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1.  Alternative Translation Initiation of a Haloarchaeal Serine Protease Transcript Containing Two In-Frame Start Codons 
Journal of Bacteriology  2016;198(13):1892-1901.
ABSTRACT
Recent studies have shown that haloarchaea employ leaderless and Shine-Dalgarno (SD)-less mechanisms for translation initiation of leaderless transcripts with a 5′ untranslated region (5′ UTR) of <10 nucleotides (nt) and leadered transcripts with a 5′ UTR of ≥10 nt, respectively. However, whether the two mechanisms can operate on the same naturally occurring haloarchaeal transcript carrying multiple potential start codons is unknown. In this study, the transcript of the sptA gene (encoding an extracellular serine protease of Natrinema sp. strain J7-2) was experimentally determined and found to contain two potential in-frame AUG codons (AUG1 and AUG2) located 5 and 29 nt, respectively, downstream of the transcription start site. Mutational analysis revealed that both AUGs can function as the translation start codon for production of active SptA, although AUG1 is more efficient than AUG2 for translation initiation. Insertion of a stable stem-loop structure between the two AUGs completely abolished initiation at AUG1 but did not affect initiation at AUG2, indicating that AUG2-initiated translation does not involve ribosome scanning from the 5′ end of the transcript. Furthermore, the efficiency of AUG2-initiated translation was not influenced by an upstream SD-like sequence. In addition, both AUG1 and AUG2 contribute to transcript stability, probably by recruiting ribosomes to protect the transcript against degradation. These data suggest that depending on which of two in-frame start codons is used, the sptA transcript can act as either a leaderless or a leadered transcript for SptA production in haloarchaea.
IMPORTANCE In eukaryotes and bacteria, alternative translation start sites contribute to proteome complexity and can be used as a functional mechanism to increase translation efficiency. However, little is known about alternative translation initiation in archaea. Our results demonstrate that leaderless and SD-less mechanisms can be used for translation initiation of the sptA transcript from two in-frame start codons, raising the possibility that in haloarchaea, alternative translation initiation on one transcript functions to increase translation efficiency and/or contribute to proteome complexity.
doi:10.1128/JB.00202-16
PMCID: PMC4907116  PMID: 27137502
3.  Head to Head Comparison of Two Point-of-care Platelet Function Tests Used for Assessment of On-clopidogrel Platelet Reactivity in Chinese Acute Myocardial Infarction Patients Undergoing Percutaneous Coronary Intervention 
Chinese Medical Journal  2016;129(19):2269-2274.
Background:
Platelet function tests are widely used in clinical practice to guide personalized antiplatelet therapy. In China, the thromboelastography (TEG) test has been well accepted in clinics, whereas VerifyNow, mainly used for scientific research, has not been used in routine clinical practice. The aim of the current study was to compare these two point-of-care platelet function tests and to analyze the consistency between the two tests for evaluating on-clopidogrel platelet reactivity in Chinese acute myocardial infarction patients undergoing percutaneous coronary intervention (PCI).
Methods:
A total of 184 patients admitted to Fuwai Hospital between August 2014 and May 2015 were enrolled in the study. On-clopidogrel platelet reactivity was assessed 3 days after PCI by TEG and VerifyNow using adenosine diphosphate as an agonist. Based on the previous reports, an inhibition of platelet aggregation (IPA) <30% for TEG or a P2Y12 reaction unit (PRU) >230 for VerifyNow was defined as high on-clopidogrel platelet reactivity (HPR). An IPA >70% or a PRU <178 was defined as low on-clopidogrel platelet reactivity (LPR). Correlation and agreement between the two methods were analyzed using the Spearman correlation coefficient (r) and kappa value (κ), respectively.
Results:
Our results showed that VerifyNow and TEG had a moderate but significant correlation in evaluating platelet reactivity (r = −0.511). A significant although poor agreement (κ = 0.225) in identifying HPR and a significantly moderate agreement in identifying LPR (κ = 0.412) were observed between TEG and VerifyNow. By using TEG as the reference for comparison, the cutoff values of VerifyNow for the Chinese patients in this study were identified as PRU >205 for HPR and PRU <169 for LPR.
Conclusions:
By comparing VerifyNow to TEG which has been widely used in clinics, VerifyNow could be an attractive alternative to TEG for monitoring on-clopidogrel platelet reactivity in Chinese patients.
doi:10.4103/0366-6999.190664
PMCID: PMC5040010  PMID: 27647183
Blood Platelets; Clopidogrel; Thromboelastography; VerifyNow
4.  Tigecycline combination for ventilator-associated pneumonia caused by extensive drug-resistant Acinetobacter baumannii 
Journal of Thoracic Disease  2016;8(10):2784-2792.
Background
Extensive drug-resistant Acinetobacter baumannii (XDR A. baumannii) has emerged as an important pathogen in patients with ventilator-associated pneumonia (VAP) worldwide. This study determined whether or not combination tigecycline (TGC) treatment improved the short-term outcome of patients with XDR A. baumannii-induced VAP.
Methods: Fifty-eight patients admitted to our intensive care unit (ICU) with confirmed XDR A. baumannii VAP between January 2011 and June 2013 were retrospectively studied. Fourteen patients were excluded. The included subjects were classified into two groups depending on treatment regimens with or without TGC (TGC group, n=20; non-TGC group, n=24). Thirty-day mortality rates, and clinical and microbiologic responses were reviewed and compared in detail.
Results
Microbiological eradication was observed in 3 patients (15.0%) in the TGC group and 7 patients (29.2%) in the non-TGC group (P=0.264). The mean time-to-eradication of XDR A. baumannii was 5.3±2.1 versus 7.6±4.0 days (P=0.395). Ten of 20 (50%) patients developed resistance to TGC after initiation of TGC therapy in the TGC group. Clinical cure were achieved in 50.0% of the patients (10/20) in the TGC group and 45.8% of the patients (7/24) in the non-TGC group (P=1.000). No differences existed in the 30-day mortality, length of ICU stay, length of hospital stay (LOS), and length of invasive mechanical ventilation (MV) between the two groups. The occurrence of septic shock was significantly lower in the TGC group (20.0% vs. 54.2%; P=0.030).
Conclusions
TGC combination therapy did not improve the clinical cure and microbiologic eradication in patients with XDR A. baumannii VAP. TGC combination therapy did not decrease all-cause mortality in patients with XDR A. baumannii VAP. TGC combination therapy reduced the incidence of septic shock in patients with XDR A. baumannii VAP, and might decrease the incidence of poly-microbial VAP. TGC combination therapy can only be recommended as an option when other optimized therapeutics, such as colistin, are unavailable.
doi:10.21037/jtd.2016.10.29
PMCID: PMC5107514  PMID: 27867554
Tigecycline (TGC); ventilator-associated pneumonia (VAP); Acinetobacter baumannii (A. baumannii); combination therapy; outcome
5.  Electroacupuncture Treatment Alleviates Central Poststroke Pain by Inhibiting Brain Neuronal Apoptosis and Aberrant Astrocyte Activation 
Neural Plasticity  2016;2016:1437148.
Electroacupuncture (EA) is reported to effectively relieve the central poststroke pain (CPSP). However, the underlying mechanism remains unclear. The present study investigated the detailed mechanisms of action of EA treatment at different frequencies for CPSP. A CPSP model was established with a single collagenase injection to the left ventral posterolateral nucleus of the thalamus. The EA-treated groups then received EA treatment at frequency of 2, 2/15, or 15 Hz for 30 min daily for five days. The pain-related behavioral responses, neuronal apoptosis, glial activation, and the expression of pain signal transmission-related factors (β-catenin, COX-2, and NK-1R) were assessed using behavioral tests, Nissl staining, TUNEL staining, and immunohistochemical staining, respectively. The low-frequency EA treatment significantly (1) reduced brain tissue damage and hematoma sizes and (2) inhibited neuronal apoptosis, thereby exerting abirritative effects. Meanwhile, the high-frequency EA treatment induced a greater inhibition of the aberrant astrocyte activation, accompanied by the downregulation of the expressions of COX-2, β-catenin, and subsequently NK-1R, thereby alleviating inflammation and producing strong analgesic effects. Together, these findings suggest that CPSP is closely related to pathological changes of the neocortex and hippocampus. EA treatments at different frequencies may exert abirritative effects by inhibiting brain neuronal apoptosis and aberrant astrocyte activation in the brain.
doi:10.1155/2016/1437148
PMCID: PMC5059615  PMID: 27774321
6.  Microwave ablation of hepatocellular carcinoma as first-line treatment: long term outcomes and prognostic factors in 221 patients 
Scientific Reports  2016;6:32728.
This retrospective study aimed at evaluating the long-term outcomes and prognostic factors of microwave ablation (MWA) as a first-line treatment for hepatocellular carcinoma (HCC). 221 consecutive patients receiving MWA in our center between October 11, 2010 and December 31, 2013 were enrolled. Technique effectiveness was evaluated one month post-ablation. Initial complete ablation (CA1st) was gained in 201 (90.95%) patients, secondary CA (CA2nd) in 8 (3.62%) patients and the remaining 12 (5.43%) patients suffered from incomplete ablation (IA2nd) after two sessions of MWA. Patients with tumor size >5 cm were less likely to gain CA1st. Procedure-related complications were recorded and no procedure-related death occurred. 22 (10.4%) complications occurred with 8 (3.8%) being major ones. Tumor characteristics (size, number, location) do not significantly influence complication rates. After a median follow-up of 41.0 (ranging 25.0–63.5) months, the median RFS and OS was 14.0 months (95% CI: 9.254–18.746) and 41.0 months (95% CI: 33.741–48.259) respectively. Multivariate analysis identified two significant prognosticators (levels of alpha fetal protein [AFP] and gamma-glutamyl transpeptidase [GGT]) of RFS and five significant prognosticators (tumor number, tumor size, AFP, GGT and recurrence type) of OS. In conclusion, MWA provides high technique effectiveness rate and is well tolerated in patients with HCC as a first-line treatment.
doi:10.1038/srep32728
PMCID: PMC5020644  PMID: 27620527
7.  Sweroside ameliorates α-naphthylisothiocyanate-induced cholestatic liver injury in mice by regulating bile acids and suppressing pro-inflammatory responses 
Acta Pharmacologica Sinica  2016;37(9):1218-1228.
Aim:
Sweroside is an iridoid glycoside with diverse biological activities. In the present study we investigated the effects of sweroside on α-naphthylisothiocyanate (ANIT)-induced cholestatic liver injury in mice.
Methods:
Mice received sweroside (120 mg·kg−1·d−1, ig) or a positive control INT-747 (12 mg·kg−1·d−1, ig) for 5 d, and ANIT (75 mg/kg, ig) was administered on d 3. The mice were euthanized on d 5, and serum biochemical markers, hepatic bile acids and histological changes were analyzed. Hepatic expression of genes related to pro-inflammatory mediators and bile acid metabolism was also assessed. Primary mouse hepatocytes were exposed to a reconstituted mixture of hepatic bile acids, which were markedly elevated in the ANIT-treated mice, and the cell viability and expression of genes related to pro-inflammatory mediators were examined.
Results:
Administration of sweroside or INT-747 effectively ameliorated ANIT-induced cholestatic liver injury in mice, as evidenced by significantly reduced serum biochemical markers and attenuated pathological changes in liver tissues. Furthermore, administration of sweroside or INT-747 significantly decreased ANIT-induced elevation of individual hepatic bile acids, such as β-MCA, CA, and TCA, which were related to its effects on the expression of genes responsible for bile acid synthesis and transport as well as pro-inflammatory responses. Treatment of mouse hepatocytes with the reconstituted bile acid mixture induced significant pro-inflammatory responses without affecting the cell viability.
Conclusion:
Sweroside attenuates ANIT-induced cholestatic liver injury in mice by restoring bile acid synthesis and transport to their normal levels, as well as suppressing pro-inflammatory responses.
doi:10.1038/aps.2016.86
PMCID: PMC5022106  PMID: 27498779
sweroside; INT-747; α-naphthylisothiocyanate; bile acids; cholestasis; hepatotoxicity; hepatocytes; inflammation
8.  Continuous infusion of high‐dose ulinastatin during surgery does not improve early postoperative clinical outcomes in patients undergoing radical lung cancer surgery: A pilot study 
Thoracic Cancer  2016;7(5):581-587.
Background
Ulinastatin can prevent the perioperative increase in proinflammatory cytokines for lung resection surgery; however, its impact on early clinical outcomes remains unknown.
Methods
The study enrolled 108 non‐small cell lung cancer (NSCLC) patients who were randomly allocated into two groups: ulinastatin (group U) and control (group C). Patients in group U (n = 52) were continuously intravenously infused with ulinastatin at a rate of 20 000 U/kg/hour for the first hour after anesthesia induction, and then at a rate of 5000 U/kg/hour until the conclusion of surgery. Patients in group C (n = 56) received an equivalent volume of normal saline. The primary outcome was to record the postoperative pulmonary complications that occurred during hospital stay. Other clinical courses, such as hospital mortality, blood loss, respiratory parameters, postoperative chest drainage, and duration of intensive care unit and postoperative hospital stay, were also observed and analyzed.
Results
There were no significant differences between the two groups in early postoperative pulmonary complications, hospital mortality, blood loss, or other perioperative laboratory values, except for the duration of postoperative chest drainage and serum creatinine level. The frequency of pulmonary complications was lower in patients treated with ulinastatin compared with the control (38.46% in group U vs. 48.21% in group C).
Conclusion
Administration of high‐dose ulinastatin during surgery did not reduce postoperative pulmonary complications, hospital mortality, or hospital stay for patients undergoing lung radical thoracotomy. However, a protective trend of ulinastatin was observed.
doi:10.1111/1759-7714.12371
PMCID: PMC5129221  PMID: 27766771
Non‐small cell lung cancer; postoperative pulmonary complications; thoracotomy; ulinastatin
9.  A Numerical Simulation of Cell Separation by Simplified Asymmetric Pinched Flow Fractionation 
As a typical microfluidic cell sorting technique, the size-dependent cell sorting has attracted much interest in recent years. In this paper, a size-dependent cell sorting scheme is presented based on a controllable asymmetric pinched flow by employing an immersed boundary-lattice Boltzmann method (IB-LBM). The geometry of channels consists of 2 upstream branches, 1 transitional channel, and 4 downstream branches (D-branches). Simulations are conducted by varying inlet flow ratio, the cell size, and the ratio of flux of outlet 4 to the total flux. It is found that, after being randomly released in one upstream branch, the cells are aligned in a line close to one sidewall of the transitional channel due to the hydrodynamic forces of the asymmetric pinched flow. Cells with different sizes can be fed into different downstream D-branches just by regulating the flux of one D-branch. A principle governing D-branch choice of a cell is obtained, with which a series of numerical cases are performed to sort the cell mixture involving two, three, or four classes of diameters. Results show that, for each case, an adaptive regulating flux can be determined to sort the cell mixture effectively.
doi:10.1155/2016/2564584
PMCID: PMC5002493  PMID: 27597877
10.  Identification of Ethanol and 4-Nitroquinoline-1-Oxide Induced Epigenetic and Oxidative Stress Markers During Oral Cavity Carcinogenesis 
Background
Head and neck squamous cell carcinoma (HNSCC) is a cancer that is characterized by its high morbidity and mortality rates. While tobacco use and alcohol consumption are two major contributing factors for HNSCC carcinogenesis, how the combination of tobacco and alcohol increases HNSCC risk is not understood.
Methods
We combined the 4-nitroquinoline-1-oxide (4-NQO) oral carcinogenesis and Meadows-Cook alcohol mouse models to elucidate the molecular events and to identify novel biomarkers associated with oral cancer development.
Results
By genome-wide RNA-seq of tongue samples (three mice per group) we identified changes in transcripts that mediate alcohol metabolism and oxidative stress (Aldh2, Aldh1a3, Adh1, Adh7, and Cyp2a5) in mice treated with 4-NQO followed by ethanol (4-NQO/EtOH) as compared to the vehicle control/untreated samples (V.C./Untr.). We measured major, global increases in specific histone acetylation and methylation epigenetic marks (H3K27ac, H3K9/14ac, H3K27me3, and H3K9me3) in the oral cavities of V.C./EtOH, 4-NQO/Untr. and 4-NQO/EtOH treatment groups compared to the V.C./Untr. group. We detected changes in histone epigenetic marks near regulatory regions of genes involved in ethanol metabolism by chromatin immunoprecipitation (ChIP). For instance, the Aldh2 promoter showed increased H3K27me3 marks, and Aldh2 mRNA levels were reduced by 10-fold in 4NQO/EtOH vs. V.C./Untr. tongue samples. 4-NQO/EtOH treatment also caused increases in markers of oxidative stress, including 4-HNE, MCT4/Slc16a3, and TOM20, as measured by immunohistochemistry.
Conclusions
We delineate a mechanism by which 4-NQO and ethanol can regulate gene expression during the development of HNSCC, and suggest that histone epigenetic marks and oxidative stress markers could be novel biomarkers and targets for the prevention of HNSCC.
doi:10.1111/acer.12772
PMCID: PMC4597780  PMID: 26207766
head and neck cancer; epigenetics; oxidative stress; tobacco; alcohol
11.  Genetic Structure of Water Chestnut Beetle: Providing Evidence for Origin of Water Chestnut 
PLoS ONE  2016;11(7):e0159557.
Water chestnut beetle (Galerucella birmanica Jacoby) is a pest of the water chestnut (Trapa natans L.). To analyze the phylogeny and biogeography of the beetle and provide evidence for the origin of T. natans in China, we conducted this by using three mitochondrial genes (COI, COII and Cytb) and nuclear ITS2 ribosomal DNA of G. birmanica. As for mtDNA genes, the beetle could be subdivided into three groups: northeastern China (NEC), central-northern-southern China (CC-NC-SC) and southwestern China (SWC) based on SAMOVA, phylogenetic analyses and haplotype networks. But for ITS2, no obvious lineages were obtained but individuals which were from NEC region clustered into one clade, which might be due to sequence conservation of ITS2. Significant genetic variation was observed among the three groups with infrequent gene flow between groups, which may have been restricted due to natural barriers and events in the Late Pleistocene. Based on our analyses of genetic variation in the CC-NC-SC geographical region, the star-like haplotype networks, approximate Bayesian computation, niche modelling and phylogeographic variation of the beetle, we concluded that the beetle population has been lasting in the lower, central reaches of the Yangtze River Basin with its host plant, water chestnut, which is consistent with archaeological records. Moreover, we speculate that the CC-NC-SC population of G. birmanica may have undergone a period of expansion coincident with domestication of the water chestnut approximately 113,900–126,500 years ago.
doi:10.1371/journal.pone.0159557
PMCID: PMC4961436  PMID: 27459279
12.  Hydrogen Sulfide Protects against Chronic Unpredictable Mild Stress-Induced Oxidative Stress in Hippocampus by Upregulation of BDNF-TrkB Pathway 
Chronic unpredictable mild stress (CUMS) induces hippocampal oxidative stress. H2S functions as a neuroprotectant against oxidative stress in brain. We have previously shown the upregulatory effect of H2S on BDNF protein expression in the hippocampus of rats. Therefore, we hypothesized that H2S prevents CUMS-generated oxidative stress by upregulation of BDNF-TrkB pathway. We showed that NaHS (0.03 or 0.1 mmol/kg/day) ameliorates the level of hippocampal oxidative stress, including reduced levels of malondialdehyde (MDA) and 4-hydroxy-2-trans-nonenal (4-HNE), as well as increased level of glutathione (GSH) and activity of superoxide dismutase (SOD) in the hippocampus of CUMS-treated rats. We also found that H2S upregulated the level of BDNF and p-TrkB protein in the hippocampus of CUMS rats. Furthermore, inhibition of BDNF signaling by K252a, an inhibitor of the BDNF receptor TrkB, blocked the antioxidant effects of H2S on CUMS-induced hippocampal oxidative stress. These results reveal the inhibitory role of H2S in CUMS-induced hippocampal oxidative stress, which is through upregulation of BDNF/TrkB pathway.
doi:10.1155/2016/2153745
PMCID: PMC4976147  PMID: 27525050
13.  Maturation of Fibrinolytic Bacillopeptidase F Involves both Hetero- and Autocatalytic Processes 
Bacillopeptidase F (Bpr) is a fibrinolytic serine protease produced by Bacillus subtilis. Its precursor is composed of a signal peptide, an N-terminal propeptide, a catalytic domain, and a long C-terminal extension (CTE). Several active forms of Bpr have been previously reported, but little is known about the maturation of this enzyme. Here, a gene encoding a Bpr (BprL) was cloned from B. subtilis LZW and expressed in B. subtilis WB700, and three fibrinolytic mature forms with apparent molecular masses of 45, 75, and 85 kDa were identified in the culture supernatant. After treatment with urea, the 75-kDa mature form had the same molecular mass as the 85-kDa mature form, from which we infer that they adopt different conformations. Mutational analysis revealed that while the 85-kDa mature form is generated via heterocatalytic processing of a BprL proform by an unidentified protease of B. subtilis, the production of the 75- and 45-kDa mature forms involves both hetero- and autocatalytic events. From in vitro analysis of BprL and its sequential C-terminal truncation variants, it appears that partial removal of the CTE is required for the initiation of autoprocessing of the N-terminal propeptide, which is composed of a core domain (N*) and a 15-residue linker peptide, thereby yielding the 45-kDa mature form. These data suggest that the differential processing of BprL, either heterocatalytically or autocatalytically, leads to the formation of multiple mature forms with different molecular masses or conformations.
doi:10.1128/AEM.02673-15
PMCID: PMC4702618  PMID: 26497454
14.  Long noncoding RNA DANCR promotes invasion of prostate cancer through epigenetically silencing expression of TIMP2/3 
Oncotarget  2016;7(25):37868-37881.
LncRNA DANCR suppresses differentiation of epithelial cells, however, its function in prostate cancer development is still unknown. In the present study, we found the expression of DANCR increases in prostate cancer tissues and cells compared to normal prostate tissues and cells, moreover, DANCR promotes invasion and migration of prostate cancer cells in vitro and metastasis of tumor xenografts in nude mice. Mechanistically, we found that TIMP2/3, which are critical metastasis inhibitor of prostate cancer, were down-regulated by DANCR synergistically with EZH2 through epigenetically silencing their promoter by chromatin immunoprecipitation assay. In addition, we further investigated whether DANCR is regulated by the differentiation-promoting androgen-androgen receptor (AR) pathway and found that DANCR expression is repressed by androgen-AR; furthermore, DANCR impedes the upregulation of TIMP2/3 and the suppression of invasion and migration by androgen-AR. On the other hand, interestingly, we found that in prostate cancer cells DANCR knockdown decreased the promotion of invasion and migration by the treatment of enzalutamide, which is an AR inhibitor. In summary, our results indicate that DANCR promotes prostate cancer invasion and metastasis through repressing the expression of TIMP2/3, and suggest that DANCR could be a potential target for preventing prostate cancer metastasis, and knockdown DANCR may lessen the potential side effect of AR inhibitor.
doi:10.18632/oncotarget.9350
PMCID: PMC5122356  PMID: 27191265
DANCR; prostate cancer; TIMP2; TIMP3; EZH2
15.  Can S-1 replace fluorouracil for advanced gastric cancer? A PRISMA-compliant systematic review and meta-analysis 
Medicine  2016;95(24):e3916.
Abstract
It remains to be seen whether S-1 can be a replacement for infusional fluorouracil (5-FU) for advanced gastric cancer (AGC). The aim of this study was to compare the efficacy and safety of S-1 with 5-FU in AGC.
PubMed and Cochrane Library were searched. Randomized controlled trials and meta-analyses comparing S-1 with 5-FU for AGC were eligible. Meta-analysis was performed using RevMan 5.2.
Seven trials involving 2443 patients were included. Compared with 5-FU, S-1 showed no significant prolongation of overall survival (OS) (hazard ratio [HR] = 0.91, 95% confidence interval [CI] [0.83–1.01], P = 0.07) and progression-free survival (HR = 0.89, 95% CI [0.70–1.13], P = 0.35), but longer time to treatment failure (HR = 0.74, 95% CI [0.56–0.97], P = 0.03). The objective response rates were comparable (risk ratio [RR] = 1.36, 95% CI [0.95, 1.96], P = 0.10). Regarding treatment-related deaths and hematological toxicities, there was significant heterogeneity between Asian and non-Asian trials, and subgroup analysis was applied. In Asian patients, there was a significant increase in hematological toxicities such as leukopenia (grade 1–4: RR = 1.22, 95% CI [1.08, 1.37], P = 0.001; grade 3–4: RR = 2.21, 95% CI [1.52, 3.21], P < 0.0001), neutropenia (grade 1–4: RR = 1.29, 95% CI [1.11, 1.48], P = 0.0005; grade 3–4: RR = 1.87, 95% CI [1.11, 3.17], P = 0.02), and thrombocytopenia (grade 1–4: RR = 1.71, 95% CI [1.22, 2.41], P = 0.002) in S-1-containing regimens compared with 5-FU-containing regimens, but without significant difference in treatment-related mortality rate (risk difference [RD] = 0.00, 95% CI [−0.01, 0.01], P = 0.68). In non-Asian patients, S-1-containing regimens were, however, associated with significantly fewer treatment-related deaths (RD = −0.02, 95% CI [−0.05, −0.00], P = 0.04), as well as less all grade 1–4 and grade 3–4 hematological toxicities except anemia. There was no significant heterogeneity in nonhematologic toxicities between Asian and non-Asian trials. Lower incidence of grade 1–4 nausea, diarrhea, mucositis, grade 3–4 mucositis, increased creatinine, and decreased calculated creatinine clearance was observed in S-1-containing regimens.
S-1 could not improve OS, but increase some hematological toxicities in Asian patients. Therefore, special attention on hematological toxicities should be paid to Asian patients because S-1 is administered on an outpatient basis.
doi:10.1097/MD.0000000000003916
PMCID: PMC4998483  PMID: 27310997
Efficacy; fluorouracil; heterogeneity; meta-analysis; S-1; stomach neoplasms; toxicity
16.  Regulator of G protein signalling 14 attenuates cardiac remodelling through the MEK–ERK1/2 signalling pathway 
In the past 10 years, several publications have highlighted the role of the regulator of G protein signalling (RGS) family in multiple diseases, including cardiovascular diseases. As one of the multifunctional family members, RGS14 is involved in various biological processes, such as synaptic plasticity, cell division, and phagocytosis. However, the role of RGS14 in cardiovascular diseases remains unclear. In the present study, we used a genetic approach to examine the role of RGS14 in pathological cardiac remodelling in vivo and in vitro. We observed that RGS14 was down-regulated in human failing hearts, murine hypertrophic hearts, and isolated hypertrophic cardiomyocytes. Moreover, the extent of aortic banding-induced cardiac hypertrophy and fibrosis was exacerbated in RGS14 knockout mice, whereas RGS14 transgenic mice exhibited a significantly alleviated response to pressure overload. Furthermore, research of the underlying mechanism revealed that the RGS14-dependent rescue of cardiac remodelling was attributed to the abrogation of mitogen-activated protein kinase (MEK)–extracellular signal-regulated protein kinase (ERK) 1/2 signalling. The results showed that constitutive activation of MEK1 nullified the cardiac protection in RGS14 transgenic mice, and inhibition of MEK–ERK1/2 by U0126 reversed RGS14 deletion-related hypertrophic aggravation. These results demonstrated that RGS14 attenuated the development of cardiac remodelling through MEK–ERK1/2 signalling. RGS14 exhibited great potential as a target for the treatment of pathological cardiac remodelling.
Electronic supplementary material
The online version of this article (doi:10.1007/s00395-016-0566-1) contains supplementary material, which is available to authorized users.
doi:10.1007/s00395-016-0566-1
PMCID: PMC4906057  PMID: 27298141
Cardiac remodelling; Cardiac dysfunction; RGS14; MEK1/2; ERK1/2
17.  Harmine combined with paclitaxel inhibits tumor proliferation and induces apoptosis through down-regulation of cyclooxygenase-2 expression in gastric cancer 
Oncology Letters  2016;12(2):983-988.
Cyclooxygenase-2 (COX-2) serves an important role in the carcinogenesis and progression of gastric cancer. Harmine (HM) and paclitaxel (PTX) are reported as promising drug candidates for cancer therapy, but whether a synergistic anti-tumor effect of HM combined with PTX exists in human gastric cancer remains unknown. The present study evaluated the effects of HM and/or PTX on cell proliferation and apoptosis in a gastric cancer cell line, SGC-7901. HM and PTX inhibited cell proliferation in a dose-dependent manner. Both HM and PTX alone induced apoptosis in gastric cancer cells. The combination of HM and PTX exerted synergistic effects on proliferation inhibition and apoptosis induction in SGC-7901 cells, with down-regulation of COX-2, PCNA and Bcl-2 and up-regulation of Bax expression. The results indicated that combination chemotherapy using HM with PTX exerts an anti-tumor effect for treating gastric cancer. The combination of the two drugs inhibits gastric cancer development more effectively than each drug alone through down-regulation of COX-2 expression.
doi:10.3892/ol.2016.4696
PMCID: PMC4950597  PMID: 27446381
harmine; paclitaxel; cyclooxygenase-2; gastric cancer; apoptosis
18.  Acidic pH increases airway surface liquid viscosity in cystic fibrosis 
Cystic fibrosis (CF) disrupts respiratory host defenses, allowing bacterial infection, inflammation, and mucus accumulation to progressively destroy the lungs. Our previous studies revealed that mucus with abnormal behavior impaired mucociliary transport in newborn CF piglets prior to the onset of secondary manifestations. To further investigate mucus abnormalities, here we studied airway surface liquid (ASL) collected from newborn piglets and ASL on cultured airway epithelia. Fluorescence recovery after photobleaching revealed that the viscosity of CF ASL was increased relative to that of non-CF ASL. CF ASL had a reduced pH, which was necessary and sufficient for genotype-dependent viscosity differences. The increased viscosity of CF ASL was not explained by pH-independent changes in HCO3– concentration, altered glycosylation, additional pH-induced disulfide bond formation, increased percentage of nonvolatile material, or increased sulfation. Treating acidic ASL with hypertonic saline or heparin largely reversed the increased viscosity, suggesting that acidic pH influences mucin electrostatic interactions. These findings link loss of cystic fibrosis transmembrane conductance regulator–dependent alkalinization to abnormal CF ASL. In addition, we found that increasing Ca2+ concentrations elevated ASL viscosity, in part, independently of pH. The results suggest that increasing pH, reducing Ca2+ concentration, and/or altering electrostatic interactions in ASL might benefit early CF.
doi:10.1172/JCI83922
PMCID: PMC4767348  PMID: 26808501
19.  BMPR2-pSMAD1/5 signaling pathway regulates RUNX2 expression and impacts the progression of dedifferentiated chondrosarcoma 
American Journal of Cancer Research  2016;6(6):1302-1316.
Bone morphogenetic protein receptors (BMPRs) are multifunctional proteins; they have indispensible roles in the process of BMP signaling. However, their function in dedifferentiated chondrosarcoma is uncertain. It has been reported that BMPR2 is associated with chondrosarcoma. Moreover, the detection of BMPR2 is more frequent in dedifferentiated chondrosarcomas (DDCS) than in conventional chondrosarcomas (CCS). BMPR2, phospho-SMAD1/5 (pSMAD1/5), and runt-related transcription factor 2 (RUNX2) expressions were found to be associated with the pathological grades of chondrosarcoma and could be a promising target of treatment outcome. Moreover, BMPR2 was found to induce the RUNX2 expression via pSmad1/5. Knockdown of BMPR2 and pSmad1/5 results in the downregulation of RUNX2 expression in DDCS cells, while the upregulation of BMPR2 and Smad1/5 in CCS cells leads to increased RUNX2 expression. The luciferase reporter gene assay suggested that BMPR2 can induce the RUNX2 expression at the transcriptional level. By chromatin immunoprecipitation (ChIP) and electrophoresis mobility shift assay (EMSA), it was found that pSmad1/5 combined directly to RUNX2. The in vivo tumorigenicity assay in mice showed that the inhibition of BMPR2 or Smad1/5 in DDCS cell line reduced tumor growth, while the upregulation of BMPR2 or Smad1/5 in CCS cell line increased tumor growth. Furthermore, a BMPR signaling inhibitor, LDN-193189, was introduced to investigate its role as a potential drug to treat DDCS. Taken together, the present-study results suggest that BMPR2-pSmad1/5 signaling pathway has an important role in regulating not only the RUNX2 expression but also the tumorigenesis of DDCS.
PMCID: PMC4937734  PMID: 27429845
Dedifferentiated chondrosarcoma; conventional chondrosarcoma; BMPR2; RUNX2; p-Smad1/5; progression
20.  Rapid formation and evolution of an extreme haze episode in Northern China during winter 2015 
Scientific Reports  2016;6:27151.
We investigate the rapid formation and evolutionary mechanisms of an extremely severe and persistent haze episode that occurred in northern China during winter 2015 using comprehensive ground and vertical measurements, along with receptor and dispersion model analysis. Our results indicate that the life cycle of a severe winter haze episode typically consists of four stages: (1) rapid formation initiated by sudden changes in meteorological parameters and synchronous increases in most aerosol species, (2) persistent evolution with relatively constant variations in secondary inorganic aerosols and secondary organic aerosols, (3) further evolution associated with fog processing and significantly enhanced sulfate levels, and (4) clearing due to dry, cold north-northwesterly winds. Aerosol composition showed substantial changes during the formation and evolution of the haze episode but was generally dominated by regional secondary aerosols (53–67%). Our results demonstrate the important role of regional transport, largely from the southwest but also from the east, and of coal combustion emissions for winter haze formation in Beijing. Also, we observed an important downward mixing pathway during the severe haze in 2015 that can lead to rapid increases in certain aerosol species.
doi:10.1038/srep27151
PMCID: PMC4886685  PMID: 27243909
21.  Airway acidification initiates host defense abnormalities in cystic fibrosis mice 
Science (New York, N.Y.)  2016;351(6272):503-507.
Cystic fibrosis (CF) is caused by mutations in the gene that encodes the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel. In humans and pigs, the loss of CFTR impairs respiratory host defenses, causing airway infection. But CF mice are spared. We found that in all three species, CFTR secreted bicarbonate into airway surface liquid. In humans and pigs lacking CFTR, unchecked H+ secretion by the nongastric H+/K+ adenosine triphosphatase (ATP12A) acidified airway surface liquid, which impaired airway host defenses. In contrast, mouse airways expressed little ATP12A and secreted minimal H+; consequently, airway surface liquid in CF and non-CF mice had similar pH. Inhibiting ATP12A reversed host defense abnormalities in human and pig airways. Conversely, expressing ATP12A in CF mouse airways acidified airway surface liquid, impaired defenses, and increased airway bacteria. These findings help explain why CF mice are protected from infection and nominate ATP12A as a potential therapeutic target for CF.
doi:10.1126/science.aad5589
PMCID: PMC4852973  PMID: 26823428
22.  A Tumor-Specific Neo-Antigen Caused by a Frameshift Mutation in BAP1 Is a Potential Personalized Biomarker in Malignant Peritoneal Mesothelioma 
Malignant peritoneal mesothelioma (MPM) is an aggressive rare malignancy associated with asbestos exposure. A better understanding of the molecular pathogenesis of MPM will help develop a targeted therapy strategy. Oncogene targeted depth sequencing was performed on a tumor sample and paired peripheral blood DNA from a patient with malignant mesothelioma of the peritoneum. Four somatic base-substitutions in NOTCH2, NSD1, PDE4DIP, and ATP10B and 1 insert frameshift mutation in BAP1 were validated by the Sanger method at the transcriptional level. A 13-amino acids neo-peptide of the truncated Bap1 protein, which was produced as a result of this novel frameshift mutation, was predicted to be presented by this patient’s HLA-B protein. The polyclonal antibody of the synthesized 13-mer neo-peptide was produced in rabbits. Western blotting results showed a good antibody-neoantigen specificity, and Immunohistochemistry (IHC) staining with the antibody of the neo-peptide clearly differentiated neoplastic cells from normal cells. A search of the Catalogue of Somatic Mutations in Cancer (COSMIC) database also revealed that 53.2% of mutations in BAP1 were frameshift indels with neo-peptide formation. An identified tumor-specific neo-antigen could be the potential molecular biomarker for personalized diagnosis to precisely subtype rare malignancies such as MPM.
doi:10.3390/ijms17050739
PMCID: PMC4881561  PMID: 27187383
neo-antigen; BAP1; personalized immunotherapy target; mesothelioma
23.  Nicotinate-Curcumin Impedes Foam Cell Formation from THP-1 Cells through Restoring Autophagy Flux 
PLoS ONE  2016;11(4):e0154820.
Our previous studies have indicated that a novel curcumin derivate nicotinate-curcumin (NC) has beneficial effects on the prevention of atherosclerosis, but the precise mechanisms are not fully understood. Given that autophagy regulates lipid metabolism, the present study was designed to investigate whether NC decreases foam cell formation through restoring autophagy flux in oxidized low-density lipoprotein (ox-LDL)-treated THP-1 cells. Our results showed that ox-LDL (100 μg/ml) was accumulated in THP-1 cells and impaired autophagy flux. Ox-LDL-induced impairment of autophagy was enhanced by treatment with the autophagy inhibitor chloroquine (CQ) and rescued by the autophagy inducer rapamycin. The aggregation of ox-LDL was increased by CQ, but decreased by rapamycin. In addition, colocalization of lipid droplets with LC3-II was remarkably reduced in ox-LDL group. In contrast, NC (10 μM) rescued the impaired autophagy flux by significantly increasing level of LC3-II, the number of autophagolysosomes, and the degradation of p62 in ox-LDL-treated THP-1 cells. Inhibition of the PI3K-Akt-mTOR signaling was required for NC-rescued autophagy flux. Notably, our results showed that NC remarkably promoted the colocalization of lipid droplets with autophagolysosomes, increased efflux of cholesterol, and reduced ox-LDL accumulation in THP-1 cells. However, treatment with 3-methyladenine (3-MA) or CQ reduced the protective effects of NC on lipid accumulation. Collectively, the findings suggest that NC decreases lipid accumulation in THP-1 cells through restoring autophagy flux, and further implicate that NC may be a potential therapeutic reagent to reverse atherosclerosis.
doi:10.1371/journal.pone.0154820
PMCID: PMC4851383  PMID: 27128486
24.  Netrin-1 suppresses the MEK/ERK pathway and ITGB4 in pancreatic cancer 
Oncotarget  2016;7(17):24719-24733.
The axon guidance factor netrin-1 promotes tumorigenesis in multiple types of cancers, particularly at their advanced stages. Here, we investigate whether netrin-1 is involved in the in vivo growth of pancreatic adenocarcinoma. We show that netrin-1 is significantly under-expressed in stage-I/II pancreatic ductal adenocarcinoma (PDAC). Netrin-1 over-expression effectively arrests the growth of xenografted PDAC cells without decreasing cell proliferation or increasing apoptosis in two-dimensional cultures in vitro. Integrin-beta4 (ITGB4) expression is significantly reduced, and ITGB4-knockdown mimics the tumor-suppressive effect of netrin-1, implying that ITGB4 is a main target of netrin-1 in constraining PDAC. We further show that netrin-1 signals to UNC5B/FAK to stimulate nitric oxide production, which promotes PP2A-mediated inhibition of the MEK/ERK pathway and decreases phosphorylated-c-Jun recruitment to the ITGB4 promoter. Our findings suggest that netrin-1 can suppress the growth of PDAC and provide a mechanistic insight into this suppression.
doi:10.18632/oncotarget.8348
PMCID: PMC5029736  PMID: 27034160
netrin-1; pancreatic ductal adenocarcinoma; PP2A; MEK/ERK; integrin-beta4
25.  Cervical Metastasis from Renal Cell Carcinoma 
Chinese Medical Journal  2016;129(8):1005-1006.
doi:10.4103/0366-6999.179790
PMCID: PMC4831518  PMID: 27064049

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