
PMCID: PMC3564469  PMID: 22974371
24.  Experimental study of image-guided percutaneous microwave ablation in rabbit lung VX2 tumor model 
Purpose: To investigate the efficacy and safety of percutaneous microwave ablation. Methods: Twenty-six rabbits with lung VX2 tumor were randomly divided into experimental and control group. In the experimental group, microwave ablation guided by ultrasound or CT was performed based on location of the tumor. Enhanced CT scan was carried out immediately before and after the ablation for all animals. Two animals from each group were sacrificed immediately or 1 week after the ablation respectively and the others were followed for the rest of their lives. Results: CT scan revealed that the tumor was greatly reduced or ablated after ablation. Pathological examination immediately after ablation also confirmed the tumor reduction or ablation. The survival time of the animals in the experimental group was significantly longer than that in the control group. Conclusions: Microwave ablation is a safe and effective method for treating lung cancer in rabbits, showing potential clinical applicability.
PMCID: PMC3971292
Microwave ablation; VX2 tumor; lung cancer
25.  X-Aptamers: A bead-based selection method for random incorporation of drug-like moieties onto next-generation aptamers for enhanced binding 
Biochemistry  2012;51(42):8321-8323.
By combining pseudo-random bead-based aptamer libraries with conjugation chemistry, we have created next-generation aptamers, X-aptamers (XAs). Several X ligands can be added in a directed or random fashion to the aptamers to further enhance their binding affinities to the target proteins. Here we describe the addition of a drug (N-acetyl-2,3-dehydro-2-deoxyneuraminic acid) demonstrated to bind to CD44-HABD, to a complete monothioate backbone substituted aptamer to increase its binding affinity to the target protein by up to 23-fold, while increasing the drugs’ binding 1-million fold.
PMCID: PMC3924539  PMID: 23057694
X-Aptamer; thioaptamer; aptamer selection; bead-based library; CD44-HABD

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