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1.  Influence of cell physiological state on gene delivery to T lymphocytes by chimeric adenovirus Ad5F35 
Scientific Reports  2016;6:22688.
Adoptive transfer of genetically-modified T cells is a promising approach for treatment of both human malignancies and viral infections. Due to its ability to efficiently infect lymphocytes, the chimeric adenovirus Ad5F35 is potentially useful as an immunotherapeutic for the genetic modification of T cells. In previous studies, it was found that the infection efficiency of Ad5F35 was significantly increased without enhanced expression of the viral receptor after T cell stimulation; however, little is known about the underlying mechanism. Nonetheless, cell physiology has long been thought to affect viral infection. Therefore, we aimed to uncover the physiologic changes responsible for the increased infection efficiency of Ad5F35 following T cell stimulation. Given the complexity of intracellular transport we analyzed viral binding, entry, and escape using a Jurkat T cell model and found that both cell membrane fluidity and endosomal escape of Ad5F35 were altered under different physiological states. This, in turn, resulted in differences in the amount of virus entering cells and reaching the cytoplasm. These results provide additional insight into the molecular mechanisms underlying Ad5F35 infection of T cells and consequently, will help further the clinical application of genetically-modified T cells for immunotherapy.
doi:10.1038/srep22688
PMCID: PMC4789598  PMID: 26972139
2.  A novel M2e-multiple antigenic peptide providing heterologous protection in mice 
Journal of Veterinary Science  2016;17(1):71-78.
Swine influenza viruses (SwIVs) cause considerable morbidity and mortality in domestic pigs, resulting in a significant economic burden. Moreover, pigs have been considered to be a possible mixing vessel in which novel strains loom. Here, we developed and evaluated a novel M2e-multiple antigenic peptide (M2e-MAP) as a supplemental antigen for inactivated H3N2 vaccine to provide cross-protection against two main subtypes of SwIVs, H1N1 and H3N2. The novel tetra-branched MAP was constructed by fusing four copies of M2e to one copy of foreign T helper cell epitopes. A high-yield reassortant H3N2 virus was generated by plasmid based reverse genetics. The efficacy of the novel H3N2 inactivated vaccines with or without M2e-MAP supplementation was evaluated in a mouse model. M2e-MAP conjugated vaccine induced strong antibody responses in mice. Complete protection against the heterologous swine H1N1 virus was observed in mice vaccinated with M2e-MAP combined vaccine. Moreover, this novel peptide confers protection against lethal challenge of A/Puerto Rico/8/34 (H1N1). Taken together, our results suggest the combined immunization of reassortant inactivated H3N2 vaccine and the novel M2e-MAP provided cross-protection against swine and human viruses and may serve as a promising approach for influenza vaccine development.
doi:10.4142/jvs.2016.17.1.71
PMCID: PMC4808646  PMID: 27051342
H3N2; M2e-multiple antigenic peptide; high-yield; inactivated vaccine; swine influenza virus
3.  Antacid Use and De Novo Brain Metastases in Patients with Epidermal Growth Factor Receptor-Mutant Non-Small Cell Lung Cancer Who Were Treated Using First-Line First-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors 
PLoS ONE  2016;11(2):e0149722.
Background
Antacid treatments decrease the serum concentrations of first-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs), although it is unknown whether antacids affect clinical outcomes. As cerebrospinal fluid concentrations of TKIs are much lower than serum concentrations, we hypothesized that this drug-drug interaction might affect the prognosis of patients with de novo brain metastases.
Materials and Methods
This retrospective study evaluated 269 patients with EGFR-mutant non-small cell lung cancer (NSCLC) who had been diagnosed between December 2010 and December 2013, and had been treated using first-line first-generation EGFR-TKIs. Among these patients, we identified patients who concurrently used H2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs) as antacids. Patients who exhibited >30% overlap between the use of TKIs and antacids were considered antacid users.
Results
Fifty-seven patients (57/269, 21.2%) were antacid users, and antacid use did not significantly affect progression-free survival (PFS; no antacids: 11.2 months, H2RAs: 9.4 months, PPIs: 6.7 months; p = 0.234). However, antacid use significantly reduced overall survival (OS; no antacids: 25.0 months, H2RAs: 15.5 months, PPIs: 11.3 months; p = 0.002). Antacid use did not affect PFS for various metastasis sites, although antacid users with de novo brain metastases exhibited significantly shorter OS, compared to non-users (11.8 vs. 16.3 months, respectively; p = 0.041). Antacid use did not significantly affect OS in patients with bone, liver, or pleural metastases.
Conclusion
Antacid use reduced OS among patients with EGFR-mutant NSCLC who were treated using first-line first-generation EGFR-TKIs, and especially among patients with de novo brain metastases.
doi:10.1371/journal.pone.0149722
PMCID: PMC4760710  PMID: 26894507
4.  Serum Calcium Concentration Is Inversely Associated With Radiographic Knee Osteoarthritis 
Medicine  2016;95(6):e2838.
Abstract
To examine the relationship between serum calcium (Ca) concentration and radiographic knee osteoarthritis (OA).
This study covered a total of 2855 subjects. The serum Ca concentration was detected by the Arsenazo III method. The radiographic OA of the knee was defined as changes equivalent to Kellgren–Lawrence grade 2 on 1 side at least. The serum Ca concentration was categorized into 4 quartiles, which are ≤2.27, 2.28–2.34, 2.35–2.41, and ≥2.42 mmol/L, respectively. The relationship between serum Ca and radiographic knee OA was examined using the multivariable logistic analysis after adjusting a series of potential confounding factors. For each quartile of the relationship between serum Ca concentration and radiographic knee OA, the OR with 95% CI was calculated, and the one with the lowest value was considered to be the reference.
An inverse association existed between serum Ca concentration and radiographic OA of the knee in the multivariable model and the model where the factors of age, sex, and BMI were adjusted. The multivariable-adjusted OR (95% CI) for radiographic knee OA in the second, third, and fourth quartiles of serum Ca concentration were 1.05 (95% CI: 0.83–1.31), 1.01 (95% CI: 0.80–1.27), and 0.79 (95% CI: 0.62–1.00), respectively, in comparison with the reference (first) quartile. A trend approaching to statistical significant (P = 0.06) was observed. Meanwhile, the relative odds of radiographic OA of the knee were decreased by 0.79 times in the fourth quartile in comparison with the reference.
There is likely to be an inverse association between serum Ca concentration and radiographic OA of the knee.
doi:10.1097/MD.0000000000002838
PMCID: PMC4753953  PMID: 26871857
5.  Associations of 6p21.3 Region with Age-related Macular Degeneration and Polypoidal Choroidal Vasculopathy 
Scientific Reports  2016;6:20914.
Neovascular age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV) are leading causes of blindness in aging populations. This study was conducted to investigate the associations of chromosome 6p21.3 region, including CFB-SKIV2L-TNXB-FKBPL-NOTCH4 genes, with both neovascular AMD and PCV. Six single nucleotide polymorphisms (SNPs) in this region and two known AMD-associated SNPs in CFH (rs800292) and HTRA1 (rs11200638) were genotyped in a Han Chinese cohort composed of 490 neovascular AMD patients, 419 PCV patients and 1316 controls. Among the SNPs, TNXB rs12153855 and FKBPL rs9391734 conferred an increased susceptibility to neovascular AMD (P = 2.8 × 10−4 and 0.001, OR = 1.80 and 1.76, respectively), while SKIV2L exerted a protective effect on neovascular AMD (P = 2.2 × 10−4, OR = 0.49). Rs12153855C and rs9391734A alleles could further increase the susceptibility to AMD in subjects with rs800292, rs11200638 and rs429608 risk alleles. However, only the association of SKIV2L rs429608 remained significant after adjusting for rs800292, rs11200638 and the other 5 SNPs. The protective haplotype AATGAG exhibited significant association with neovascular AMD (permutation P = 0.015, OR = 0.34). None of the SNPs in this region was associated with PCV. Association profiles of 6p21.3 region showed discrepancy between neovascular AMD and PCV, indicating possible molecular and pathological differences between these two retinal disorders.
doi:10.1038/srep20914
PMCID: PMC4748259  PMID: 26861912
6.  Tumor growth suppression by inhibiting both autophagy and STAT3 signaling in HNSCC 
Oncotarget  2015;6(41):43581-43593.
Autophagy is considered as a double-edged sword. It can prolong the survival of cancer cells and enhance its resistance to apoptosis, and paradoxically, defective autophagy has been linked to increased tumorigenesis, but the mechanism behind this phenomenon is unclear. In this study, we demonstrated that decreased phosphorylation of signal transducer and activator of transcription 3 (p-STAT3) was correlated with increased autophagy through the Akt/mTOR and Erk signaling pathways in human head and neck squamous cell carcinoma (HNSCC). We also showed that blockage of STAT3 by NSC74859 could markedly induce apoptotic cell death and autophagy. Meanwhile, increased autophagy inhibited apoptosis. The pharmacological or genetic inhibition of autophagy and STAT3 further sensitized HNSCC cells to apoptosis. Furthermore, evidence from xenograft model proved that suppressed STAT3 activity combined with inhibition of autophagy promoted tumor regression better than either treatment alone. Taken together, this present study demonstrated that autophagy alleviates apoptotic cell death in HNSCC, and combination of inhibition of STAT3 by NSC74859 and autophagy might be a promising new therapeutic strategy for HNSCC.
PMCID: PMC4791252  PMID: 26561201
autophagy; STAT3; head and neck cancer; apoptosis
7.  STAT3 blockade enhances the efficacy of conventional chemotherapeutic agents by eradicating head neck stemloid cancer cell 
Oncotarget  2015;6(39):41944-41958.
Signaling transducer and activator 3 (STAT3) and cancer stem cells (CSCs) have garnered huge attention as a therapeutic focus, based on evidence that they may represent an etiologic root of tumor initiation and radio-chemoresistance. Here, we investigated the high phosphorylation status of STAT3 (p-STAT3) and its correlation with self-renewal markers in head neck squamous cell carcinoma (HNSCC). Over-expression of p-STAT3 was found to have increased in post chemotherapy HNSCC tissue. We showed that blockade of p-STAT3 eliminated both bulk tumor and side population (SP) cells with characteristics of CSCs in vitro. Inhibition of p-STAT3 using small molecule S3I-201 significantly delayed tumorigenesis of spontaneous HNSCC in mice. Combining blockade of p-STAT3 with cytotoxic drugs cisplatin, docetaxel, 5-fluorouracil (TPF) enhanced the antitumor effect in vitro and in vivo with decreased tumor sphere formation and SP cells. Taken together, our results advocate blockade of p-STAT3 in combination with conventional chemotherapeutic drugs enhance efficacy by improving CSCs eradication in HNSCC.
PMCID: PMC4747200  PMID: 26556875
STAT3; head neck squamous cell carcinoma; cancer stem cell; S3I-201; chemotherapy
8.  PD-1 blockade attenuates immunosuppressive myeloid cells due to inhibition of CD47/SIRPα axis in HPV negative head and neck squamous cell carcinoma 
Oncotarget  2015;6(39):42067-42080.
Myeloid-derived suppressor cells (MDSCs) and tumor associated macrophages (TAMs) play key roles in the tumor immune suppressive network and tumor progression. However, precise roles of programmed death-1 (PD-1) in immunological functions of MDSCs and TAMs in head and neck squamous cell carcinoma (HNSCC) have not been clearly elucidated. In the present study, we show that PD-1 and PD-L1 levels were significantly higher in human HNSCC specimen than in normal oral mucosa. MDSCs and TAMs were characterized in mice and human HNSCC specimen, correlated well with PD-1 and PD-L1 expression. αPD-1 treatment was well tolerated and significantly reduced tumor growth in the HNSCC mouse model along with significant reduction in MDSCs and TAMs in immune organs and tumors. Molecular analysis suggests a reduction in the CD47/SIRPα pathway by PD-1 blockade, which regulates MDSCs, TAMs, dendritic cell as well as effector T cells. Hence, these data identify that PD-1/PD-L1 axis is significantly increased in human and mouse HNSCC. Adoptive αPD-1 immunotherapy may provide a novel therapeutic approach to modulate the micro- and macro- environment in HNSCC.
PMCID: PMC4747210  PMID: 26573233
HNSCC; myeloid-derived suppressor cell; tumor associated macrophagy; PD-1
9.  An Atypically Large, Free-Floating Thrombus Extending From the Lung to the Left Atrium via a Pulmonary Vein 
Medicine  2015;94(46):e1853.
Abstract
An atypically large, free-floating thrombus extending from primary pulmonary malignancy into the left atrium (LA) is a rare phenomenon. Here, we report a 61-year-old man presenting with a large mass in the lower lobe of the left lung, extending to LA via the left inferior pulmonary vein.
The thrombus remained clinically silent and was detected by computed tomography (CT) and transthoracic echocardiography. To prevent life-threatening complications including systemic embolism and sudden death, the patient underwent surgical excision of the mass under cardiopulmonary bypass. Pathology of the tumor and the embolus was confirmed as moderately differentiated squamous cell carcinoma. Furthermore, immunohistochemical studies demonstrated consistency of the tumor cells in this pathological category.
The patient tolerated the surgery well and his condition began to improve gradually after the operation.
doi:10.1097/MD.0000000000001853
PMCID: PMC4652807  PMID: 26579798
10.  Cytokine profiles in peritoneal dialysis effluent predicts the peritoneal solute transport rate in continuous ambulatory peritoneal dialysis patients 
Cytokine profiles in peritoneal dialysis effluent (PDE) vary among patients of continuous ambulatory peritoneal dialysis (CAPD), which may indicate the therapeutic efficiency of CAPD. We examined the cytokine profiles of PDE with stable CAPD and analyzed their relation with the peritoneal solute transport rate (PSTR). The peritoneal equilibration test (PET) was performed to evaluate peritoneal solute transport rate (PSTR) by calculating dialysate/plasma creatinine (D/P Cr). Patients were then divided into either low and low-average transport (L/A), or high and high average transport (H/A) groups according PET results. Overnight PDE were collected from 30 CAPD patients and various cytokines and growth factors were detected using the Luminex Flex Map 3D system. The concentrations of interleukin (IL)-6, monocyte chemoattractant protein (MCP)-1 and tumor necrosis factor (TNF)-α in dialysate were 66.4±59.8, 221±96.1 and 1.79±0.34 pg/mL respectively while IL-17A, IL-17F, IL-21, IL-22 or IL-23 could not be detected. Higher IL-6 levels were found in the H/A group as compared with the L/A group (P<0.05); however MCP-1, TNF-α, transforming growth factor (TGF)-β1 and VEGF levels were not significantly different between these two groups (P>0.05). We found that IL-6, MCP-1, vascular endothelial growth factor (VEGF) and TGF-β1 levels were closely correlated with each other and all significantly associated with D/P Cr. Multivariate analysis showed that D/P Cr was independently correlated with IL-6 and negatively correlated with serum albumin (r=-0.369, P=0.045). In conclusion, our study indicates that systemic analysis of cytokine profiles in PDE reveals the transport characteristics of CAPD patients. Long-term follow-up study should be necessary to further confirm the value of cytokine detection in evaluation of PD therapeutic efficiency.
PMCID: PMC4723803  PMID: 26884958
Peritoneal dialysis; inflammation; Luminex; MT; neovascularization
11.  C4.4A as a biomarker of head and neck squamous cell carcinoma and correlated with epithelial mesenchymal transition 
American Journal of Cancer Research  2015;5(12):3505-3515.
C4.4A, a member of the Ly6/uPAR family of membrane proteins, has been identified as a metastasis-associated molecule, but little is known about its actual expression and possible function in head and neck squamous cell carcinoma (HNSCC). To explore diagnostic and prognostic roles of C4.4A in HNSCC, we investigated the expression of C4.4A in human HNSCC tissue array which contains 43 HNSCC, 6 epithelial dysplasia and 16 normal oral mucosa. Expression of C4.4A was significantly increased in epithelial dysplasia and HNSCC when compared with normal oral mucosa. Moreover, high C4.4A expression indicated a rather poor prognosis of HNSCC patients. To better understand the function of C4.4A in HNSCC progression, we investigated epithelial to mesenchymal transition (EMT) associated proteins including transforming growth factor (TGF-β1), Slug and CD147 in HNSCC. The expression of TGF-β1, Slug, and CD147 was significantly increased in HNSCC when compared with normal oral mucosa. Meanwhile, the expression of C4.4A was significantly correlated with TGF-β1, Slug, and CD147 in HNSCC tissue array. Furthermore, knockdown of C4.4A decreased the cell invasion and migration in CAL27 cell line and suppressed the EMT with increased E-cadherin and decreased N-cadherin and Slug. Our study demonstrated that C4.4A was a potential marker for prognosis of HNSCC, and C4.4A participated in EMT program in HNSCC progression.
PMCID: PMC4731626  PMID: 26885441
C4.4A; TGF-β1; slug; CD147; head and neck squamous cell carcinoma; EMT
12.  Volasertib suppresses tumor growth and potentiates the activity of cisplatin in cervical cancer 
American Journal of Cancer Research  2015;5(12):3548-3559.
Volasertib (BI 6727), a highly selective and potent inhibitor of PLK1, has shown broad antitumor activities in the preclinical and clinical studies for the treatment of several types of cancers. However, the anticancer effect of volasertib on cervical cancer cells is still unknown. In the present study, we show that volasertib can markedly induce cell growth inhibition, cell cycle arrest at G2/M phase and apoptosis with the decreased protein expressions of PLK1 substrates survivin and wee1 in human cervical cancer cells. Furthermore, volasertib also enhances the intracellular reactive oxidative species (ROS) levels, and pretreated with ROS scavenger N-acety-L-cysteine totally blocks ROS generation but partly reverses volasertib-induced apoptosis. In addition, volasertib significantly potentiates the activity of cisplatin to inhibit the growth of cervical cancer in vitro and in vivo. In brief, volasertib suppresses tumor growth and potentiates the activity of cisplatin in cervical cancer, suggesting the combination of volasertib and cisplatin may be a promising strategy for the treatment of patients with cervical cancer.
PMCID: PMC4731630  PMID: 26885445
Volasertib; cisplatin; cervical cancer; combination therapy
13.  Choledochoduodenal fistula in Mainland China: a review of epidemiology, etiology, diagnosis and management 
Purpose
Choledochoduodenal fistula (CDF) is an extremely rare condition even in the most populous nations. However, diagnostic tools are inadequate for the young surgeon to be made aware of such a rare condition before surgery. Hence, basic understanding of the epidemiology, etiology, and management for this unusual but discoverable condition are necessary and essential.
Methods
The exclusive case reports of CDF, which were published from 1983 to 2014 concerning mainland Chinese people, were performed to review the epidemiology, etiology, and management.
Results
A total of 728 cases were incorporated into this review among 48 papers. More than half of the CDF cases were female (416) with an average age of 57.3 years. CDF was usually caused by cholelithiasis (573 of 728). Epigastric pain (589 of 728) and cholangitis (395 of 728) were the most common symptoms of CDF. CDF was usually detected and confirmed by endoscopic retrograde cholangiopancreatography (ERCP) (475 of 728) in Mainland China. The fistulas larger than 1 cm (82 of 654) were recommended for surgical biliary reconstruction. Fistulas between 0.5 cm and 1.0 cm (467 of 654) which were followed frequently by cholangitis attacks also required surgery; the rest were recommended to have stone removal and/or the application of an effective biliary drainage. Fistulas less than 0.5 cm (105 of 654) were usually received conservative therapy.
Conclusion
CDF should be considered in differential diagnosis of recurrent epigastric pain and cholangitis. A possible ERCP should be arranged to investigate carefully. Depending on the size of fistula and clinical presentation, different programs for CDF are indicated, ranging from drug therapy to choledochojejunostomy.
doi:10.4174/astr.2015.89.5.240
PMCID: PMC4644904  PMID: 26576403
Biliary fistula; Epidemiology; Disease management
14.  Time-averaged serum potassium levels and its fluctuation associate with 5-year survival of peritoneal dialysis patients: two-center based study 
Scientific Reports  2015;5:15743.
The time-averaged serum potassium was more comprehensive to reflect the all-time changes of serum potassium levels during peritoneal dialysis (PD). However, the association of fluctuation of time-averaged serum potassium level with long-time survival of PD patients remains unknown. In this retrospective study, we included 357 incident PD patients in 2 centers from January 1, 2007 to October 31, 2012 with follow-up through October 31, 2014. Our data demonstrated that it was the lower time-averaged serum potassium level rather than baseline of serum potassium level that was associated with high risk of death. Patients with higher standard deviation (SD) had significantly poorer all-cause (p = 0.016) and cardiovascular mortality (p = 0.041). Among the patients with time-averaged serum potassium levels below 4.0 mEq/L, a lower mean value was more important than its SD to predict death risk. In contrast, the patients with time-averaged serum potassium levels above 4.0 mEq/L, those with serum potassium SD < 0.54 mEq/L, exhibited a higher 3-year and 5-year survival rate for both all-cause and cardiovascular mortality compared to the control groups. Our data clearly suggested both time-averaged serum potassium and its fluctuation contributed disproportionately to the high death risk in PD patients.
doi:10.1038/srep15743
PMCID: PMC4623707  PMID: 26507157
15.  Enhanced Dispersion of TiO2 Nanoparticles in a TiO2/PEDOT:PSS Hybrid Nanocomposite via Plasma-Liquid Interactions 
Scientific Reports  2015;5:15765.
A facile method to synthesize a TiO2/PEDOT:PSS hybrid nanocomposite material in aqueous solution through direct current (DC) plasma processing at atmospheric pressure and room temperature has been demonstrated. The dispersion of the TiO2 nanoparticles is enhanced and TiO2/polymer hybrid nanoparticles with a distinct core shell structure have been obtained. Increased electrical conductivity was observed for the plasma treated TiO2/PEDOT:PSS nanocomposite. The improvement in nanocomposite properties is due to the enhanced dispersion and stability in liquid polymer of microplasma treated TiO2 nanoparticles. Both plasma induced surface charge and nanoparticle surface termination with specific plasma chemical species are proposed to provide an enhanced barrier to nanoparticle agglomeration and promote nanoparticle-polymer binding.
doi:10.1038/srep15765
PMCID: PMC4620561  PMID: 26497265
16.  Identification and Classification of Rhizobia by Matrix-Assisted Laser Desorption/Ionization Time-Of-Flight Mass Spectrometry 
Mass spectrometry (MS) has been widely used for specific, sensitive and rapid analysis of proteins and has shown a high potential for bacterial identification and characterization. Type strains of four species of rhizobia and Escherichia coli DH5α were employed as reference bacteria to optimize various parameters for identification and classification of species of rhizobia by matrix-assisted laser desorption/ionization time-of-flight MS (MALDI TOF MS). The parameters optimized included culture medium states (liquid or solid), bacterial growth phases, colony storage temperature and duration, and protein data processing to enhance the bacterial identification resolution, accuracy and reliability. The medium state had little effects on the mass spectra of protein profiles. A suitable sampling time was between the exponential phase and the stationary phase. Consistent protein mass spectral profiles were observed for E. coli colonies pre-grown for 14 days and rhizobia for 21 days at 4°C or 21°C. A dendrogram of 75 rhizobial strains of 4 genera was constructed based on MALDI TOF mass spectra and the topological patterns agreed well with those in the 16S rDNA phylogenetic tree. The potential of developing a mass spectral database for all rhizobia species was assessed with blind samples. The entire process from sample preparation to accurate identification and classification of species required approximately one hour.
doi:10.4172/jpb.1000357
PMCID: PMC4616259  PMID: 26500417
Bacterial identification; Bacterial classification; MALDI TOF MS; Rhizobium
17.  High PD-L1 expression was associated with poor prognosis in 870 Chinese patients with breast cancer 
Oncotarget  2015;6(32):33972-33981.
Background
To investigate the role of PD-L1 expression in tumor recurrence and metastasis in Chinese patients with breast cancer.
Methods
Suitable tissue samples were available from 870 patients with breast cancer. Paraffin-embedded tumor sections were stained with PD-L1 antibody. The correlations between PD-L1 expression and clinical characteristics, ER/PR/HER2 status and survival parameters were analyzed. Kaplan-Meier and univariate Cox proportional hazards model analyses were used to compare the survival of patients with high PD-L1 expression and patients with no PD-L1 expression.
Results
The median follow-up time was 98 months(range, 17–265 months). The positive rate of PD-L1 expression in breast cancer was 21.7% (189/870). PD-L1 high expression was inversely associated with larger tumor size, higher tumor grade, more positive lymph node number, as well as negative ER and PR status. PD-L1 expression was particularly higher in TNBC compared with non-TNBC, although no statistical significance was observed. Nomogram logistic regression results based on clinical and pathological features showed that the following factors were more likely associated with high PD-L1 expression: patient age younger than 35 years, larger tumor size, lymphovascular invasion and advanced stage. Our data indicated that patients with high PD-L1 expression had poor DFS, DMFS and overall survival compared with those with no PD-L1 expression. Univariate Cox proportional hazards model analysis showed that PD-L1 was an independent prognostic factor for tumor prognosis.
Conclusions
PD-L1 expression is an important indicator of unfavorable prognosis in breast cancer patients.
PMCID: PMC4741818  PMID: 26378017
PD-L1; breast cancer; ER; PR; prognosis; nomogram
18.  Dressed Gain from the Parametrically Amplified Four-Wave Mixing Process in an Atomic Vapor 
Scientific Reports  2015;5:15058.
With a forward cone emitting from the strong pump laser in a thermal rubidium atomic vapor, we investigate the non-degenerate parametrically amplified four-wave mixing (PA-FWM) process with dressing effects in a three-level “double-Λ” configuration both theoretically and experimentally. By seeding a weak probe field into the Stokes or anti-Stokes channel of the FWM, the gain processes are generated in the bright twin beams which are called conjugate and probe beams, respectively. However, the strong dressing effect of the pump beam will dramatically affect the gain factors both in the probe and conjugate channels, and can inevitably impose an influence on the quantum effects such as entangled degree and the quantum noise reduction between the two channels. We systematically investigate the intensity evolution of the dressed gain processes by manipulating the atomic density, the Rabi frequency and the frequency detuning. Such dressing effects are also visually evidenced by the observation of Autler-Townes splitting of the gain peaks. The investigation can contribute to the development of quantum information processing and quantum communications.
doi:10.1038/srep15058
PMCID: PMC4604462  PMID: 26463588
19.  Recql5 protects against lipopolysaccharide/D-galactosamine-induced liver injury in mice 
World Journal of Gastroenterology : WJG  2015;21(36):10375-10384.
AIM: To investigate the effects of Recql5 deficiency on liver injury induced by lipopolysaccharide/D-galactosamine (LPS/D-Gal).
METHODS: Liver injury was induced in wild type (WT) or Recql5-deficient mice using LPS/D-Gal, and assessed by histological, serum transaminases, and mortality analyses. Hepatocellular apoptosis was quantified by transferase dUTP nick end labeling assay and Western blot analysis of cleaved caspase-3. Liver inflammatory chemokine and cytochrome P450 expression was analyzed by quantitative reverse transcription-PCR. Neutrophil infiltration was evaluated by myeloperoxidase activity. Expression and phosphorylation of ERK, JNK, p65, and H2A.X was determined by Western blot. Oxidative stress was evaluated by measuring malondialdehyde production and nitric oxide synthase, superoxide dismutase, glutathione peroxidase, catalase, and glutathione reductase activity.
RESULTS: Following LPS/D-Gal exposure, Recql5-deficient mice exhibited enhanced liver injury, as evidenced by more severe hepatic hemorrhage, higher serum aspartate transaminase and alanine transaminase levels, and lower survival rate. As compared to WT mice, Recql5-deficient mice showed an increased number of apoptotic hepatocytes and higher cleaved caspase-3 levels. Recql5-deficient mice exhibited increased DNA damage, as evidenced by increased γ-H2A.X levels. Inflammatory cytokine levels, neutrophil infiltration, and ERK phosphorylation were also significantly increased in the knockout mice. Additionally, Recql5-deficicent mice exhibited increased malondialdehyde production and elevated inducible nitric oxide synthase, superoxide dismutase, glutathione peroxidase, catalase, and glutathione reductase activity, indicative of enhanced oxidative stress. Moreover, CYP450 expression was significantly downregulated in Recql5-deficient mice after LPS/D-Gal treatment.
CONCLUSION: Recql5 protects the liver against LPS/D-Gal-induced injury through suppression of hepatocyte apoptosis and oxidative stress and modulation of CYP450 expression.
doi:10.3748/wjg.v21.i36.10375
PMCID: PMC4579884  PMID: 26420964
Recql5; Liver injury; Apoptosis; Oxidative stress; CYP450
20.  Higher blood hematocrit predicts hyperuricemia: a prospective study of 62897 person-years of follow-up 
Scientific Reports  2015;5:13765.
This prospective study aimed to investigate the relationship between higher hematocrit (Hct) level and hyperuricemia (HU) incidence. A total of 27540 subjects were included. Baseline Hct was classified into four categories based on the quartile distribution of the study population. A cox proportional hazards regression was used to evaluate the risk of HU incidence across the Hct quartiles after adjusting a number of potential confounding factors. Out of the 62897 person-years of follow-up, 2745 new cases of HU were developed. In models adjusted for known risk factors of HU, higher Hct was used to predict HU incidence independently in a graded manner (p = 0.02): compared with subjects in the lowest quartile, subjects in the highest quartile of Hct (hazard ratio = 1.20; 95% confidence interval: 1.03–1.41) were n20% more likely to develop HU. Sensitivity analysis indicated that the hazard ratios increased with the extension of the minimum follow-up interval. When the minimum follow-up interval was restricted to 4 years, subjects in the highest quartile of Hct were 70% more likely to develop HU, compared with the lowest quartile. Higher Hct, a routinely measured inexpensive biomarker was independently associated with the incidence of HU even within the normal range.
doi:10.1038/srep13765
PMCID: PMC4559718  PMID: 26337238
21.  Baseline and Trend of Lymphocyte-to-Monocyte Ratio as Prognostic Factors in Epidermal Growth Factor Receptor Mutant Non-Small Cell Lung Cancer Patients Treated with First-Line Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors 
PLoS ONE  2015;10(8):e0136252.
Background
Patients with early-stage lung cancer who have a high baseline lymphocyte-to-monocyte ratio (LMR) have a favorable prognosis. However, the prognostic significance of LMR in patients with advanced-stage EGFR-mutant non-small cell lung cancer (NSCLC) receiving first-line epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) has not been established. We conducted a retrospective analysis to investigate the influence of LMR on clinical outcomes including progression-free survival (PFS) and overall survival (OS) in EGFR-mutant patients with NSCLC.
Materials and Methods
Of 1310 lung cancer patients diagnosed between January 2011 and October 2013, 253 patients receiving first-line EGFR-TKIs for EGFR-mutant NSCLC were included. The cut-off values for baseline and the 1-month-to-baseline ratio of LMR (MBR), determined by using receiver operating characteristic curves, were 3.29 and 0.63, respectively. Patients were divided into 3 prognostic groups: high LMR and MBR, high LMR or MBR, and low LMR and MBR.
Results
The mean patient age was 65.2 years, and 41% were men. The median PFS and OS were 10.3 and 22.0 months, respectively. The PFS in patients with high LMR and MBR, high LMR or MBR, and low LMR and MBR were 15.4, 7.1, and 2.0 months, respectively (p < 0.001), whereas the OS were 32.6, 13.7, and 5.1 months, respectively (p < 0.001).
Conclusion
A combination of baseline and trend of LMR can be used to identify patients with a high mortality risk in EGFR-mutant NSCLC patients receiving first-line EGFR-TKIs.
doi:10.1371/journal.pone.0136252
PMCID: PMC4552380  PMID: 26313661
22.  ING5 suppresses proliferation, apoptosis, migration and invasion, and induces autophagy and differentiation of gastric cancer cells: a good marker for carcinogenesis and subsequent progression 
Oncotarget  2015;6(23):19552-19579.
Here, we found that ING5 overexpression increased autophagy, differentiation, and decreased proliferation, apoptosis, migration, invasion and lamellipodia formation in gastric cancer cells, while ING5 knockdown had the opposite effects. In SGC-7901 transfectants, ING5 overexpression caused G1 arrest, which was positively associated with 14-3-3 overexpression, Cdk4 and c-jun hypoexpression. The induction of Bax hypoexpression, Bcl-2, survivin, 14-3-3, PI3K, p-Akt and p70S6K overexpression by ING5 decreased apoptosis in SGC-7901 cells. The hypoexpression of MMP-9, MAP1B and flotillin 2 contributed to the inhibitory effects of ING5 on migration and invasion of SGC-7901 cells. ING5 overexpression might activate both β-catenin and NF-κB pathways in SGC-7901 cells, and promote the expression of down-stream genes (c-myc, VEGF, Cyclin D1, survivin, and interleukins). Compared with the control, ING5 transfectants displayed drug resistance to triciribine, paclitaxel, cisplatin, SAHA, MG132 and parthenolide, which was positively related to their apoptotic induction and the overexpression of chemoresistance-related genes (MDR1, GRP78, GRP94, IRE, CD147, FBXW7, TOP1, TOP2, MLH1, MRP1, BRCP1 and GST-π). ING5 expression was higher in gastric cancer than matched mucosa. It was inversely associated with tumor size, dedifferentiation, lymph node metastasis and clinicopathological staging of cancer. ING5 overexpression suppressed growth, blood supply and lung metastasis of SGC-7901 cells by inhibiting proliferation, enhancing autophagy and apoptosis in xenograft models. It was suggested that ING5 expression might be employed as a good marker for gastric carcinogenesis and subsequent progression by inhibiting proliferation, growth, migration, invasion and metastasis. ING5 might induce apoptotic and chemotherapeutic resistances of gastric cancer cells by activating β-catenin, NF-κB and Akt pathways.
PMCID: PMC4637305  PMID: 25980581
gastric cancer; ING5; aggressive phenotypes; progression; carcinogenesis
23.  BTG1 expression correlates with pathogenesis, aggressive behaviors and prognosis of gastric cancer: a potential target for gene therapy 
Oncotarget  2015;6(23):19685-19705.
Here, we found that BTG1 overexpression inhibited proliferation, migration and invasion, induced G2/M arrest, differentiation, senescence and apoptosis in BGC-823 and MKN28 cells (p < 0.05). BTG1 transfectants showed a higher mRNA expression of Cyclin D1 and Bax, but a lower mRNA expression of cdc2, p21, mTOR and MMP-9 than the control and mock (p < 0.05). After treated with cisplatin, MG132, paclitaxel and SAHA, both BTG1 transfectants showed lower mRNA viability and higher apoptosis than the control in both time- and dose-dependent manners (p < 0.05) with the hypoexpression of chemoresistance-related genes (slug, CD147, GRP78, GRP94, FBXW7 TOP1, TOP2 and GST-π). BTG1 expression was restored after 5-aza-2′-deoxycytidine treatment in gastric cancer cells. BTG1 expression was statistically lower in gastric cancer than non-neoplastic mucosa and metastatic cancer in lymph node (p < 0.05). BTG1 expression was positively correlated with depth of invasion, lymphatic and venous invasion, lymph node metastasis, TNM staging and worse prognosis (p < 0.05). The diffuse-type carcinoma showed less BTG1 expression than intestinal- and mixed-type ones (p < 0.05). BTG1 overexpression suppressed tumor growth and lung metastasis of gastric cancer cells by inhibiting proliferation, enhancing autophagy and apoptosis in xenograft models. It was suggested that down-regulated BTG1 expression might promote gastric carcinogenesis partially due to its promoter methylation. BTG1 overexpression might reverse the aggressive phenotypes and be employed as a potential target for gene therapy of gastric cancer.
PMCID: PMC4637314  PMID: 26050197
gastric cancer; BTG1; pathobiological behaviors; carcinogenesis; gene therapy
24.  The roles of BTG3 expression in gastric cancer: a potential marker for carcinogenesis and a target molecule for gene therapy 
Oncotarget  2015;6(23):19841-19867.
BTG (B-cell translocation gene) can inhibit cell proliferation, metastasis and angiogenesis, cell cycle progression, and induce differentiation in various cells. Here, we found that BTG3 overexpression inhibited proliferation, induced S/G2 arrest, differentiation, autophagy, apoptosis, suppressed migration and invasion in MKN28 and MGC803 cells (p < 0.05). BTG3 transfectants showed a higher mRNA expression of p27, Bax, 14-3-3, Caspase-3, Caspase-9, Beclin 1, NF-κB, IL-1, -2, -4, -10 and -17, but a lower mRNA expression of p21, MMP-9 and VEGF than the control and mock (p < 0.05). At protein level, BTG3 overexpression increased the expression of CDK4, AIF, LC-3B, Beclin 1 and p38 (p < 0.05), but decreased the expression of p21 and β-catenin in both transfectants (p < 0.05). After treated with cisplatin, MG132, paclitaxel and SAHA, both BTG3 transfectants showed lower viability and higher apoptosis than the control in both time- and dose-dependent manners (p < 0.05). BTG3 expression was restored after 5-aza-2′-deoxycytidine or MG132 treatment in gastric cancer cells. BTG3 expression was decreased in gastric cancer in comparison to the adjacent mucosa (p < 0.05), and positively correlated with venous invasion and dedifferentiation of cancer (p < 0.05). It was suggested that BTG3 expression might contribute to gastric carcinogenesis. BTG3 overexpression might reverse the aggressive phenotypes and be employed as a potential target for gene therapy of gastric cancer.
PMCID: PMC4637325  PMID: 25904053
gastric cancer; BTG3; carcinogenesis; pathobiological behaviors; gene therapy

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