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1.  Relationship between UGT1A1*6/*28 polymorphisms and severe toxicities in Chinese patients with pancreatic or biliary tract cancer treated with irinotecan-containing regimens 
The aim of this retrospective study was to investigate the relationship between UGT1A1 polymorphisms and toxicities in Chinese patients with pancreatic or biliary tract cancer receiving irinotecan-containing regimens as the second- or third-line chemotherapy.
Patients and methods
A total of 36 patients with unresectable pancreatic cancer and 12 patients with unresectable biliary tract cancer were included. Approximately 33 patients were treated with FOLFIRI regimen, a chemotherapy regimen, where FOL stands for folinic acid, F for fluorouracil, and IRI for irinotecan (irinotecan 180 mg/m2 at day 1, CF 200 mg/m2 at day 1–2, 5-FU 400 mg/m2 at day 1–2, followed by continuous infusion of 5-FU 600 mg/m2 for 22 hours at day 1–2, every 2 weeks). The other 15 patients were treated with irinotecan monotherapy (180 mg/m2, every 2 weeks). UGT1A1*6/*28 polymorphisms were detected by direct sequencing.
The frequencies of GG, GA, AA genotypes for UGT1A1*6 were 70.8% (n=34), 25.0% (n=12), and 4.2% (n=2), respectively. And those of TA6/TA6, TA6/TA7, TA7/TA7 for UGT1A1*28 were 79.2% (n=38), 18.8% (n=9), and 2.0% (n=1), respectively. A total of 22 patients (45.8%) had grade III–IV neutropenia, and six patients (12.5%) experienced grade III–IV diarrhea. The incidence of grade III–IV neutropenia in patients with UGT1A1*6 GA or AA genotype was 71.4%, which was significantly higher than that with GG genotype (35.3%, P=0.022). No relationship was found between grade III–IV neutropenia and UGT1A1*28 polymorphism. The statistical analysis between grade III–IV diarrhea and UGT1A1*6/*28 polymorphisms was not conducted in view of the limited number of patients.
In Chinese patients with pancreatic or biliary tract cancer administered irinotecan-containing regimens, those with UGT1A1*6 variant may have a high risk of severe neutropenia.
PMCID: PMC4514347
UGT1A1 polymorphism; irinotecan; pancreatic cancer; biliary tract cancer; neutropenia; diarrhea
2.  Clinical Impact of Speed Variability to Identify Ultramarathon Runners at Risk for Acute Kidney Injury 
PLoS ONE  2015;10(7):e0133146.
Ultramarathon is a high endurance exercise associated with a wide range of exercise-related problems, such as acute kidney injury (AKI). Early recognition of individuals at risk of AKI during ultramarathon event is critical for implementing preventative strategies.
To investigate the impact of speed variability to identify the exercise-related acute kidney injury anticipatively in ultramarathon event.
This is a prospective, observational study using data from a 100 km ultramarathon in Taipei, Taiwan. The distance of entire ultramarathon race was divided into 10 splits. The mean and variability of speed, which was determined by the coefficient of variation (CV) in each 10 km-split (25 laps of 400 m oval track) were calculated for enrolled runners. Baseline characteristics and biochemical data were collected completely 1 week before, immediately post-race, and one day after race. The main outcome was the development of AKI, defined as Stage II or III according to the Acute Kidney Injury Network (AKIN) criteria. Multivariate analysis was performed to determine the independent association between variables and AKI development.
26 ultramarathon runners were analyzed in the study. The overall incidence of AKI (in all Stages) was 84.6% (22 in 26 runners). Among these 22 runners, 18 runners were determined as Stage I, 4 runners (15.4%) were determined as Stage II, and none was in Stage III. The covariates of BMI (25.22 ± 2.02 vs. 22.55 ± 1.96, p = 0.02), uric acid (6.88 ± 1.47 vs. 5.62 ± 0.86, p = 0.024), and CV of speed in specific 10-km splits (from secondary 10 km-split (10th – 20th km-split) to 60th – 70th km-split) were significantly different between runners with or without AKI (Stage II) in univariate analysis and showed discrimination ability in ROC curve. In the following multivariate analysis, only CV of speed in 40th – 50th km-split continued to show a significant association to the development of AKI (Stage II) (p = 0.032).
The development of exercise-related AKI was not infrequent in the ultramarathon runners. Because not all runners can routinely receive laboratory studies after race, variability of running speed (CV of speed) may offer a timely and efficient tool to identify AKI early during the competition, and used as a surrogate screening tool, at-risk runners can be identified and enrolled into prevention trials, such as adequate fluid management and avoidance of further NSAID use.
PMCID: PMC4503592  PMID: 26176768
3.  Current systemic treatment of hepatocellular carcinoma: A review of the literature 
World Journal of Hepatology  2015;7(10):1412-1420.
Hepatocellular carcinoma (HCC) is the fifth most common form of human cancer worldwide and the third most common cause of cancer-related deaths. The strategies of various treatments for HCC depend on the stage of tumor, the status of patient’s performance and the reserved hepatic function. The Barcelona Clinic Liver Cancer (BCLC) staging system is currently used most for patients with HCC. For example, for patients with BCLC stage 0 (very early stage) and stage A (early stage) HCC, the curable treatment modalities, including resection, transplantation and radiofrequency ablation, are taken into consideration. If the patients are in BCLC stage B (intermediate stage) and stage C (advanced stage) HCC, they may need the palliative transarterial chemoembolization and even the target medication of sorafenib. In addition, symptomatic treatment is always recommended for patients with BCLC stage D (end stage) HCC. In this review, we will attempt to summarize the historical perspective and the current developments of systemic therapies in BCLC stage B and C in HCC.
PMCID: PMC4450204  PMID: 26052386
Hepatocellular carcinoma; Transarterial chemoembolization; Sorafenib; Systemic treatment; Molecular target therapy
4.  Consumption of hot beverages and foods and the risk of esophageal cancer: a meta-analysis of observational studies 
BMC Cancer  2015;15:449.
Previous studies have mostly focused on the effects of specific constituents of beverages and foods on the risk of esophageal cancer (EC). An increasing number of studies are now emerging examining the health consequences of the high temperature of beverages and foods. We conducted a meta-analysis to summarize the evidence and clarify the association between hot beverages and foods consumption and EC risk.
We searched the PubMed, Embase, and Web of Science databases for relevant studies, published before May 1, 2014, with the aim to estimate the association between hot beverage and food consumption and EC risk. A random-effect model was used to pool the results from the included studies. Publication bias was assessed by using the Begg test, the Egger test, and funnel plot.
Thirty-nine studies satisfied the inclusion criteria, giving a total of 42,475 non-overlapping participants and 13,811 EC cases. Hot beverage and food consumption was significantly associated with EC risk, with an odds ratio (OR) of 1.82 (95% confidence interval [CI], 1.53–2.17). The risk was higher for esophageal squamous cell carcinoma, with a pooled OR of 1.60 (95% CI, 1.29–2.00), and was insignificant for esophageal adenocarcinoma (OR: 0.79; 95% CI: 0.53–1.16). Subgroup analyses suggests that the association between hot beverage and food consumption and EC risk were significant in Asian population (OR: 2.06; 95% CI: 1.62-2.61) and South American population (OR: 1.52; 95% CI: 1.25-1.85), but not significant in European population (OR: 0.95; 95% CI: 0.68-1.34).
Hot beverage and food consumption is associated with a significantly increased risk of EC, especially in Asian and South American populations, indicating the importance in changing people’s dietary habits to prevent EC.
PMCID: PMC4457273  PMID: 26031666
Hot; Beverage; Food; Esophageal cancer; Meta-analysis
5.  Comparative genomics reveals diversified CRISPR-Cas systems of globally distributed Microcystis aeruginosa, a freshwater bloom-forming cyanobacterium 
Microcystis aeruginosa is one of the most common and dominant bloom-forming cyanobacteria in freshwater lakes around the world. Microcystis cells can produce toxic secondary metabolites, such as microcystins, which are harmful to human health. Two M. aeruginosa strains were isolated from two highly eutrophic lakes in China and their genomes were sequenced. Comparative genomic analysis was performed with the 12 other available M. aeruginosa genomes and closely related unicellular cyanobacterium. Each genome of M. aeruginosa containing at least one clustered regularly interspaced short palindromic repeat (CRISPR) locus and total 71 loci were identified, suggesting it is ubiquitous in M. aeruginosa genomes. In addition to the previously reported subtype I-D cas gene sets, three CAS subtypes I-A, III-A and III-B were identified and characterized in this study. Seven types of CRISPR direct repeat have close association with CAS subtype, confirming that different and specific secondary structures of CRISPR repeats are important for the recognition, binding and process of corresponding cas gene sets. Homology search of the CRISPR spacer sequences provides a history of not only resistance to bacteriophages and plasmids known to be associated with M. aeruginosa, but also the ability to target much more exogenous genetic material in the natural environment. These adaptive and heritable defense mechanisms play a vital role in keeping genomic stability and self-maintenance by restriction of horizontal gene transfer. Maintaining genomic stability and modulating genomic plasticity are both important evolutionary strategies for M. aeruginosa in adaptation and survival in various habitats.
PMCID: PMC4428289  PMID: 26029174
comparative genomics; Microcystis aeruginosa; CRISPR-Cas system; harmful algal blooms; freshwater cyanobacterium
6.  Clinical efficacy of administering oxaliplatin combined with S-1 in the treatment of advanced triple-negative breast cancer 
Triple-negative breast cancer (TNBC) is not amenable to current targeted therapies and carries a poor prognosis; however, a specific systemic regimen cannot yet be recommended. The optimal duration of oxaliplatin (OXA) and S-1 combinatorial chemotherapy in patients with advanced breast cancer is not currently known and is likely to be patient-specific based on efficacy and toxicity. In the present study, 52 patients with advanced TNBC received OXA and S-1 chemotherapy. The efficacy and toxicity were observed. The results showed that the median number of regimens was 4 (range 2–6). The therapeutic efficacy was evaluated in all patients. The complete response, partial response, overall response and disease control rates were 3.8, 30.8, 34.6 and 69.2%, respectively. Four patients were lost to follow-up, and the median follow-up time was 13.7 months. The median progression-free survival time was 6.7 months [95% confidence interval (CI), 4.5–9.0] and the median overall survival (OS) time was 13.3 months (95% CI, 9.1–17.5). From the subgroup analysis, it was found that the median OS time of patients with stage IV disease and ≥2 metastases was significantly shorter than that of patients with stage IIIC disease and only 1 metastasis [11.3 vs. 22.7 months, P=0.010 (stage IV vs. stage IIC); 11.3 vs. 15.7 months, P=0.048 (≥2 vs. 1 metastasis)]. The main grade 3/4 toxic effects were neutropenia (11.5%), nausea (7.7%) and nerve toxicity (3.8%). The other toxic effects were mainly of grades 1–2 and included diarrhea, liver dysfunction, stomatitis, anemia and hand-foot syndrome. In conclusion, OXA combined with S-1 is an effective and tolerable regimen for the treatment of patients with advanced TNBC.
PMCID: PMC4487007  PMID: 26170966
oxaliplatin; S-1; advanced triple-negative breast cancer; chemotherapy
7.  Phaeodactylum tricornutum photorespiration takes part in glycerol metabolism and is important for nitrogen-limited response 
Microalgae are potential sources of biofuels and high-value compounds. Mixotrophic conditions usually promote growth of microalgae. The pennate diatom Phaeodactylum tricornutum, with its short life cycle, completely sequenced genome, and ease of transformation, can be used as a model for studying carbon metabolism in microalgae.
We compared the growth rate of P. tricornutum (IOCAS-001) under different conditions and labeled the cells using [13C]glycerol (GL). The results revealed GL promoted the growth of P. tricornutum. Ser and Gly were synthesized via photorespiration. The 13C enrichment of Ser and Gly under nitrogen-limited conditions was much higher compared to other amino acids, indicating the enhancement of photorespiration. Addition of sodium acetate decreased the growth rate of P. tricornutum under nitrogen-limited conditions. Our results indicated that the GL carbon backbone enters the Calvin cycle in the form of dihydroxyacetone phosphate (DHAP), producing xylulose 5-phosphate (X5P) with a GL2_3-generated carbon backbone distributed at X5P1_2 and ribose 5-phosphate (R5P) with GL1-derived carbon atoms at R5P1 and R5P2. Both R5P and X5P can be converted into ribulose-1,5-bisphosphate (RuBP). By oxygenation of RuBP carboxylase/oxygenase (Rubisco) and metabolism through photorespiration, these RuBPs generate Ser and Gly with GL1 or GL2-derived carbon atoms at position 1 and GL1 or GL3-derived carbon atoms at other positions, resulting in a low level of 13C enrichment of Gly1 and Ser1.
Our results indicated different strains of P. tricornutum have different mechanisms for organic carbon metabolism. Photorespiration is involved in GL metabolism and is important for the nitrogen-limited response in P. tricornutum.
Metabolic flux analysis, microalgae
Electronic supplementary material
The online version of this article (doi:10.1186/s13068-015-0256-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4424561  PMID: 25960767
Phaeodactylum tricornutum; Photorespiration; Glycerol metabolism; Nitrogen-limited response
8.  IL-12/Th1 and IL-23/Th17 Biliary Microenvironment in Primary Biliary Cirrhosis: Implications for Therapy 
Hepatology (Baltimore, Md.)  2014;59(5):1944-1953.
The interleukin (IL)-12/IL-23 mediated Th1/Th17 signaling pathway has been associated with the etiopathogenesis of primary biliary cirrhosis (PBC). To address the cytokine microenvironment specifically in the liver, we examined the localized expression of cytokine subunits and their corresponding receptors using previously optimized immunohistochemistry with an extensive panel of antibodies directed at IL-12p70, IL-12p35, IFN-γ, IL-12RB2, IL-23p40, IL-23p19, IL-17 and IL-23R using liver from PBC (n=51) and non-PBC (n=80) control liver disease patients. Multiple portal tracts in each patient were blindly evaluated and individually scored. We report herein that although IL-12/Th1 and IL-23/Th17 staining were detected in all of the liver sections, they were primarily localized around the damaged interlobular bile ducts in PBC. Most importantly, Th17 skewing was prominent in advanced PBC patients with intensive secretion of IL-23p19 by inflamed hepatocytes around IL-23R, IL-12RB2, and IFN-γ expressing degenerated cholangiocytes. Our novel finding on the direct association of Th17 skewing and disease severity illustrates the significance of the IL-23/Th17 pathway in the perpetuation of IL-12/Th1-mediated immunopathology in PBC. Furthermore, localized IL-23p19 production by hepatocytes may enhance pro-fibrotic Th17 signaling and pro-inflammatory IFN-γ production that contribute to PBC pathology. In conclusion, our data emphasize the pathogenic relevance of IL-12/Th1 and IL-23/Th17 in the evolution of PBC. Of significance, however, the shift from a Th1 to a Th17 imbalance at advanced stages of the disease suggests the necessity to consider modulation of the IL-23/Th17 pathway as a potential target for therapeutic intervention.
PMCID: PMC3999171  PMID: 24375552
immunohistochemistry; Th1; IL-12; Th17; IL-23; primary biliary cirrhosis
We report that PGE2 promotes Smad2-Smad4 complex formation and this phenomenon could be blocked by DIDS, an anion transporter inhibitor. Our data suggest that PGE2 had no effects on Smad2 phosphorylation, suggesting that PGE2-mediated Smad2-Smad4 complex formation is independent of TGF-β signaling and that PGE2 induced Smad2 modification which is different from TGF-β-mediated phosphorylation. We demonstrate that in primary human glomerular mesangial cells PGE2 caused modification of Smad2 as detected by Smad2N antibody, raised against a peptide near the N-terminus of Smad2. We hypothesize that Smad2 protein is post-translationaly modified by PGE2. Direct evidence of Smad2 modification by PGE2 was achieved by avidin pulldown assay which showed that endogenous Smad2 and recombinant Smad2 protein were attached by biotin-labeled PGE2. Taken together, our results provided evidence that post-translational modification of Smad2 could be a mechanism for the action of PGE2 in the pathogenesis of human pathologies.
PMCID: PMC4036222  PMID: 24613014
10.  Redox-Responsive Repressor Rex Modulates Alcohol Production and Oxidative Stress Tolerance in Clostridium acetobutylicum 
Journal of Bacteriology  2014;196(22):3949-3963.
Rex, a transcriptional repressor that modulates its DNA-binding activity in response to NADH/NAD+ ratio, has recently been found to play a role in the solventogenic shift of Clostridium acetobutylicum. Here, we combined a comparative genomic reconstruction of Rex regulons in 11 diverse clostridial species with detailed experimental characterization of Rex-mediated regulation in C. acetobutylicum. The reconstructed Rex regulons in clostridia included the genes involved in fermentation, hydrogen production, the tricarboxylic acid cycle, NAD biosynthesis, nitrate and sulfite reduction, and CO2/CO fixation. The predicted Rex-binding sites in the genomes of Clostridium spp. were verified by in vitro binding assays with purified Rex protein. Novel members of the C. acetobutylicum Rex regulon were identified and experimentally validated by comparing the transcript levels between the wild-type and rex-inactivated mutant strains. Furthermore, the effects of exposure to methyl viologen or H2O2 on intracellular NADH and NAD+ concentrations, expression of Rex regulon genes, and physiology of the wild type and rex-inactivated mutant were comparatively analyzed. Our results indicate that Rex responds to NADH/NAD+ ratio in vivo to regulate gene expression and modulates fermentation product formation and oxidative stress tolerance in C. acetobutylicum. It is suggested that Rex plays an important role in maintaining NADH/NAD+ homeostasis in clostridia.
PMCID: PMC4248821  PMID: 25182496
11.  IL28B Is Associated with Outcomes of Chronic HBV Infection 
Yonsei Medical Journal  2015;56(3):625-633.
The role of IL28B gene variants and expression in hepatitis B virus (HBV) infections are not well understood. Here, we evaluated whether IL28B gene expression and rs12979860 variations are associated with HBV outcomes.
Materials and Methods
IL28B genetic variations (rs12979860) were genotyped by pyrosequencing of DNA samples from 137 individuals with chronic HBV infection [50 inactive carriers (IC), 34 chronic hepatitis B (CHB), 27 cirrhosis, 26 hepatocellular carcinoma (HCC)], and 19 healthy controls. IL28A/B mRNA expression in peripheral blood mononuclear cells was determined by qRT-PCR, and serum IL28B protein was measured by ELISA.
Patients with IL28B C/C genotype had greater IL28A/B mRNA expression and higher IL28B protein levels than C/T patients. Within the various disease stages, compared to IC and healthy controls, IL28B expression was reduced in the CHB, cirrhosis, and HCC cohorts (CHB vs. IC, p=0.02; cirrhosis vs. IC, p=0.01; HCC vs. IC, p=0.001; CHB vs. controls, p<0.01; cirrhosis vs. controls, p<0.01; HCC vs. controls, p<0.01). When stratified with respect to serum HBV markers in the IC and CHB cohorts, IL28B mRNA and protein levels were higher in HBeAg-positive than negative individuals (p=0.01). Logistic regression analysis revealed that factors associated with high IL28B protein levels were C/C versus C/T genotype [p=0.016, odds ratio (OR)=0.25, 95% confidence interval (CI)=0.08-0.78], high alanine aminotransferase values (p<0.001, OR=8.02, 95% CI=2.64-24.4), and the IC stage of HBV infection (p<0.001).
Our data suggest that IL28B genetic variations may play an important role in long-term development of disease in chronic HBV infections.
PMCID: PMC4397430  PMID: 25837166
Hepatitis B virus; interleukin 28B; cirrhosis; hepatocellular carcinoma; genetic variation
12.  Dystrophin hydrophobic regions in the pathogenesis of Duchenne and Becker muscular dystrophies 
The aim of our study was to determine the role of dystrophin hydrophobic regions in the pathogenesis of Duchenne (DMD) and Becker (BMD) muscular dystrophies, by the Kyte-Doolittle scale mean hydrophobicity profile and 3D molecular models. A total of 1038 cases diagnosed with DMD or BMD with the in-frame mutation were collected in our hospital and the Leiden DMD information database in the period 2002-2013. Correlation between clinical types and genotypes were determined on the basis of these two sources. In addition, the Kyte-Doolittle scale mean hydrophobicity of dystrophin was analyzed using BioEdit software and the models of the hydrophobic domains of dystrophin were constructed. The presence of four hydrophobic regions is confirmed. They include the calponin homology CH2 domain on the actin-binding domain (ABD), spectrin-type repeat 16, hinge III and the EF Hand domain. The severe symptoms of DMD usually develop as a result of the mutational disruption in the hydrophobic regions I, II and IV of dystrophin – those that bind associated proteins of the dystrophin-glycoprotein complex (DGC). On the other hand, when the hydrophobic region III is deleted, the connection of the ordered repeat domains of the central rod domain remains intact, resulting in the less severe clinical presentation. We conclude that mutational changes in the structure of hydrophobic regions of dystrophin play an important role in the pathogenesis of DMD.
PMCID: PMC4469935  PMID: 26042512
DMD; BMD; dystrophin; Kyte-Doolittle scale mean hydrophobicity profile; 3D model; genotype–phenotype analysis
13.  Rapamycin reverses paraquat-induced acute lung injury in a rat model through inhibition of NFκB activation 
Objective: To evaluate the role of rapamycin (RAPA) in paraquat (PQ)-induced acute lung injury. Methods: Lung tissues were stained with HE and lung histology was observed. Mortality rate, and neutrophil and leukocyte count in blood and bronchoalveolar lavage fluid (BALF) were recorded. Protein content in BALF was determined by Coomassie blue staining. Malondialdehyde (MDA) content, glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activity in blood were determined by thiobarbituric acid (TBA) assay, pyrogallol autoxidation method, and modified Haefman method, respectively. The NF-κB activity was measured by gel electrophoretic mobility shift assay (EMSA). Carbon dioxide partial pressure (PaCO2), partial pressure of oxygen (PaO2) and pH values were measured by automated blood gas analyzer. Results: HE staining results demonstrated RAPA alleviated pathological changes of acute alveolitis in SD rats. Trend of protein content in BALF was PQ group > RAPA treatment group > control group (P < 0.05). Neutrophil and leukocyte count in RAPA treatment group was significantly lower than PQ group at 3, 5, and 7 days after injection (P < 0.05). Trend of MDA content was RAPA treatment group > PQ group > control group (P < 0.05). Trend of GSH-Px and SOD activity was control group > RAPA treatment group > PQ group (P < 0.05). Compared with PQ group, PaO2 in RAPA treatment group was markedly higher and PaCO2 was lower (P < 0.05). Conclusion: PQ-induced acute lung injury was effectively reversed with RAPA, through inhibition of NF-κB activation.
PMCID: PMC4503025  PMID: 26191153
Rapamycin; paraquat; acute lung injury; paraquat-induced acute lung injury rat model; malondialdehyde; glutathione peroxidase; superoxide dismutase; NF-κB
14.  Incremental value of resting three-dimensional speckle-tracking echocardiography in detecting coronary artery disease 
The aim of the present study was to investigate the incremental value of resting three-dimensional speckle-tracking echocardiography (3D-STE) in the detection of early-stage left ventricular dysfunction in patients with coronary artery disease (CAD). A total of 110 patients suspected of having CAD were recruited. All patients underwent 3D-STE and coronary artery angiography (CAG). They were divided to a CAD group and a normal group according to the results of CAG. Using 3D-STE software, the peak values of longitudinal strain (LS), circumferential strain (CS), radial strain (RS) and area strain (AS) and the time to peak value of these strains (T-LS, T-CS, T-RS and T-AS) were measured. A receiver operator characteristic curve (ROC) was used to analyze the sensitivity of these strains for the diagnosis of CAD. ROC analysis indicated that T-LS and composite indices combining the peak strain value and time to peak of LS, CS and AS have diagnostic value for the early detection of CAD; the area under the curve (AUC) values were 0.667, 0.692, 0.621 and 0.672 respectively (P<0.005). The composite index of longitudinal strain demonstrated the highest diagnostic value for CAD with 62% sensitivity and 76% specificity. These results indicate that 3D-STE has incremental value for the diagnosis of CAD in patients at rest.
PMCID: PMC4473507  PMID: 26136933
three-dimensional speckle-tracking echocardiography; coronary artery disease; strain; left ventricular dysfunction
15.  Recoding of the Vesicular Stomatitis Virus L Gene by Computer-Aided Design Provides a Live, Attenuated Vaccine Candidate 
mBio  2015;6(2):e00237-15.
Codon pair bias (CPB), which has been observed in all organisms, is a neglected genomic phenomenon that affects gene expression. CPB results from synonymous codons that are paired more or less frequently in ORFeomes regardless of codon bias. The effect of an individual codon pair change is usually small, but when it is amplified by large-scale genome recoding, strikingly altered biological phenotypes are observed. The utility of codon pair bias in the development of live attenuated vaccines was recently demonstrated by recodings of poliovirus (a positive-strand RNA virus) and influenza virus (a negative-strand segmented RNA virus). Here, the L gene of vesicular stomatitis virus (VSV), a nonsegmented negative-sense RNA virus, was partially recoded based on codon pair bias. Totals of 858 and 623 silent mutations were introduced into a 5′-terminal segment of the viral L gene (designated L1) to create sequences containing either overrepresented or underrepresented codon pairs, designated L1sdmax and L1min, respectively. Analysis revealed that recombinant VSV containing the L1min sequence could not be recovered, whereas the virus with the sdmax sequence showed a modest level of attenuation in cell culture. More strikingly, in mice the L1sdmax virus was almost as immunogenic as the parental strain but highly attenuated. Taken together, these results open a new road to attain a balance between VSV virulence and immunogenicity, which could serve as an example for the attenuation of other negative-strand, nonsegmented RNA viruses.
Vesicular stomatitis virus (VSV) is the prototypic rhabdovirus in the order Mononegavirales. A wide range of human pathogens belong to this family. Using a unique computer algorithm and large-scale genome synthesis, we attempted to develop a live attenuated vaccine strain for VSV, which could be used as an antigen delivery platform for humans. Recombinant VSVs with distinct codon pair biases were rationally designed, constructed, and analyzed in both cell culture and an animal model. One such recombinant virus, L1sdmax, contained extra overrepresented codon pairs in its L gene open reading frame (ORF) and showed promise as an effective vaccine candidate because of a favorable balance between virulence and immunogenicity. Our study not only contributes to the understanding of the underlying mechanism of codon pair bias but also may facilitate the development of live attenuated vaccines for other viruses in the order Mononegavirales.
PMCID: PMC4453547  PMID: 25827413
16.  Incidence and risk factors of chylous ascites after pancreatic resection 
Chylous ascites (CA) is a rare postoperative complication. It also occurs in pancreatic surgery and can influence the patient’s prognosis after pancreatic resection. There are few studies focusing on CA following pancreatic resection. We aimed to evaluate the incidence and risk factors of CA following pancreatic resection. Patients who underwent pancreatic resection from the year 2007 to 2013 were retrospectively reviewed. The diagnosis of CA was based on the presence of a non-infectious milky or creamy peritoneal fluid greater than 100 ml/day with a triglyceride concentration ≥110 mg/dl. The incidence and possible risk factors following pancreatic resection were evaluated. In this study, 1921 patients who underwent pancreatic resection were included. 49 patients developed CA. The overall incidence was 2.6 percent (49 out of 1921). The incidence following pancreaticoduodenectomy and distal pancreatectomy was much higher (35 out of 1241, 12 out of 332, respectively). A multivariable analysis demonstrated that manipulating para-aortic area and superior mesenteric artery root area; retroperitoneal invasion; focal chronic pancreatitis and early enteral feeding were the independent risk factors for CA after pancreatic surgery. In conclusion, CA is a rare complication after pancreatic resection. Some clinicopathological factors were associated with the development of CA following pancreatic resection.
PMCID: PMC4443208  PMID: 26064374
Chylous ascites; risk factor; pancreatic resection
17.  Nasal Mucosa Derived-Mesenchymal Stem Cells from Mice Reduce Inflammation via Modulating Immune Responses 
PLoS ONE  2015;10(3):e0118849.
Mesenchymal stem cells (MSCs) have arisen the attention to be a new attractive therapeutic tool treating autoimmune diseases such as allergic rhinitis (AR). AR is a chronic reversible allergic inflammation caused by the excessive activation of T-helper 2 (Th2) cells. Recently, MSCs have been proposed as a new therapy of AR as it can suppress some cytokines to control allogeneic Th2 response and functions. However, how MSCs function to reduce inflammation remains unclear. In this study, we aimed to investigate the role of ectomesenchymal stem cells (ECTO-MSCs) derived from nasal mucosa in eosinophilic inflammation and how it affects some immunoglobulins and cytokines. We used ovalbumin (OVA) as a sensitizer to induce nasal inflammation in mice by both injection and inhalation. In order to obtain deeper insights into the influences of ECTO-MSCs on nasal inflammation, the migration of ECTO-MSCs was assessed, the numbers of eosinophils and sneezing were counted, and several immunoglobulins and cytokines were measured. Here we show the ECTO-MSCs are able to migrate to inflammation site via tail vein injection. Eosinophils and sneezing were suppressed by ECTO-MSCs. Interestingly, IgE, interleukin (IL)-4, IL-5 and IL-10 secreted by Th-2 cells were down-regulated by ECTO-MSCs whereas IgG2 and IFN-γ were up-regulated. In conclusion, we have observed that ECTO-MSCs are associated with enhanced Th-1 immune response to nasal inflammation and reduced Th-2 immune response. Given the contributions of Th-2 cells to AR, the injection of ECTO-MSCs can be a promising therapy of AR through balancing immune response.
PMCID: PMC4349652  PMID: 25739057
18.  Morphological and Hydrodynamic Correlations with Increasing Outflow Facility by Rho-Kinase Inhibitor Y-27632 
Rho-kinase inhibitors affect actomyosin cytoskeletal networks and have been shown to significantly increase outflow facility and lower intraocular pressure in various animal models and human eyes. This article summarizes common morphological changes in the trabecular meshwork induced by Rho-kinase inhibitors and specifically compares the morphological and hydrodynamic correlations with increased outflow facility by Rho-kinase inhibitor, Y-27632, in bovine, monkey, and human eyes under similar experimental conditions. Interspecies comparison has shown that morphological changes in the juxtacanalicular connective tissue (JCT) of these 3 species were different. However, these different morphological changes in the JCT, no matter if it's separation between the JCT and inner wall in bovine eyes, or separation between the JCT cells or between the JCT cells and their matrix in monkey eyes, or even no separation between the inner wall and the JCT but a more subtle expansion of the JCT in human eyes, appear to correlate with the increased percent change of outflow facility. More importantly, these different morphological changes all resulted in an increase in effective filtration area, which was positively correlated with increased outflow facility in all 3 species. These results suggest a link among changes in outflow facility, tissue architecture, and aqueous outflow pattern. Y-27632 increases outflow facility by redistributing aqueous outflow through a looser and larger area in the JCT.
PMCID: PMC3991982  PMID: 24460021
19.  Rosuvastatin attenuates contrast-induced nephropathy through modulation of nitric oxide, inflammatory responses, oxidative stress and apoptosis in diabetic male rats 
Contrast-induced nephropathy (CIN) is an important cause of acute renal failure. We observe the effect of rosuvastatin on preventing CIN in diabetic rats in current study.
Diabetic rats were then divided into five groups: 1 diabetic rats (D), 2 diabetic rats + contrast media (DCM), 3 diabetic rats + rosuvastatin (DR), 4 diabetic rats + contrast media + rosuvastatin (DRCM), 5 non-diabetic rat control (NDCM). Contrast-induced nephropathy was induced by intravenous injection a single dose of indomethacin (10 mg/kg), double doses of N-nitro-L-arginine methyl ester (10 mg/kg) and a single dose of high-osmolar contrast medium meglumine amidotrizoate (6 ml/kg). DR and DRCM group rats were treated with rosuvastatin (10 mg/kg/day) by gavage for 5 days. At the end of treatment, the experimental groups were sacrificed, and their renal tissues were investigated histopathologically beside assessments of functional activities, nitric oxide metabolites, and oxidative stress and apoptic markers.
After 6 days, serum creatinine and urine microprotein were increased, and creatinine clearance, kidney nitrite were decreased in DCM rats compared with NDCM, D, DR and DRCM groups. Histopathology scores in group DCM were increased compared with groups NDCM, D and DR, but lower in group DRCM than in group DCM (p < 0.01). Kidney thiobarbituric acid-reacting substances (TBARS), serum malondialdehyde (MDA), and serum protein carbonyl content (PCC) were increased, and serum thiol was decreased in the DCM group compared with groups NDCM, D and DR; however, these results were reversed in group DRCM compared with group DCM. Both expression of IL-6, TNF-α and the percentage of apoptotic cells were increased in group DCM than in groups NDCM, D and DR, but they were decreased in group DRCM than in group DCM. The expression of phospho-p38, cleaved capase-3, and the Bax/Bcl-2 ratio, were increased in group DCM than in groups NDCM, D and DR, but were decreased in group DRCM than in group DCM.
Our study demonstrated that rosuvastatin treatment attenuated both inflammatory processes and apoptosis and inhibited oxidative stress and the p38 MAPK pathway in a diabetic rat model in the setting of CIN.
PMCID: PMC4329210  PMID: 25880311
Diabetic; Contrast-induced nephropathy (CIN); Rosuvastatin
20.  Sitagliptin attenuates sympathetic innervation via modulating reactive oxygen species and interstitial adenosine in infarcted rat hearts 
We investigated whether sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, attenuates arrhythmias through inhibiting nerve growth factor (NGF) expression in post-infarcted normoglycemic rats, focusing on adenosine and reactive oxygen species production. DPP-4 bound adenosine deaminase has been shown to catalyse extracellular adenosine to inosine. DPP-4 inhibitors increased adenosine levels by inhibiting the complex formation. Normoglycemic male Wistar rats were subjected to coronary ligation and then randomized to either saline or sitagliptin in in vivo and ex vivo studies. Post-infarction was associated with increased oxidative stress, as measured by myocardial superoxide, nitrotyrosine and dihydroethidium fluorescent staining. Measurement of myocardial norepinephrine levels revealed a significant elevation in vehicle-treated infarcted rats compared with sham. Compared with vehicle, infarcted rats treated with sitagliptin significantly increased interstitial adenosine levels and attenuated oxidative stress. Sympathetic hyperinnervation was blunted after administering sitagliptin, as assessed by immunofluorescent analysis and western blotting and real-time quantitative RT-PCR of NGF. Arrhythmic scores in the sitagliptin-treated infarcted rats were significantly lower than those in vehicle. Ex vivo studies showed a similar effect of erythro-9-(2-hydroxy-3-nonyl) adenine (an adenosine deaminase inhibitor) to sitagliptin on attenuated levels of superoxide and NGF. Furthermore, the beneficial effects of sitagliptin on superoxide anion production and NGF levels can be reversed by 8-cyclopentyl-1,3-dipropulxanthine (adenosine A1 receptor antagonist) and exogenous hypoxanthine. Sitagliptin protects ventricular arrhythmias by attenuating sympathetic innervation via adenosine A1 receptor and xanthine oxidase-dependent pathways, which converge through the attenuated formation of superoxide in the non-diabetic infarcted rats.
PMCID: PMC4407589  PMID: 25388908
adenosine; arrhythmia; nerve growth factor; myocardial infarction; reactive oxygen species
21.  A phenylalanine rotameric switch for signal-state control in bacterial chemoreceptors 
Nature communications  2013;4:2881.
Bacterial chemoreceptors are widely used as a model system for elucidating the molecular mechanisms of transmembrane signaling and have provided a detailed understanding of how ligand binding by the receptor modulates the activity of its associated kinase CheA. However, the mechanisms by which conformational signals move between signaling elements within a receptor dimer and how they control kinase activity remain unknown. Here, using long molecular dynamics simulations, we show that the kinase-activating cytoplasmic tip of the chemoreceptor fluctuates between two stable conformations in a signal-dependent manner. A highly conserved residue, Phe396, appears to serve as the conformational switch, because flipping of the stacked aromatic rings of an interacting F396-F396' pair in the receptor homodimer takes place concomitantly with the signal-related conformational changes. We suggest that interacting aromatic residues, which are common stabilizers of protein tertiary structure, might serve as rotameric molecular switches in other biological processes as well.
PMCID: PMC4310728  PMID: 24335957
22.  When does Subliminal Affective Image Priming Influence the Ability of Schizophrenic Patients to Perceive Face Emotions? 
Deficits in face emotion perception are among the most pervasive aspects of schizophrenia impairments which strongly affects interpersonal communication and social skills.
Schizophrenic patients (PSZ) and healthy control subjects (HCS) performed 2 psychophysical tasks. One, the SAFFIMAP test, was designed to determine the impact of subliminally presented affective or neutral images on the accuracy of face-expression (angry or neutral) perception. In the second test, FEP, subjects saw pictures of face-expression and were asked to rate them as angry, happy, or neutral. The following clinical scales were used to determine the acute symptoms in PSZ: Positive and Negative Syndrome (PANSS), Young Mania Rating (YMRS), Hamilton Depression (HAM-D), and Hamilton Anxiety (HAM-A).
On the SAFFIMAP test, different from the HCS group, the PSZ group tended to categorize the neutral expression of test faces as angry and their response to the test-face expression was not influenced by the affective content of the primes. In PSZ, the PANSS-positive score was significantly correlated with correct perception of angry faces for aggressive or pleasant primes. YMRS scores were strongly correlated with PSZ’s tendency to recognize angry face expressions when the prime was a pleasant or a neutral image. The HAM-D score was positively correlated with categorizing the test-faces as neutral, regardless of the affective content of the prime or of the test-face expression (angry or neutral).
Despite its exploratory nature, this study provides the first evidence that conscious perception and categorization of facial emotions (neutral or angry) in PSZ is directly affected by their positive or negative symptoms of the disease as defined by their individual scores on the clinical diagnostic scales.
PMCID: PMC4282928  PMID: 25537115
Affective Symptoms; Schizophrenia; Subliminal Stimulation
24.  Resolution and measurement of heteronuclear dipolar couplings of a noncrystalline protein immobilized in a biological supramolecular assembly by proton-detected MAS solid-state NMR spectroscopy 
Two-dimensional 15N chemical shift/1H chemical shift and three-dimensional 1H-15N dipolar coupling/15N chemical shift/1H chemical shift MAS solid-state NMR correlation spectra of the filamentous bacteriophage Pf1 major coat protein show single-site resolution in noncrystalline, intact-phage preparations. The high sensitivity and resolution result from 1H detection at 600 MHz under 50 kHz magic angle spinning using ~ 0.5 mg of perdeuterated and uniformly 15N-labeled protein in which the exchangeable amide sites are partially or completely back-exchanged (reprotonated). Notably, the heteronuclear 1H-15N dipolar coupling frequency dimension is shown to select among 15N resonances, which will be useful in structural studies of larger proteins where the resonances exhibit a high degree of overlap in multidimensional chemical shift correlation spectra.
PMCID: PMC3915937  PMID: 24225529
perdeuteration; proton detection; variable contact time cross-polarization; Pf1 bacteriophage; separated local field spectroscopy; two-dimensional NMR; three-dimensional NMR; fast MAS
25.  Genetic Analysis of Loop Sequences in the Let-7 Gene Family Reveal a Relationship between Loop Evolution and Multiple IsomiRs 
PLoS ONE  2014;9(11):e113042.
While mature miRNAs have been widely studied, the terminal loop sequences are rarely examined despite regulating both primary and mature miRNA functions. Herein, we attempted to understand the evolutionary pattern of loop sequences by analyzing loops in the let-7 gene family. Compared to the stable miRNA length distributions seen in most metazoans, higher metazoan species exhibit a longer length distribution. Examination of these loop sequence length distributions, in addition to phylogenetic tree construction, implicated loop sequences as the main evolutionary drivers in miRNA genes. Moreover, loops from relevant clustered miRNA gene families showed varying length distributions and higher levels of nucleotide divergence, even between homologous pre-miRNA loops. Furthermore, we found that specific nucleotides were dominantly distributed in the 5′ and 3′ terminal loop ends, which may contribute to the relatively precise cleavage that leads to a stable isomiR expression profile. Overall, this study provides further insight into miRNA processing and maturation and further enriches our understanding of miRNA biogenesis.
PMCID: PMC4232593  PMID: 25397967

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