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1.  A novel inflammation-based prognostic score in esophageal squamous cell carcinoma: the C-reactive protein/albumin ratio 
BMC Cancer  2015;15:350.
Plenty of studies have demonstrated the prognostic value of various inflammation-based indexes in cancer. This study was designed to investigate the prognostic value of the C-reactive protein/albumin (CRP/Alb) ratio in esophageal squamous cell carcinoma.
A retrospective study of 423 cases with newly diagnosed esophageal squamous cell carcinoma was conducted. We analyzed the association of the CRP/Alb ratio with clinicopathologic characteristics. The prognostic value was explored by univariate and multivariate survival analysis. In addition, we compared the discriminatory ability of the CRP/Alb ratio with other inflammation-based prognostic scores by evaluating the area under the receiver operating characteristics curves (AUC), including the modified Glasgow Prognostic Score (mGPS), neutrophil lymphocyte ratio (NLR) and platelet lymphocyte ratio (PLR).
The optimal cut-off value was identified to be 0.095 for the CRP/Alb ratio. A higher level of the CRP/Alb ratio was associated with larger tumor size (P < 0.001), poorer differentiation (P = 0.019), deeper tumor invasion (P = 0.003), more lymph node metastasis (P = 0.015), more distant metastasis (P < 0.001) and later TNM stage (P < 0.001). The CRP/Alb ratio was identified to be the only inflammation-based prognostic score with independent association with overall survival by multivariate analysis (P = 0.031). The AUC value of the CRP/Alb ratio was higher compared with the NLR and PLR, but not mGPS at 6, 12 and 24 months of follow-up. In addition, the CRP/Alb ratio could identify a group of patients with mGPS score of 0 who had comparable overall survival with those with mGPS score of 1.
The CRP/Alb ratio is a novel but promising inflammation-based prognostic score in esophageal squamous cell carcinoma. It is a valuable coadjutant for the mGPS to further identify patients’ survival differences.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-015-1379-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4423167  PMID: 25934640
Esophageal squamous cell carcinoma; C-reactive protein; Albumin; The modified Glasgow Prognostic Score; Inflammation-based prognostic score; Survival
2.  Role of capecitabine in treating metastatic colorectal cancer in Chinese patients 
OncoTargets and therapy  2014;7:501-511.
The China Food and Drug Administration approved the use of capecitabine in patients with metastatic colorectal cancer (mCRC) in 2004. This paper reviews the available information of capecitabine in Chinese patients with mCRC, focusing on its effectiveness and safety against mCRC. Identification of all eligible studies was made by searching the PubMed and Wanfang database from 2000 to 2013. Published data examining various aspects of clinical response and tolerability with capecitabine alone or in combination with other chemotherapeutic or biological agents for first- and second-line mCRC were examined. Capecitabine and its combination displayed high efficacy in Chinese patients with mCRC. Toxicities are generally manageable, and elderly patients can tolerate capecitabine well.
PMCID: PMC3979786  PMID: 24729715
capecitabine; metastatic colorectal cancer; Chinese
3.  Primary small cell carcinoma of the esophagus: clinicopathological study of 44 cases 
BMC Cancer  2014;14:222.
Primary small cell carcinoma of the esophagus (SCCE) is a highly aggressive disease characterized by early dissemination and poor prognosis. Because of the rarity of this disease, few previous studies have investigated the biomarkers associated with its prognosis. Leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5) is a stem cell marker and a member of the canonical Wnt-signaling cascade. However, the clinical role of Lgr5 in SCCE remains unknown.
Tissue sections were obtained from 44 patients diagnosed with SCCE and expression of Lgr5 was examined by immunohistochemistry. The correlations between Lgr5 expression, and clinical parameters and prognostic significance were evaluated.
Lgr5 was expressed in SCCE cancer tissues. High Lgr5 expression was significantly correlated with lymph node metastasis (p = 0.003), late stage (p = 0.003) and unfavorable response to chemotherapy (p = 0.013) according to RECIST 1.0 criteria. Patients with higher Lgr5 expression levels had shorter overall survival times than those with lower expression levels.
These results demonstrated that overexpression of Lgr5 was significantly correlated with lymph node metastasis, tumor stage, and response to chemotherapy. Furthermore, high levels of Lgr5 expression appeared to be associated with poorer survival in patients with SCCE.
PMCID: PMC3987173  PMID: 24666414
Small cell carcinoma; Esophagus; Prognosis; Lgr5
4.  S-1-Based Chemotherapy versus Capecitabine-Based Chemotherapy as First-Line Treatment for Advanced Gastric Carcinoma: A Meta-Analysis 
PLoS ONE  2013;8(12):e82798.
Although both oral fluoropyrimidines were reported effective and safe, doubts exist about whether S-1 or capecitabine is more advantageous in advanced gastric carcinoma (AGC). Herein, we performed a meta-analysis to comprehensively compare the efficacy and safety of S-1-based chemotherapy versus capecitabine-based chemotherapy as first-line treatment for AGC.
PubMed/Medline, EmBase, Cochrane library, and China National Knowledge Infrastructure databases were searched for articles comparing S-1-based chemotherapy to capecitabine-based chemotherapy for AGC. Primary outcomes were overall response rate (ORR), time to progression (TTP), overall survival (OS), progression-free probability, and survival probability. Secondary outcomes were toxicities. Fixed-effects model were used and all the results were confirmed by random-effects model.
Five randomized controlled trials and five cohort studies with 821 patients were included. We found equivalent ORR (38.3% vs. 39.1%, odds ratio [OR] 0.92, 95% confidence interval [CI] 0.69-1.24, P = 0.59), TTP (harzad ratio [HR] 0.98, 95% CI 0.82-1.16, P = 0.79), OS (HR 0.99, 95% CI 0.87-1.13, P = 0.91), progression-free probability (3-month OR 1.02, 95% CI 0.62-1.68, P = 0.94; 6-month OR 1.34, 95% CI 0.88-2.04, P = 0.18) and survival probability (0.5-year OR 0.90, 95% CI 0.61-1.31, P =0.57; 1-year OR 0.97, 95% CI 0.70- 1.33, P = 0.84; 2-year OR 1.15, 95% CI 0.61-2.17, P = 0.66). Equivalent grade 3 to 4 hematological and non-hematological toxicities were found except hand-foot syndrome was less prominent in S-1-based chemotherapy (0.3% vs. 5.9%, OR 0.19, 95% CI 0.06-0.56, P = 0.003). There’re no significant heterogeneity and publication bias. Cumulative analysis found stable time-dependent trend. Consistent results stratified by study design, age, regimen, cycle, country were observed.
S-1-based chemotherapy was associated with non-inferior antitumor efficacy and better safety profile, compared with capecitabine-based therapy. We recommended S-1 and capecitabine can be used interchangeably for AGC, at least in Asia.
PMCID: PMC3861463  PMID: 24349363
5.  Abnormal expression of paxillin correlates with tumor progression and poor survival in patients with gastric cancer 
Paxillin (PXN) has been found to be aberrantly regulated in various malignancies and involved in tumor growth and invasion. The clinicopathological and prognostic significance of PXN in gastric cancer is still unclear.
The expression of PXN was determined in paired gastric cancer tissues and adjacent normal tissues by Western blotting and real-time PCR. Immunohistochemistry was performed to detect the expression of PXN in 239 gastric cancer patients. Statistical analysis was applied to investigate the correlation between PXN expression and clinicopathological characteristics and prognosis in patients. Additionally, the effects of PXN on gastric cancer cell proliferation and migration were also evaluated.
PXN was up-regulated in gastric cancer tissues and cell lines as compared with adjacent normal tissues and normal gastric epithelial cell line GES-1. Overexpression of PXN was correlated with distant metastasis (P = 0.001) and advanced tumor stage (P = 0.021) in gastric cancer patients. Patients with high PXN expression tended to have poor prognosis compared with patients with low PXN expression (P < 0.001). Multivariate analysis demonstrated that PXN expression was an independent prognostic factor (P = 0.020). Moreover, ectopic expression of PXN promotes cell proliferation and migration in AGS cells whereas knockdown of PXN inhibits cell proliferation and migration in SGC7901 cells.
PXN plays an important role in tumor progression and may be used as a potential prognostic indicator in gastric cancer.
PMCID: PMC4228400  PMID: 24180516
Gastric cancer; Paxillin; Tumor progression; Prognosis
6.  The status of HBV infection influences metastatic pattern and survival in Chinese patients with pancreatic cancer 
It has been proved that hepatitis B virus (HBV) infection alters the metastatic pattern and affects survival in colorectal cancer (CRC) and hepatocellular carcinoma (HCC), while the influence of HBV infection on metastatic pattern and survival in patients with pancreatic cancer (PC) has not been investigated yet.
We conducted an investigation to evaluate the impact of HBV infection on metastatic pattern and overall survival in PC. We collected the data of 460 PC patients treated in our hospital from 1999 to 2010. Serum HBV markers were tested with enzyme-linked immunosorbent assay. The impact of HBV infection on metastatic pattern and overall survival was analyzed.
We found that the incidence of synchronous liver metastasis was significantly higher in patients with HBsAg positive than those with HBsAg negative (46.0% vs 32.0%, P < 0.05), and higher in chronic HBV infection (CHB) group than both non HBV infection and resolved HBV infection group (61.1% vs 33.9%, P < 0.05, and 61.1% vs 28.7%, P < 0.05, respectively). What’s more, Kaplan-Meier analysis showed that CHB, resolved HBV infection and non HBV infection group had significant longer overall survival (OS) compared with inactive HBsAg carriers (IC) group (P=0.037, P=0.009, and P=0.019 respectively). But, in the multivariate analysis, only the CHB and non HBV infection group had significant better overall survival compared with IC group (P=0.010 and P=0.018 respectively).
Our study found that HBV infection increased synchronous liver metastasis rate, and HBV infection status was an independent prognostic factor in PC patients.
PMCID: PMC3851713  PMID: 24099678
Hepatitis B virus; Pancreatic cancer; Liver metastasis; Survival
7.  Microbial mediation of biogeochemical cycles revealed by simulation of global changes with soil transplant and cropping 
The ISME Journal  2014;8(10):2045-2055.
Despite microbes' key roles in driving biogeochemical cycles, the mechanism of microbe-mediated feedbacks to global changes remains elusive. Recently, soil transplant has been successfully established as a proxy to simulate climate changes, as the current trend of global warming coherently causes range shifts toward higher latitudes. Four years after southward soil transplant over large transects in China, we found that microbial functional diversity was increased, in addition to concurrent changes in microbial biomass, soil nutrient content and functional processes involved in the nitrogen cycle. However, soil transplant effects could be overridden by maize cropping, which was attributed to a negative interaction. Strikingly, abundances of nitrogen and carbon cycle genes were increased by these field experiments simulating global change, coinciding with higher soil nitrification potential and carbon dioxide (CO2) efflux. Further investigation revealed strong correlations between carbon cycle genes and CO2 efflux in bare soil but not cropped soil, and between nitrogen cycle genes and nitrification. These findings suggest that changes of soil carbon and nitrogen cycles by soil transplant and cropping were predictable by measuring microbial functional potentials, contributing to a better mechanistic understanding of these soil functional processes and suggesting a potential to incorporate microbial communities in greenhouse gas emission modeling.
PMCID: PMC4184012  PMID: 24694714
climate change; soil transplant; microbial community; biogeochemical cycle; GeoChip
8.  Nutritional Risk Screening 2002 as a Predictor of Outcome During General Ward-Based Noninvasive Ventilation in Chronic Obstructive Pulmonary Disease with Respiratory Failure 
Noninvasive ventilation (NIV) may reduce the need for intubation and mortality associated with chronic obstructive pulmonary disease (COPD) with type II respiratory failure. Early and simple predictors of NIV outcome could improve clinical management. This study aimed to assess whether nutritional risk screening 2002 (NRS2002) is a useful outcome predictor in COPD patients with type II respiratory failure treated by noninvasive positive pressure ventilation (NIPPV).
This prospective observational study enrolled COPD patients with type II respiratory failure who accepted NIPPV. Patients were submitted to NRS2002 evaluation upon admission. Biochemical tests were performed the next day and blood gas analysis was carried out prior to NIPPV treatment and 4 hours thereafter. Patients were divided into NRS2002 score ≥3 and NRS2002 score <3 groups and NIV failure rates were compared between both groups.
Of the 233 patients, 71 (30.5%) were not successfully treated by NIPPV. The failure rate was significantly higher in the NRS2002 score ≥3 group (35.23%) in comparison with patients with NRS2002 score <3 (15.79%) (p<0.05). Multivariate analysis indicated that PaCO2 (OR 1.25, 95%CI 1.172–1.671, p<0.05) prior to NIPPV treatment and NRS2002 score ≥3 (OR 1.76, 95%CI 1.303–2.374, p<0.05) were independent predictive factors for NIPPV treatment failure.
NRS2002 score ≥3 and PaCO2 values at admission may predict unsuccessful NIPPV treatment of COPD patients with type II respiratory failure and help to adjust therapeutic strategies. NRS2002 is a noninvasive and simple method for predicting NIPPV treatment outcome.
PMCID: PMC4581684  PMID: 26386778
Biological Markers; Lung Diseases, Obstructive; Noninvasive Ventilation; Nutritional Status; Respiratory Insufficiency
9.  A New Bioactive Polylactide-based Composite with High Mechanical Strength 
A new bioresorbable polylactide/calcium phosphate composite with improved mechanical strengths and a more basic filler, tetracalcium phosphate (TTCP), was prepared by melt compounding. N-(2-aminoethyl)-3-aminoproplytrimethoxysilane (AEAPS) and pyromellitic dianhydride (PMDA) were used to improve the interfacial adhesion between TTCP and polylactide (PLA). While AEAPS improved the dispersion of TTCP in the matrix, PMDA might react with the terminal hydroxyl group of PLA and the amino group on the surface of AEAPS modified TTCP, which could further enhance the interfacial strength. The tensile strength was improved to 68.4 MPa for the PLA/TTCP-AEAPS composite from 51.5 MPa for the PLA/TTCP composite (20 wt% of TTCP). Dynamic mechanical analysis suggested that there was a 51 % improvement in storage modulus compared to that of PLA alone, when PMDA (0.2 wt% of PMDA) was incorporated into the PLA/TTCP-AEAPS composite (5 wt% of TTCP). Using this new bioresorbable PLA composite incorporated with a more basic filler for biomedical application, the inflammation and allergic effect resulted from the degraded acidic product are expected to be reduced.
PMCID: PMC4235798  PMID: 25419050
polylactide; tetracalcium phosphate; mechanical properties; composite
10.  TRB3 links insulin/IGF to tumour promotion by interacting with p62 and impeding autophagic/proteasomal degradations 
Nature Communications  2015;6:7951.
High insulin/IGF is a biologic link between diabetes and cancers, but the underlying molecular mechanism remains unclear. Here we report a previously unrecognized tumour-promoting mechanism for stress protein TRB3, which mediates a reciprocal antagonism between autophagic and proteasomal degradation systems and connects insulin/IGF to malignant promotion. We find that several human cancers express higher TRB3 and phosphorylated insulin receptor substrate 1, which correlates negatively with patient's prognosis. TRB3 depletion protects against tumour-promoting actions of insulin/IGF and attenuates tumour initiation, growth and metastasis in mice. TRB3 interacts with autophagic receptor p62 and hinders p62 binding to LC3 and ubiquitinated substrates, which causes p62 deposition and suppresses autophagic/proteasomal degradation. Several tumour-promoting factors accumulate in cancer cells to support tumour metabolism, proliferation, invasion and metastasis. Interrupting TRB3/p62 interaction produces potent antitumour efficacies against tumour growth and metastasis. Our study opens possibility of targeting this interaction as a potential novel strategy against cancers with diabetes.
High insulin/IGF is a biologic link between diabetes and cancer. Here, the authors show a tumour promoting mechanism for stress protein TRB3 which mediates a reciprocal antagonism between autophagic and proteasomal degradation systems and connects insulin/IGF to malignant promotion.
PMCID: PMC4557121  PMID: 26268733
11.  Next-Generation Sequencing and Novel Variant Determination in a Cohort of 92 Familial Exudative Vitreoretinopathy Patients 
Familial exudative vitreoretinopathy (FEVR) is a developmental disease that can cause visual impairment and retinal detachment at a young age. Four genes involved in the Wnt signaling pathway were previously linked to this disease: NDP, FDZ4, LRP5, and TSPAN12. Identification of novel disease-causing alleles allows for a deeper understanding of the disease, better molecular diagnosis, and improved treatment.
Sequencing libraries from 92 FEVR patients were generated using a custom capture panel to enrich for 163 known retinal disease-causing genes in humans. Samples were processed using next generation sequencing (NGS) techniques followed by data analysis to identify and classify single nucleotide variants and small insertions and deletions. Sanger validation and segregation testing were used to verify suspected variants.
Of the cohort of 92, 45 patients were potentially solved (48.9%). Solved cases resulted from the determination of 49 unique mutations, 41 of which are novel. Of the novel variants discovered, 13 were highly likely to cause FEVR due to the nature of these variants (frameshifting indels, splicing mutations, and nonsense variants types). To our knowledge, this is the largest study of a FEVR cohort using NGS.
We were able to determine probable disease-causing variants in a large number of FEVR patients, the majority of which were novel. Knowledge of these variants will help to further characterize and diagnose FEVR.
We were able to determine probable disease-causing variants in 45 of 92 FEVR patients, the majority of which were novel. To our knowledge, this is the largest study of a FEVR cohort using NGS. Knowledge of these variants will help to further characterize and diagnose FEVR.
PMCID: PMC4365990  PMID: 25711638
next-generation sequencing; FEVR; novel alleles; familial segregation
12.  Clinical Effect Analysis of Microscopic Surgery for Epiglottis Cysts with Coblation 
This study aims to explore the effects and advantages of coblation combined with microscopy to treat epiglottis cysts. Ninety patients with epiglottis cysts were randomly assigned to three groups: the first group: marsupialisation + electric coagulation group, n = 30; the second group: marsupialisation + coblation, n = 30; and the third group: marsupialisation + coblation + microsurgery, n = 30. To compare the cure rate, intraoperative bleeding volume, postoperative pain, operation time and postoperative complications were investigated among these three groups. The comparison among three procedures showed a significant difference for intraoperative bleeding volume, operation time and postoperative pain (P < 0.05), whereas no significant difference was observed for cure rate (P > 0.05). These three procedures are effective in treating epiglottis cysts. Microscopic surgery with coblation has the advantages of less bleeding, short procedure duration, less pain and few complications. Thus, microscopic surgery is worthy of clinical application.
PMCID: PMC4071429  PMID: 25032112
Epiglottis cysts; Coblation; Microsurgery; Surgery
13.  ABCF1 extrinsically regulates retinal pigment epithelial cell phagocytosis 
Molecular Biology of the Cell  2015;26(12):2311-2320.
Intracellular ABCF1 is identified and characterized as a new ligand to extrinsically stimulate retinal pigment epithelial cell phagocytosis. A new approach developed in this study is broadly applicable to many other phagocytes and will enable systematic elucidation of their ligands to broaden understanding of extrinsic regulation and cargo recognition.
Phagocytosis of shed photoreceptor outer segments (POSs) by retinal pigment epithelial (RPE) cells is critical to retinal homeostasis and shares many conserved signaling pathways with other phagocytes, including extrinsic regulations. Phagocytotic ligands are the key to cargo recognition, engulfment initiation, and activity regulation. In this study, we identified intracellular protein ATP-binding cassette subfamily F member 1 (ABCF1) as a novel RPE phagocytotic ligand by a new approach of functional screening. ABCF1 was independently verified to extrinsically promote phagocytosis of shed POSs by D407 RPE cells. This finding was further corroborated with primary RPE cells and RPE explants. Internalized POS vesicles were colocalized with a phagosome marker, suggesting that ABCF1-mediated engulfment is through a phagocytic pathway. ABCF1 was released from apoptotic cells and selectively bound to shed POS vesicles and apoptotic cells, possibly via externalized phosphatidylserine. ABCF1 is predominantly expressed in POSs and colocalized with the POS marker rhodopsin, providing geographical convenience for regulation of RPE phagocytosis. Collectively these results suggest that ABCF1 is released from and binds to shed POSs in an autocrine manner to facilitate RPE phagocytosis through a conserved pathway. Furthermore, the new approach is broadly applicable to many other phagocytes and will enable systematic elucidation of their ligands to understand extrinsic regulation and cargo recognition.
PMCID: PMC4462947  PMID: 25904329
14.  Comparison of bipolar hemiarthroplasty and total hip arthroplasty for displaced femoral neck fractures in the healthy elderly: a meta-analysis 
Displaced femoral neck fractures (FNFs) in healthy elderly patients have traditionally been managed with hemiarthroplasty (HA) or total hip arthroplasty (THA), with studies suggesting that THA may be the better option. However, it has recently been reported that bipolar HA (BHA) also provides good outcomes, and it is not clear as to whether BHA or THA is most appropriate. The purpose of this study was to conduct a meta-analysis of randomized controlled trials (RCTs) comparing the outcomes of BHA with THA for treating FNF in healthy elderly patients.
We searched the following databases from inception to May 2015 for relevant RCTs without language restrictions: PubMed, the Cochrane Central Register of Controlled Trials, Ovid MEDLINE and EMBASE, CINAHL, the China Biological Medicine Database, International Clinical Trials Registry Platform, Current Controlled Trials, and RCTs that met the inclusion criteria were statistically analyzed using the Cochrane review methods.
Eight RCTs were included (total 1,014 patients; 523 had BHA and 491 had THA). The data from included RCTs were divided into four subgroups according to different follow-up durations. The Harris Hip Score after BHA was not different from that after THA in all subgroups. Both reoperation rate and acetabular erosion rate were higher after BHA after more than 4 years, while there was a higher dislocation rate associated with THA within 4 years. THA was more favorable regarding the EQindex-5D and the mobility and pain rate, while BHA was more favorable regarding operating time. No significant differences were found regarding infection rate, general complications, 1-year mortality, blood loss, and length of postoperative hospital stay.
For healthy elderly patients with displaced FNFs, treatment with BHA led to better outcomes regarding dislocation rate, while THA was better regarding acetabular erosion rate and reoperation rate. When comparing BHA with THA, there were no significant differences in other important outcomes such as Harris Hip Score, infection rate, general complications, and 1-year mortality. Further high-quality RCTs are needed to provide robust evidence and evaluate the treatment options.
PMCID: PMC4552391  PMID: 26316274
15.  Small molecule PZL318: forming fluorescent nanoparticles capable of tracing their interactions with cancer cells and activated platelets, slowing tumor growth and inhibiting thrombosis 
Low selectivity of chemotherapy correlates with poor outcomes of cancer patients. To improve this issue, a novel agent, N-(1-[3-methoxycarbonyl-4-hydroxyphenyl]-β-carboline-3-carbonyl)-Trp-Lys-OBzl (PZL318), was reported here. The transmission electron microscopy, scanning electron microscopy, and atomic force microscopy images demonstrated that PZL318 can form nanoparticles. Fluorescent and confocal images visualized that PZL318 formed fluorescent nanoparticles capable of targeting cancer cells and tracing their interactions with cancer cells. In vitro, 40 μM of PZL318 inhibited the proliferation of tumorigenic cells, but not nontumorigenic cells. In vivo, 10 nmol/kg of PZL318 slowed the tumor growth of S180 mice and alleviated the thrombosis of ferric chloride-treated ICR mice, while 100 μmol/kg of PZL318 did not injure healthy mice and they exhibited no liver toxicity. By analyzing Fourier transform–mass spectrometry and rotating-frame Overhauser spectroscopy (ROESY) two-dimensional nuclear magnetic resonance spectra, the chemical mechanism of PZL318-forming trimers and nanoparticles was explored. By using mesoscale simulation, a nanoparticle of 3.01 nm in diameter was predicted containing 13 trimers. Scavenging free radicals, downregulating sP-selectin expression and intercalating toward DNA were correlated with the antitumor mechanism of PZL318.
PMCID: PMC4554418  PMID: 26345234
nanoparticles; cancer target; sP-selectin; nanomechanism; action mechanism; fluorescent tracer
16.  Discovery of Imigliptin, a Novel Selective DPP-4 Inhibitor for the Treatment of Type 2 Diabetes 
ACS Medicinal Chemistry Letters  2014;5(8):921-926.
We report our discovery of a novel series of potent and selective dipeptidyl peptidase IV (DPP-4) inhibitors. Starting from a lead identified by scaffold-hopping approach, our discovery and development efforts were focused on exploring structure–activity relationships, optimizing pharmacokinetic profile, improving in vitro and in vivo efficacy, and evaluating safety profile. The selected candidate, Imigliptin, is now undergoing clinical trial.
PMCID: PMC4137375  PMID: 25147615
Diabetes; dipeptidyl peptidase IV (DPP-4); inhibitor; scaffold-hopping; imigliptin; OGTT; pyridinylimidazolone
17.  Association of the Apolipoprotein E polymorphism with migraine: a meta-analysis 
BMC Neurology  2015;15:138.
Apolipoprotein E (ApoE) gene has been reported to be associated with migraine and tension-type headache (TTH), but the results are conflicting. This study aimed to evaluate the association of ApoE with migraine by a meta-analysis.
MEDLINE, ISI Web of Knowledge, The Cochrane Central Register of Controlled Trials, and EMBASE databases were searched to identify eligible studies published in English from 2000 to 2014. Data were extracted using standardized forms. The association was assessed by relative risk (RR) with 95 % confidence intervals (CIs) using a fixed or random effects model.
Four studies, comprising 649 migraineurs, 229 TTH subjects and 975 controls, met all the criteria and were included in the meta-analysis. No significant difference was found comparing genotypic and allelic frequencies in the case of migraineurs versus controls and TTH subjects versus controls. Only when migraineurs and TTH subjects were considered as a whole group, ApoE4 was found to increase the relative risk of headache by 1.48 (95 % CI 1.16, 1.90; P = 0.002), compared to controls.
ApoE ε4 allele is not associated with migraine susceptibility, but is positively related to headache (including migraine and TTH).
PMCID: PMC4534059  PMID: 26264634
18.  Esophagojejunostomy after laparoscopic total gastrectomy by OrVilTM or hemi-double stapling technique 
AIM: To investigate the feasibility, advantages and disadvantages of two types of anvil insertion techniques for esophagojejunostomy after laparoscopic total gastrectomy.
METHODS: This was an open-label prospective cohort study. Laparoscopy-assisted radical total gastrectomy with D2 lymph node dissection was performed in 84 patients with primary non-metastatic gastric cancer confirmed by pre-operative histological examination. Overweight patients were excluded, as well as patients with peritoneal dissemination and invasion of adjacent organs. After total gastrectomy, all patients were randomized into two groups. Patients in Group I underwent esophagojejunostomy using a transorally-inserted anvil (OrVilTM), while patients in Group II underwent esophagojejunostomy using the hemi-double stapling technique (HDST). Both types of esophagojejunostomy were performed under laparoscopy. Patients’ baseline characteristics, preoperative characteristics, perioperative characteristics, short-term postoperative outcomes and operation cost were compared between the two groups. The primary endpoint was evaluation of the surgical outcome (operating time, time of digestive tract reconstruction and time of anvil insertion) and the medical cost of each operation (operation cost and total cost of hospitalization). The secondary endpoints were time to solid diet, post-surgical hospitalization time, time to defecation, time to ambulation and intra-operative blood loss. In addition, complications were assessed and compared.
RESULTS: Laparoscopic total gastrectomy and esophagojejunostomy were successfully performed in all 84 patients, without conversion to laparotomy. There were no significant differences in the operative time and time for total gastrectomy between the two groups (287.8 ± 38.4 min vs 271.8 ± 46.1 min, P = 0.09, and 147.7 ± 31.6 min vs 159.8 ± 33.8 min, P = 0.09, respectively). The time for digestive tract reconstruction and for anvil insertion were significantly decreased in Group II compared with Group I (47.8 ± 12.1 min vs 55.4 ± 15.7 min, P = 0.01, and 12.6 ± 4.7 min vs 18.7 ± 7.5 min, P = 0.001, respectively). Intra-operative blood loss (96.4 ± 32.7 mL vs 88.2 ± 36.9 mL, P = 0.28), time to defecation (3.5 ± 0.9 d vs 3.2 ± 1.1 d, P = 0.12), time to ambulation (3.9 ± 0.7 d vs 3.6 ± 1.1 d, P = 0.12), time to solid diet (7.6 ± 1.4 d vs 8.0 ± 2.7 d, P = 0.31) and total hospitalization (10.6 ± 2.6 d vs 10.8 ± 3.5 d, P = 0.80) were similar between the two groups. In addition, the total costs of hospitalization were similar between the two groups (73848.7 ± 11781.0 RMB vs 70870.3 ± 14003.5 RMB, P = 0.296), but operation cost was significantly higher in Group I compared with Group II (32401.9 ± 1981.6 RMB vs 26961.9 ± 2293.8 RMB, P < 0.001).
CONCLUSION: Anvil insertion was faster and easier using the HDST technique compared with OrVilTM, and was more cost-effective. There was no significant difference in safety.
PMCID: PMC4528038  PMID: 26269685
Laparoscopy; Gastrectomy; Gastric cancer; Esophagojejunostomy; Cohort analysis
19.  Next-generation sequencing-based molecular diagnosis of 82 retinitis pigmentosa probands from Northern Ireland 
Human genetics  2014;134(2):217-230.
Retinitis pigmentosa (RP) is a group of inherited retinal disorders characterized by progressive photoreceptor degeneration. An accurate molecular diagnosis is essential for disease characterization and clinical prognoses. A retinal capture panel that enriches 186 known retinal disease genes, including 55 known RP genes, was developed. Targeted next-generation sequencing was performed for a cohort of 82 unrelated RP cases from Northern Ireland, including 46 simplex cases and 36 familial cases. Disease-causing mutations were identified in 49 probands, including 28 simplex cases and 21 familial cases, achieving a solving rate of 60 %. In total, 65 pathogenic mutations were found, and 29 of these were novel. Interestingly, the molecular information of 12 probands was neither consistent with their initial inheritance pattern nor clinical diagnosis. Further clinical reassessment resulted in a refinement of the clinical diagnosis in 11 patients. This is the first study to apply next-generation sequencing-based, comprehensive molecular diagnoses to a large number of RP probands from Northern Ireland. Our study shows that molecular information can aid clinical diagnosis, potentially changing treatment options, current family counseling and management.
PMCID: PMC4347882  PMID: 25472526
20.  Bmp2 Deletion Causes an Amelogenesis Imperfecta Phenotype Via Regulating Enamel Gene Expression 
Journal of cellular physiology  2015;230(8):1871-1882.
Although Bmp2 is essential for tooth formation, the role of Bmp2 during enamel formation remains unknown in vivo. In this study, the role of Bmp2 in regulation of enamel formation was investigated by the Bmp2 conditional knock out (Bmp2 cKO) mice. Teeth of Bmp2 cKO mice displayed severe and profound phenotypes with asymmetric and misshaped incisors as well as abrasion of incisors and molars. Scanning electron microscopy analysis showed that the enamel layer was hypoplastic and enamel lacked a typical prismatic pattern. Teeth from null mice were much more brittle as tested by shear and compressive moduli. Expression of enamel matrix protein genes, amelogenin, enamelin, and enamel-processing proteases, Mmp-20 and Klk4 was reduced in the Bmp2 cKO teeth as reflected in a reduced enamel formation. Exogenous Bmp2 up-regulated those gene expressions in mouse enamel organ epithelial cells. This result for the first time indicates Bmp2 signaling is essential for proper enamel development and mineralization in vivo.
PMCID: PMC4469356  PMID: 25545831
21.  Enhanced Sensitive Immunoassay: Noncompetitive Phage Anti-Immune Complex Assay for the Determination of Malachite Green and Leucomalachite Green 
To develop a more sensitive immunoassay for malachite green (MG) and leucomalachite green (LMG), we identified the immunocomplex binding phage-borne peptides for use in the noncompetitive phage anti-immunocomplex assay (PHAIA). An anti-LMG monoclonal antibody (mAb) was used to select immunocomplex binding peptides from a circular random eight-amino-acid phage-displayed library. After three rounds of panning-elution, five peptides that bound the LMG–mAb immunocomplex were obtained. One of the phage-borne peptide clones that resulted in an assay with the highest sensitivity was chosen for further research. The concentration of LMG producing 50% of the saturated signal and the limit of detection of the assay were 7.02 and 0.55 ng/mL, respectively, with a linear range of 1.35 to 21.56 ng/mL. The PHAIA based on the same antibody was 16 times more sensitive compared to the competitive immunoassay. PHAIA was used to analyze LMG, MG, and two mixtures of spiked fish samples, with validation by high-performance liquid chromatography (HPLC) with fluorescence detector. Results showed a good correlation (R2LMG = 0.9841; R2MG = 0.993; R2Mixture = 0.9903) between the data of PHAIA and HPLC, thus the assay was an efficient method for monitoring food safety.
PMCID: PMC4150606  PMID: 25077381
malachite green; leucomalachite Green; phage anti-immunocomplex assay
22.  FGF21 protects against ox-LDL induced apoptosis through suppressing CHOP expression in THP1 macrophage derived foam cells 
FGF21,as a member of the fibroblast growth factor superfamily, is an important endogenous regulator to systemic glucose and lipid metabolism. Elevated serum FGF21 levels have been reported in subjects with coronary heart disease and carotid artery plaques. The formation and apoptosis of foam cell, induced by ox-LDL and oxysterols, are key steps in the development of atherosclerosis.
In this study, THP1 derived macrophages were induced into foam cells by ox-LDL or sterols. The formation and apoptosis of foam cells treated with or without FGF21 were analyzed.
We demonstrated that the accumulation of cholesterol was decreased after FGF21 treatment in THP1 macrophage derived foam cells. Consistently, the apoptosis of macrophage was alleviated dramatically with FGF21 treatment. ERK1/2 knockdown didn’t abrogate the effect of FGF21 on THP1 macrophage derived foam cells. However, FGF21 suppressed the induced expression of CHOP and DR5 in THP1 macrophage derived foam cells.
FGF21 protects against the formation and apoptosis of THP1 macrophages derived foam cells through suppressing the expression of CHOP.
PMCID: PMC4518604
Macrophage; ER stress; FGF21; Foam cell; CHOP
23.  Morphological Characteristics, Anatomical Structure, and Gene Expression: Novel Insights into Cytokinin Accumulation during Carrot Growth and Development 
PLoS ONE  2015;10(7):e0134166.
Cytokinins have been implicated in normal plant growth and development. These bioactive molecules are essential for cell production and expansion in higher plants. Carrot is an Apiaceae vegetable with great value and undergoes significant size changes over the process of plant growth. However, cytokinin accumulation and its potential roles in carrot growth have not been elucidated. To address this problem, carrot plants at five stages were collected, and morphological and anatomical characteristics and expression profiles of cytokinin-related genes were determined. During carrot growth and development, cytokinin levels were the highest at the second stage in the roots, whereas relatively stable levels were observed in the petioles and leaves. DcCYP735A2 showed high expression at stage 2 in the roots, which may contribute largely to the higher cytokinin level at this stage. However, expression of most metabolic genes did not follow a pattern similar to that of cytokinin accumulation, indicating that cytokinin biosynthesis was regulated through a complex network. Genes involved in cytokinin signal perception and transduction were also integrated to normal plant growth and development. The results from the present work suggested that cytokinins may regulate plant growth in a stage-dependent manner. Our work would shed novel insights into cytokinin accumulation and its potential roles during carrot growth. Further studies regarding carrot cytokinins may be achieved by modification of the genes involved in cytokinin biosynthesis, inactivation, and perception.
PMCID: PMC4517795  PMID: 26218147
24.  Rational Design of CXCR4 Specific Antibodies with Elongated CDRs 
Journal of the American Chemical Society  2014;136(30):10557-10560.
The bovine antibody (BLV1H12) which has an ultralong heavy chain complementarity determining region 3 (CDRH3) provides a novel scaffold for antibody engineering. By substituting the extended CDRH3 of BLV1H12 with modified CXCR4 binding peptides that adopt a β-hairpin conformation, we generated antibodies specifically targeting the ligand binding pocket of CXCR4 receptor. These engineered antibodies selectively bind to CXCR4 expressing cells with binding affinities in the low nanomolar range. In addition, they inhibit SDF-1-dependent signal transduction and cell migration in a transwell assay. Finally, we also demonstrate that a similar strategy can be applied to other CDRs and show that a CDRH2-peptide fusion binds CXCR4 with a Kd of 0.9 nM. This work illustrates the versatility of scaffold-based antibody engineering and could greatly expand the antibody functional repertoire in the future.
PMCID: PMC4120998  PMID: 25041362
25.  Neurod1 Modulates Opioid Antinociceptive Tolerance via Two Distinct Mechanisms 
Biological psychiatry  2014;76(10):775-784.
The activity of neurogenic differentiation 1 (Neurod1) decreases after morphine administration, which leads to impairments of the stability of dendritic spines in primary hippocampal neurons, adult neurogenesis in mouse hippocampi, and drug-associated contextual memory. The current study examined whether Neurod1 could affect the development of opioid tolerance.
Lentivirus encoding Neurod1, microRNA-190 (miR-190), or short hairpin RNA against Neurod1 was injected into mouse hippocampi separately or combined (more than eight mice for each treatment) to modulate Neurod1 activity. The antinociceptive median effective dose values of morphine and fentanyl were determined with tail-flick assay and used to calculate development of tolerance. Contextual learning and memory were assayed using the Morris water maze.
Decrease in NeuroD1 activity increased the initial antinociceptive median effective dose values of both morphine and fentanyl, which was reversed by restoring NeuroD1 activity. In contrast, decrease in NeuroD1 activity inhibited development of tolerance in a time-dependent manner, paralleling its effects on the acquisition and extinction of contextual memory. In addition, only development of tolerance, but not antinociceptive median effective dose values, was modulated by the expression of miR-190 and Neurod1 driven by Nestin promoter.
Neurod1 regulates the developments of opioid tolerance via a time-dependent pathway through contextual learning and a short-response pathway through antinociception.
PMCID: PMC4503258  PMID: 24993058
Analgesia; learning; Neurod1; opioid; tolerance; water maze

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