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1.  Essential role of aldehyde dehydrogenase 1A3 (ALDH1A3) for the maintenance of non-small cell lung cancer stem cells is associated with the STAT3 pathway 
Lung cancer stem cells (CSCs) with elevated aldehyde dehydrogenase (ALDH) activity are self-renewing, clonogenic and tumorigenic. The purpose of our study is to elucidate the mechanisms by which lung CSCs are regulated.
Experimental Design
A genome-wide gene expression analysis was performed to identify genes differentially expressed in the ALDH+ vs. ALDH− cells. RT-PCR, western blot and Aldefluor assay were used to validate identified genes. To explore the function in CSCs we manipulated their expression followed by colony and tumor formation assays.
We identified a subset of genes that were differentially expressed in common in ALDH+ cells, among which ALDH1A3 was the most upregulated gene in ALDH+ vs. ALDH− cells. ShRNA-mediated knockdown of ALDH1A3 in NSCLCs resulted in a dramatic reduction in ALDH activity, clonogenicity and tumorigenicity, indicating that ALDH1A3 is required for tumorigenic properties. By contrast, overexpression of ALDH1A3 by itself it was not sufficient to increase tumorigenicity. The ALDH+ cells also expressed more activated Signal Transducers and Activators of Transcription 3 (STAT3) than ALDH− cells. Inhibition of STAT3 or its activator EZH2 genetically or pharmacologically diminished the level of ALDH+ cells and clonogenicity. Unexpectedly, ALDH1A3 was highly expressed in female, never smokers, well differentiated tumors, or adenocarcinoma. ALDH1A3 low expression was associated with poor overall survival.
Our data show that ALDH1A3 is the predominant ALDH isozyme responsible for ALDH activity and tumorigenicity in most NSCLCs, and that inhibiting either ALDH1A3 or the STAT3 pathway are potential therapeutic strategies to eliminate the ALDH+ subpopulation in NSCLCs.
PMCID: PMC4438754  PMID: 24907115
Lung cancer; cancer stem cells; ALDH1A3; STAT3; Stattic
2.  Cigarette Smoking in Same-Sex and Different-Sex Unions: The Role of Socioeconomic and Psychological Factors 
Cigarette smoking has long been a target of public health intervention because it substantially contributes to morbidity and mortality. Individuals in different-sex marriages have lower smoking risk (i.e., prevalence and frequency) than different-sex cohabiters. However, little is known about the smoking risk of individuals in same-sex cohabiting unions. We compare the smoking risk of individuals in different-sex marriages, same-sex cohabiting unions, and different-sex cohabiting unions using pooled cross-sectional data from the 1997–2010 National Health Interview Surveys (N = 168,514). We further examine the role of socioeconomic status (SES) and psychological distress in the relationship between union status and smoking. Estimates from multinomial logistic regression models reveal that same-sex and different-sex cohabiters experience similar smoking risk when compared to one another, and higher smoking risk when compared to the different-sex married. Results suggest that SES and psychological distress factors cannot fully explain smoking differences between the different-sex married and same-sex and different-sex cohabiting groups. Moreover, without same-sex cohabiter’s education advantage, same-sex cohabiters would experience even greater smoking risk relative to the different-sex married. Policy recommendations to reduce smoking disparities among same-sex and different-sex cohabiters are discussed.
PMCID: PMC4204629  PMID: 25346559
Same-sex cohabitation; Smoking; National Health Interview Survey; Socioeconomic status; Psychological distress
3.  Role of SIRT3 in Angiotensin II-induced human umbilical vein endothelial cells dysfunction 
SIRT3, a member of the sirtuin family of NAD+-dependent deacetylases, resides primarily in the mitochondria and has been shown to deacetylate several metabolic and respiratory enzymes that regulate important mitochondrial functions. Previous researches show an important role of SIRT3 in regulating the production of reactive oxygen species (ROS), and highlight the ability of SIRT3 to protect cells from oxidative damage. A key substance of renin-angiotensin-aldosterone system (RAAS), Angiotensin II (AngII) can induce cells dysfunction by increasing the production of ROS. In this paper, we focus on the role of SIRT3 in AngII-induced human umbilical vein endothelial cells (HUVECs) dysfunction.
To study the influence of AngII on SIRT3 expression, HUVECs were treated with AngII of 10−7, 10−6, 10−5 mol/L for 24 h. SIRT3 expression was detected by wester-blotting analysis and RT-PCR. In addition, to research the role of SIRT3 in AngII-induced HUVECs,we used SIRT3 siRNA to knock down SIRT3 expression in HUVECs. Cells pretreated with negative control siRNA or SIRT3 siRNA were exposed to AngII for 24 h, and endothelial nitric oxide synthase (eNOS) expression, eNOS activity, total level of nitric oxide (NO) and ROS generation of each group were detected.
Here we show that AngII treatment could increase generation of ROS, and decrease eNOS activity and total level of NO, while upregulated eNOS expression as a compensatory mechanism. The stimulation of AngII upregulated the expression of SIRT3 in HUVECs. SIRT3 siRNA worsen the AngII-induced effects above, besides, downregulated eNOS protein expression.
These data suggest that SIRT3 plays a role of protection in AngII-induced HUVECs dysfunction via regulation of ROS generation.
PMCID: PMC4520206
SIRT3; Endothelial dysfunction; AngII; Reactive oxygen species; HUVECs
4.  Elevated Levels of Serum Tumor Markers CEA and CA15-3 Are Prognostic Parameters for Different Molecular Subtypes of Breast Cancer 
PLoS ONE  2015;10(7):e0133830.
Background & Aims
The utility of measuring carcinoembryonic antigen(CEA) and cancer antigen 15-3 (CA15-3) levels in patients with breast cancer remains controversial. The present study aims to investigate the prognostic value of preoperative serum CEA and CA15-3 levels in breast cancer patients.
Serum preoperative CEA and CA 15-3 concentration levels were measured in a total of 432 breast cancer patients. The association of tumor markers levels with clinicopathological parameters and outcomes were analyzed.
Elevated serum levels of CEA and CA15-3 were identified in 47 (10.9%) and 60(13.9%) patients, respectively. Larger tumor size, advanced axillary lymph nodal and TNM stage exhibited higher proportion of elevated CEA and CA15-3 levels. The elevation of CEA levels was significantly greater in patients with HER2 positive tumors, and the elevation of CA15-3 levels was significantly greater in ER negative breast patients. Univariate and multivariate Cox’s regression analysis revealed that elevated preoperative CEA and CA 15-3 levels were independent prognostic factors for DFS and OS. When considering the combination of both markers levels, patients with both elevated markers presented the worst survival. Independent prognostic significance of elevated preoperative serum CEA and CA15-3 levels were reconfirmed in Luminal B breast cancer.
Preoperative serum levels of CEA and CA15-3 are independent prognostic parameters for breast cancer.
PMCID: PMC4514648  PMID: 26207909
5.  Score model for predicting acute-on-chronic liver failure risk in chronic hepatitis B 
AIM: To establish a clinical scoring model to predict risk of acute-on-chronic liver failure (ACLF) in chronic hepatitis B (CHB) patients.
METHODS: This was a retrospective study of 1457 patients hospitalized for CHB between October 2008 and October 2013 at the Beijing Ditan Hospital, Capital Medical University, China. The patients were divided into two groups: severe acute exacerbation (SAE) group (n = 382) and non-SAE group (n = 1075). The SAE group was classified as the high-risk group based on the higher incidence of ACLF in this group than in the non-SAE group (13.6% vs 0.4%). Two-thirds of SAE patients were randomly assigned to risk-model derivation and the other one-third to model validation. Univariate risk factors associated with the outcome were entered into a multivariate logistic regression model for screening independent risk factors. Each variable was assigned an integer value based on the regression coefficients, and the final score was the sum of these values in the derivation set. Model discrimination and calibration were assessed using area under the receiver operating characteristic curve and the Hosmer-Lemeshow test.
RESULTS: The risk prediction scoring model included the following four factors: age ≥ 40 years, total bilirubin ≥ 171 μmol/L, prothrombin activity 40%-60%, and hepatitis B virus DNA > 107 copies/mL. The sum risk score ranged from 0 to 7; 0-3 identified patients with lower risk of ACLF, whereas 4-7 identified patients with higher risk. The Kaplan-Meier analysis showed the cumulative risk for ACLF and ACLF-related death in the two risk groups (0-3 and 4-7 scores) of the primary cohort over 56 d, and log-rank test revealed a significant difference (2.0% vs 33.8% and 0.8% vs 9.4%, respectively; both P < 0.0001). In the derivation and validation data sets, the model had good discrimination (C index = 0.857, 95% confidence interval: 0.800-0.913 and C index = 0.889, 95% confidence interval: 0.820-0.957, respectively) and calibration demonstrated by the Hosmer-Lemeshow test (χ2 = 4.516, P = 0.808 and χ2 = 1.959, P = 0.923, respectively).
CONCLUSION: Using the scoring model, clinicians can easily identify patients (total score ≥ 4) at high risk of ACLF and ACLF-related death early during SAE.
PMCID: PMC4507107  PMID: 26217089
Acute-on-chronic liver failure; Chronic hepatitis B; Prediction model; Risk score; Severe acute exacerbation
6.  Strong phylogenetic signals and phylogenetic niche conservatism in ecophysiological traits across divergent lineages of Magnoliaceae 
Scientific Reports  2015;5:12246.
The early diverged Magnoliaceae shows a historical temperate-tropical distribution among lineages indicating divergent evolution, yet which ecophysiological traits are phylogenetically conserved, and whether these traits are involved in correlated evolution remain unclear. Integrating phylogeny and 20 ecophysiological traits of 27 species, from the four largest sections of Magnoliaceae, we tested the phylogenetic signals of these traits and the correlated evolution between trait pairs. Phylogenetic niche conservatism (PNC) in water-conducting and nutrient-use related traits was identified, and correlated evolution of several key functional traits was demonstrated. Among the three evergreen sections of tropical origin, Gwillimia had the lowest hydraulic-photosynthetic capacity and the highest drought tolerance compared with Manglietia and Michelia. Contrastingly, the temperate centred deciduous section, Yulania, showed high rates of hydraulic conductivity and photosynthesis at the cost of drought tolerance. This study elucidated the regulation of hydraulic and photosynthetic processes in the temperate-tropical adaptations for Magnoliaceae species, which led to strong phylogenetic signals and PNC in ecophysiological traits across divergent lineages of Magnoliaceae.
PMCID: PMC4503962  PMID: 26179320
7.  Effect of Inoculation with Glomus versiforme on Cadmium Accumulation, Antioxidant Activities and Phytochelatins of Solanum photeinocarpum 
PLoS ONE  2015;10(7):e0132347.
The plant growth, phosphate acquisition, Cd translocation, phytochelatins (PCs) production and antioxidant parameters [superoxide dismutase (SOD), catalase (CAT), guaiacol peroxidase (POD), ascorbate peroxidase (APX), glutathione reductase (GR), glutathione (GSH), ascorbate (ASA) and malonaldehyde (MDA)] were investigated in Cd-hyperaccumulator Solanum photeinocarpum inoculated with Glomus versiforme BGC GD01C (Gv) in Cd-added soils (0, 5, 10, 20, 40 mg Cd kg-1 soil). Mycorrhizal colonization rates were generally high (from 77% to 94%), and hardly affected by Cd. Gv colonization significantly enhanced P acquisition, growth and total Cd uptakes in both shoots and roots of S. photeinocarpum at all Cd levels. Meanwhile, Gv symbiosis significantly increased Cd concentration in the roots, and decreased Cd concentration in the shoots at all Cd levels, which indicates that Gv could promote phytostabilization by enhancing Cd accumulation in the roots to inhibit its translocation to shoots and the “dilution effects” linked to an increase in plant dry matter yield and a reduced Cd partitioning to shoots. Moreover, the improvement of CAT, POD and APX activities in the leaves of mycorrhizal plants infers that Gv symbiosis helped S. photeinocarpum to relieve oxidative damage to biomolecules in Cd-contaminated soil. The evident decline of MDA content in the leaves of mycorrhizal plants indicates that Gv symbiosis evidently improved antioxidant activities, and the enhancement of PCs production in the leaves of mycorrhizal plants suggests that Gv-inoculated plant may be more efficient to relieve Cd phytotoxicity. Therefore, the possible mechanisms of Cd phytotoxicity alleviation by Gv can be concluded as the decline of Cd concentration in the shoots and the improvement of P acquisition, PCs production and activities of CAT, POD, APX in mycorrhizal plants.
PMCID: PMC4503595  PMID: 26176959
8.  Vasopressors in septic shock: a systematic review and network meta-analysis 
Vasopressor agents are often prescribed in septic shock. However, their effects remain controversial. We conducted a systematic review and Bayesian network meta-analysis to compare the effects among different types of vasopressor agents.
Data sources
We searched for relevant studies in PubMed, Embase, and the Cochrane Library databases from database inception until December 2014.
Study selection
Randomized controlled trials in adults with septic shock that evaluated different vasopressor agents were selected.
Data extraction
Two authors independently selected studies and extracted data on study characteristics, methods, and outcomes.
Data synthesis
Twenty-one trials (n=3,819) met inclusion criteria, which compared eleven vasopressor agents or vasopressor combinations (norepinephrine [NE], dopamine [DA], vasopressin [VP], epinephrine [EN], terlipressin [TP], phenylephrine [PE], TP+NE, TP + dobutamine [DB], NE+DB, NE+EN, and NE + dopexamine [DX]). Except for the superiority of NE over DA, the mortality of patients treated with any vasopressor agent or vasopressor combination was not significantly different. Compared to DA, NE was found to be associated with decreased cardiac adverse events, heart rate (standardized mean difference [SMD]: −2.10; 95% confidence interval [CI]: −3.95, −0.25; P=0.03), and cardiac index (SMD: −0.73; 95% CI: −1.14, −0.03; P=0.004) and increased systemic vascular resistance index (SVRI) (SMD: 1.03; 95% CI: 0.61, 1.45; P<0.0001). This Bayesian meta-analysis revealed a possible rank of probability of mortality among the eleven vasopressor agents or vasopressor combinations; from lowest to highest, they are NE+DB, EN, TP, NE+EN, TP+NE, VP, TP+DB, NE, PE, NE+DX, and DA.
In terms of survival, NE may be superior to DA. Otherwise, there is insufficient evidence to suggest that any other vasopressor agent or vasopressor combination is superior to another. When compared to DA, NE is associated with decreased heart rate, cardiac index, and cardiovascular adverse events, as well as increased SVRI. The effects of vasopressor agents or vasopressor combinations on mortality in patients with septic shock require further investigation.
PMCID: PMC4508075  PMID: 26203253
norepinephrine; dopamine; vasopressors; sepsis; shock; network meta-analysis
9.  Intracoronary infusion of Wharton’s jelly-derived mesenchymal stem cells in acute myocardial infarction: double-blind, randomized controlled trial 
BMC Medicine  2015;13:162.
The use of adult stem cells is limited by the quality and quantity of host stem cells. It has been demonstrated that Wharton’s jelly–derived mesenchymal stem cells (WJMSCs), a primitive stromal population, could integrate into ischemic cardiac tissues and significantly improve heart function. In this randomized, controlled trial, our aim was to assess the safety and efficacy of intracoronary WJMSCs in patients with ST-elevation acute myocardial infarction (AMI).
In a multicenter trial, 116 patients with acute ST-elevation MI were randomly assigned to receive an intracoronary infusion of WJMSCs or placebo into the infarct artery at five to seven days after successful reperfusion therapy. The primary endpoint of safety: the incidence of adverse events (AEs) within 18 months, was monitored and quantified. The endpoint of efficacy: the absolute changes in myocardial viability and perfusion of the infarcted region from baseline to four months, global left ventricular ejection fraction (LVEF) from baseline to 18 months were measured using F-18-fluorodeoxyglucose positron emission computed tomography (F-18-FDG-PET) and 99mTc-sestamibi single-photon emission computed tomography (99mTc-SPECT), and two-dimensional echocardiography, respectively.
During 18 months follow-up, AEs rates and laboratory tests including tumor, immune, and hematologic indexes were not different between the two groups. The absolute increase in the myocardial viability (PET) and perfusion within the infarcted territory (SPECT) was significantly greater in the WJMSC group [6.9 ± 0.6 % (95 %CI, 5.7 to 8.2)] and [7.1 ± 0.8 % (95 %CI, 5.4 to 8.8) than in the placebo group [3.3 ± 0.7 % (95 %CI, 1.8 to 4.7), P <0.0001] and 3.9 ± 0.6(95 %CI, 2.8 to 5.0), P = 0.002] at four months. The absolute increase in the LVEF at 18 months in the WJMSC group was significantly greater than that in the placebo group [7.8 ± 0.9 (6.0 to approximately 9.7) vs. 2.8 ± 1.2 (0.4 to approximately 5.1), P = 0.001]. Concomitantly, the absolute decreases in LV end-systolic volumes and end-diastolic volumes at 18 months in the WJMSC group were significantly greater than those in the placebo group (P = 0.0004, P = 0.004, respectively).
Intracoronary infusion of WJMSCs is safe and effective in patients with AMI, providing clinically relevant therapy within a favorable time window. This study encourages additional clinical trials to determine whether WJMSCs may serve as a novel alternative to BMSCs for cardiac stem cell-based therapy.
Trial registration
Clinical Trials NCT01291329 (02/05/2011).
PMCID: PMC4499169  PMID: 26162993
Myocardial infarction; Mesenchymal stem cells; Wharton’s jelly of umbilical cord
10.  Precision microbiome restoration of bile acid-mediated resistance to Clostridium difficile 
Nature  2014;517(7533):205-208.
The gastrointestinal tracts of mammals are colonized by hundreds of microbial species that contribute to health, including colonization resistance against intestinal pathogens1. Many antibiotics destroy intestinal microbial communities and increase susceptibility to intestinal pathogens2. Among these, Clostridium difficile, a major cause of antibiotic-induced diarrhea, greatly increases morbidity and mortality in hospitalized patients3. Which intestinal bacteria provide resistance to C. difficile infection and their in vivo inhibitory mechanisms remain unclear. By treating mice with different antibiotics that result in distinct microbiota changes and lead to varied susceptibility to C. difficile, we correlated loss of specific bacterial taxa with development of infection. Mathematical modeling augmented by microbiota analyses of hospitalized patients identified resistance-associated bacteria common to mice and humans. Using these platforms, we determined that Clostridium scindens, a bile acid 7-dehydroxylating intestinal bacterium, is associated with resistance to C. difficile infection and, upon administration, enhances resistance to infection in a secondary bile acid-dependent fashion. Using a workflow involving mouse models, clinical studies, metagenomic analyses and mathematical modeling, we identified a probiotic candidate that corrects a clinically relevant microbiome deficiency. These findings have implications for rational design of targeted antimicrobials as well as microbiome-based diagnostics and therapeutics for individuals at risk for C. difficile infection.
PMCID: PMC4354891  PMID: 25337874
11.  Core-shell Au@Pd nanoparticles with enhanced catalytic activity for oxygen reduction reaction via core-shell Au@Ag/Pd constructions 
Scientific Reports  2015;5:11949.
Core-shell nanoparticles often exhibit improved catalytic properties due to the lattice strain created in these core-shell particles. Herein, we demonstrate the synthesis of core-shell Au@Pd nanoparticles from their core-shell Au@Ag/Pd parents. This strategy begins with the preparation of core-shell Au@Ag nanoparticles in an organic solvent. Then, the pure Ag shells are converted into the shells made of Ag/Pd alloy by galvanic replacement reaction between the Ag shells and Pd2+ precursors. Subsequently, the Ag component is removed from the alloy shell using saturated NaCl solution to form core-shell Au@Pd nanoparticles with an Au core and a Pd shell. In comparison with the core-shell Au@Pd nanoparticles upon directly depositing Pd shell on the Au seeds and commercial Pd/C catalysts, the core-shell Au@Pd nanoparticles via their core-shell Au@Ag/Pd templates display superior activity and durability in catalyzing oxygen reduction reaction, mainly due to the larger lattice tensile effect in Pd shell induced by the Au core and Ag removal.
PMCID: PMC4491719  PMID: 26144550
12.  The Inner Nuclear Membrane Protein Src1 Is Required for Stable Post-Mitotic Progression into G1 in Aspergillus nidulans 
PLoS ONE  2015;10(7):e0132489.
How membranes and associated proteins of the nuclear envelope (NE) are assembled specifically and inclusively around segregated genomes during exit from mitosis is incompletely understood. Inner nuclear membrane (INM) proteins play key roles by providing links between DNA and the NE. In this study we have investigated the highly conserved INM protein Src1 in Aspergillus nidulans and have uncovered a novel cell cycle response during post mitotic formation of G1 nuclei. Live cell imaging indicates Src1 could have roles during mitotic exit as it preferentially locates to the NE abscission points during nucleokinesis and to the NE surrounding forming daughter G1 nuclei. Deletion analysis further supported this idea revealing that although Src1 is not required for interphase progression or mitosis it is required for stable post-mitotic G1 nuclear formation. This conclusion is based upon the observation that in the absence of Src1 newly formed G1 nuclei are structurally unstable and immediately undergo architectural modifications typical of mitosis. These changes include NPC modifications that stop nuclear transport as well as disassembly of nucleoli. More intriguingly, the newly generated G1 nuclei then cycle between mitotic- and interphase-like states. The findings indicate that defects in post-mitotic G1 nuclear formation caused by lack of Src1 promote repeated failed attempts to generate stable G1 nuclei. To explain this unexpected phenotype we suggest a type of regulation that promotes repetition of defective cell cycle transitions rather than preventing progression past the defective cell cycle transition. We suggest the term “reboot regulation” to define this mode of cell cycle regulation. The findings are discussed in relationship to recent studies showing the Cdk1 master oscillator can entrain subservient oscillators that when uncoupled cause cell cycle transitions to be repeated.
PMCID: PMC4492595  PMID: 26147902
13.  Anterior D-rod and titanium mesh fixation for acute mid-lumbar burst fracture with incomplete neurologic deficits: A prospective study of 56 consecutive patients 
Indian Journal of Orthopaedics  2015;49(4):471-477.
Anterior decompression and reconstruction have gained wide acceptance as viable alternatives for unstable mid-lumbar burst fracture, but there are no mid and long term prospective studies regarding clinical and radiologic results of mid-lumbar burst fractures.
Materials and Methods:
An Institutional Review Board-approved prospective study of 56 consecutive patients of mid-lumbar burst fractures with a load-sharing score of 7 or more treated with anterior plating was carried out. All patients were evaluated for radiologic and clinical outcomes. The fusion status, spinal canal compromise, segmental kyphotic angle (SKA), vertebral body height loss (VBHL), and adjacent segment degeneration was examined for radiologic outcome, whereas the American Spinal Injury Association scale, the visual analog scale (VAS), and the employment status were used for clinical evaluation.
The patients underwent clinical and radiologic followup for at least 5 years after the surgery. At the last followup, there was no case of internal fixation failure, adjacent segment degeneration, and other complications. Interbody fusion was achieved in all cases. The average fusion time was 4.5 months. No patient suffered neurological deterioration and the average neurologic recovery was 1.3 grades on final observation. Based on VAS pain scores, canal compromise, percentage of VBHL and SKA, the difference was statistically significant between the preoperative period and postoperative or final followup (P < 0.05). Results at postoperative and final followup were better than the preoperative period. However, the difference was not significant between postoperative and final followup (P > 0.05). Thirty-four patients who were employed before the injury returned to work after the operation, 15 had changed to less strenuous work.
Good mid term clinicoradiological results of anterior decompression with D-rod and titanium mesh fixation for suitable patients with mid-lumbar burst fractures with incomplete neurologic deficits can be achieved. The incident rate of complications was low. D-rod is a reliable implant and has some potential advantages in L4 vertebral fractures.
PMCID: PMC4510804
Anterior lumbar fusion; internal fixation; lumbar burst fractures; mesh cage; neurologic deficit; Lumbar vertebrae; fracture fixation; spinal cord compression; neurologic deficits
14.  Effects of electroacupuncture on corticotropin-releasing hormone in rats with chronic visceral hypersensitivity 
AIM: To investigate the effect of electroacupuncture on corticotropin-releasing hormone (CRH) in the colon, spinal cord, and hypothalamus of rats with chronic visceral hypersensitivity.
METHODS: A rat model of chronic visceral hypersensitivity was generated according to the internationally accepted method of colorectal balloon dilatation. In the 7th week after the procedure, rats were randomly divided into a model group (MG), electroacupuncture group (EA), and sham electroacupuncture group (S-EA). After treatment, the abdominal withdrawal reflex (AWR) score was used to assess the behavioral response of visceral hyperalgesia. Immunohistochemistry (EnVision method), ELISA, and fluorescence quantitative PCR methods were applied to detect the expression of CRH protein and mRNA in the colon, spinal cord, and hypothalamus.
RESULTS: The sensitivity of the rats to the colorectal distension stimulus applied at different strengths (20-80 mmHg) increased with increasing stimulus strength, resulting in increasing AWR scores in each group. Compared with NG, the AWR score of MG was significantly increased (P < 0.01). After conducting EA, the AWR scores of the rats were decreased compared with MG rats. The relative expression of CRH mRNA in the colon, spinal cord, and hypothalamus of MG rats was significantly increased compared with NG rats (P < 0.01). CRH mRNA in the colon and spinal cord of EA and S-EA rats was decreased to varying degrees (P > 0.05) compared with normal rats (NG). However, the decrease in EA compared with MG rats was statistically significant (P < 0.01). The average optical density of CRH expression in the colon of the MG rats was significantly enhanced compared with NG (P < 0.05), while the average optical density of CRH expression in the EA and S-EA rats was significantly decreased compared with MG rats (P < 0.01, P < 0.05, respectively). Compared with MG rats, the CRH concentration in the spinal cord of EA rats was significantly reduced (P < 0.01), but there was no significant change in S-EA rats (P > 0.05).
CONCLUSION: Electroacupuncture at the Shangjuxu acupoint was able to significantly reduce the visceral hypersensitivity in rats, and regulated the expression of CRH protein and mRNA in the colon, spinal cord and hypothalamus at different levels, playing a therapeutic role in this model of irritable bowel syndrome.
PMCID: PMC4476879  PMID: 26109804
Corticotropin-releasing hormone; Electroacupuncture; Irritable bowel syndrome; Visceral pain; Shangjuxu
15.  Surgical induced astigmatism correlated with corneal pachymetry and intraocular pressure: transconjunctival sutureless 23-gauge versus 20-gauge sutured vitrectomy in diabetes mellitus 
To determine the difference of surgical induced astigmatism between conventional 20-gauge sutured vitrectomy and 23-gauge transconjunctival sutureless vitrectomy, and the influence of corneal pachymetry and intraocular pressure (IOP) on surgical induced astigmatism in diabetic patients.
This retrospective, consecutive case series consisted of 40 eyes of 38 diabetic subjects who underwent either 20-gauge or 23-gauge vitrectomy. The corneal curvature and thickness were measured with Scheimpflug imaging before surgery and 1wk; 1, 3mo after surgery. We compared the surgical induced astigmatism (SIA) on the true net power in 23-gauge group with that in 20-gauge group. We determined the correlation between corneal thickness change ratio, IOP and SIA measured by Pentacam.
The mean SIAs were 1.082±0.085 D (mean±SEM), 0.689±0.070 D and 0.459±0.063 D at postoperative 1wk; 1, 3mo respectively in diabetic subjects. The vitrectomy induced astigmatisms were declined significantly with time (F2,36=33.629, P=0.000) postoperatively. The 23-gauge surgery group induced significantly less astigmatism than 20-gauge surgery group (F-1,37=11.046, P=0.020). Corneal thickness in diabetes elevated after surgery (F3,78=10.532, P=0.000). The linear regression analysis at postoperatively 1wk went as: SIA=-4.519+4.931 change ratio (Port3) +0.026 IOP (R2=0.46, P=0.000), whereas the rate of corneal thickness change and IOP showed no correlation with the change of astigmatism at postoperatively 1 and 3mo.
There are significant serial changes in both 20-gauge and 23-gauge group in diabetic subjects. 23-gauge induce less astigmatism than 20-gauge and become stable more rapidly than 20-gauge. The elevation of corneal thickness and IOP was associated with increased astigmatim at the early postoperative stage both in 23-gauge and 20-gauge surgery group.
PMCID: PMC4458657  PMID: 26086002
astigmatism; corneal pachymetry; vitrectomy; intraocular pressure; diabetes mellitus
16.  Pulsed electromagnetic fields for postmenopausal osteoporosis and concomitant lumbar osteoarthritis in southwest China using proximal femur bone mineral density as the primary endpoint: study protocol for a randomized controlled trial 
Trials  2015;16:265.
Osteoporosis (OP) and osteoarthritis (OA) are prevalent skeletal disorders among postmenopausal women. Coexistence is common especially that of postmenopausal osteoporosis (PMO) and lumbar OA. An hypothesis has been raised that OP and OA might share the same pathogenic mechanism, and pulsed electromagnetic fields (PEMFs) were reported to have anti-osteoporosis and anti-osteoarthritis properties, but this suggestion was based primarily on biomarker data. Therefore, whether these two effects could take place simultaneously has not yet been investigated. This randomized controlled trial (RCT) is designed to explore the effect of PEMFs for PMO and concomitant lumbar OA.
The study will include PMO patients (postmenopausal women; aged between 50 and 70 years; have been postmenopausal for at least 5 years and diagnosed with OP using proximal femur T-score) with concomitant lumbar OA (patients with confounding disorders like diabetes, hypertension, hyperlipidemia, and previous fracture history, etcetera, will be excluded) will be randomly assigned to two arms: PEMFs group and sham PEMFs group. There will be 25 participants in each arm (50 in total) and the outcome assessment, including the primary endpoint (proximal femur bone mineral density), will be performed at 5 weeks, 3 months and 6 months after enrollment.
PMO and lumbar OA are prominent public health problem, especially for postmenopausal women. We hope this RCT will provide scientific evidence to primary care of the postmenopausal women regarding the use of these nonpharmaceutical, noninvasive modalities, PEMFs, in managing PMO and lumbar OA.
Trial registration
Chinese Clinical Trial Registry: ChiCTR-TRC-14005156 (28 August 2014).
Electronic supplementary material
The online version of this article (doi:10.1186/s13063-015-0780-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4482283  PMID: 26058489
Menopause; Pulsed electromagnetic fields; Osteoporosis; Osteoarthritis
17.  Lysyl hydroxylase 2 induces a collagen cross-link switch in tumor stroma 
The Journal of Clinical Investigation  2015;125(3):1147-1162.
Epithelial tumor metastasis is preceded by an accumulation of collagen cross-links that heighten stromal stiffness and stimulate the invasive properties of tumor cells. However, the biochemical nature of collagen cross-links in cancer is still unclear. Here, we postulated that epithelial tumorigenesis is accompanied by changes in the biochemical type of collagen cross-links. Utilizing resected human lung cancer tissues and a p21CIP1/WAF1-deficient, K-rasG12D-expressing murine metastatic lung cancer model, we showed that, relative to normal lung tissues, tumor stroma contains higher levels of hydroxylysine aldehyde–derived collagen cross-links (HLCCs) and lower levels of lysine aldehyde–derived cross-links (LCCs), which are the predominant types of collagen cross-links in skeletal tissues and soft tissues, respectively. Gain- and loss-of-function studies in tumor cells showed that lysyl hydroxylase 2 (LH2), which hydroxylates telopeptidyl lysine residues on collagen, shifted the tumor stroma toward a high-HLCC, low-LCC state, increased tumor stiffness, and enhanced tumor cell invasion and metastasis. Together, our data indicate that LH2 enhances the metastatic properties of tumor cells and functions as a regulatory switch that controls the relative abundance of biochemically distinct types of collagen cross-links in the tumor stroma.
PMCID: PMC4362236  PMID: 25664850
18.  A Population-Based Study of Alcohol Use in Same-Sex and Different-Sex Unions 
The present study advances research on union status and health by providing a first look at alcohol use differentials among different-sex and same-sex married and cohabiting individuals using nationally representative population-based data (National Health Interview Surveys 1997–2011, N = 181,581). The results showed that both same-sex and different-sex married groups reported lower alcohol use than both same-sex and different-sex cohabiting groups. The results further revealed that same-sex and different-sex married individuals reported similar levels of alcohol use, whereas same-sex and different-sex cohabiting individuals reported similar levels of alcohol use. Drawing on marital advantage and minority stress approaches, the findings suggest that it is cohabitation status—not same-sex status—that is associated with elevated alcohol rates.
PMCID: PMC4029769  PMID: 24860195
alcohol use; cohabitation; gay and lesbian; marriage
19.  Deletion of a 4977-bp Fragment in the Mitochondrial Genome Is Associated with Mitochondrial Disease Severity 
PLoS ONE  2015;10(5):e0128624.
Large deletions in mitochondrial DNA (mtDNA) may be involved in the pathogenesis of mitochondrial disease. In this study, we investigated the relationship between a 4,977-bp deletion in the mitochondrial genome (ΔmtDNA4977) and the severity of clinical symptoms in patients with mitochondrial disease lacking known point mutations. A total of 160 patients with mitochondrial disease and 101 healthy controls were recruited for this study. The copy numbers of ΔmtDNA4977 and wild-type mtDNA were determined by real-time quantitative PCR and analyzed using Spearman’s bivariate correlation analysis, t-tests, or one-way ANOVA. The overall ΔmtDNA4977 copy number per cell and the proportion of mtDNA4977 relative to the total wild-type mtDNA, increased with patient age and symptom severity. Surprisingly, the total mtDNA copy number decreased with increasing symptom severity. Our analyses revealed that increases in the proportion and total copy number of ΔmtDNA4977 in the blood may be associated with disease severity in patients with mitochondrial dysfunction.
PMCID: PMC4449107  PMID: 26024530
20.  Scoring the correlation of genes by their shared properties using OScal, an improved overlap quantification model 
Scientific Reports  2015;5:10583.
Scoring the correlation between two genes by their shared properties is a common and basic work in biological study. A prospective way to score this correlation is to quantify the overlap between the two sets of homogeneous properties of the two genes. However the proper model has not been decided, here we focused on studying the quantification of overlap and proposed a more effective model after theoretically compared 7 existing models. We defined three characteristic parameters (d, R, r) of an overlap, which highlight essential differences among the 7 models and grouped them into two classes. Then the pros and cons of the two groups of model were fully examined by their solution space in the (d, R, r) coordinate system. Finally we proposed a new model called OScal (Overlap Score calculator), which was modified on Poisson distribution (one of 7 models) to avoid its disadvantages. Tested in assessing gene relation using different data, OScal performs better than existing models. In addition, OScal is a basic mathematic model, with very low computation cost and few restrictive conditions, so it can be used in a wide-range of research areas to measure the overlap or similarity of two entities.
PMCID: PMC4445036  PMID: 26015386
21.  Radiotherapy for asymptomatic brain metastasis in epidermal growth factor receptor mutant non-small cell lung cancer without prior tyrosine kinase inhibitors treatment: a retrospective clinical study 
Non-small cell lung cancer (NSCLC) with brain metastasis (BM) harboring an epidermal growth factor receptor (EGFR) mutation shows good response to tyrosine kinase inhibitors (TKIs). This study is to assess the appropriate timing of brain radiotherapy (RT) for asymptomatic BM in EGFR mutant NSCLC patients.
There were 628 patients diagnosed with EGFR mutant NSCLC between October 2005 and December 2011. Treatment outcomes had been retrospectively evaluated in 96 patients with asymptomatic BM without prior TKI treatment. 39 patients received first-line brain RT, 23 patients received delayed brain RT, and 34 patients did not receive brain RT.
With a median follow-up of 26 months, the 2-year OS was 40.6 %. Univariate analyses revealed that ECOG performance status (p = 0.006), other distant metastases (p = 0.002) and first line systemic treatment (p = 0.032) were significantly associated with overall survival (OS). Multivariate analyses revealed that other sites of distant metastases (p = 0.030) were prognostic factor. The timing of brain RT was not significantly related to OS (p = 0.246). The 2-year BM progression-free survival (PFS) was 26.9 %. Brain RT as first-line therapy failed to demonstrate a significant association with BM PFS (p = 0.643).
First-line brain RT failed to improve long-term survival in TKI-naïve EGFR mutant NSCLC patients with asymptomatic BM. Prospective studies are needed to validate these clinical findings.
PMCID: PMC4490723  PMID: 26014133
Asymptomatic brain metastasis; Radiotherapy; Chemotherapy; Epidermal growth factor receptor mutation; Tyrosine kinase inhibitor
22.  Low Serum Testosterone Levels Are Associated with Elevated Urinary Mandelic Acid, and Strontium Levels in Adult Men According to the US 2011–2012 National Health and Nutrition Examination Survey 
PLoS ONE  2015;10(5):e0127451.
Little is known regarding the effects of environmental exposure of chemicals on androgenic system in the general population. We studied 5,107 subjects included in the National Health and Nutrition Examination Survey (2011–2012).
Urinary, serum, and blood levels of 15 subclasses comprising 110 individual chemicals were analyzed for their association with serum testosterone levels. The subjects were divided into high and low testosterone groups according to the median testosterone concentration (374.51 ng/dL). Odds ratios (ORs) of individual chemicals in association with testosterone were estimated using logistic regression after adjusting for age, ethnicity, cotinine, body mass index, creatinine, alcohol, and the poverty income ratio.
Adjusted ORs for the highest versus lowest quartiles of exposure were 2.12 (95% CI: 1.07, 4.21; Ptrend = 0.044), 1.84 (95% CI: 1.02, 3.34; Ptrend = 0.018) for the association between urinary mandelic acid, and strontium quartiles with low testosterone concentrations in adult men, respectively. However, no association was observed for the remaining chemicals with testosterone.
The National Health and Nutrition Examination Survey data suggest that elevations in urinary mandelic acid, and strontium levels are negatively related to low serum testosterone levels in adult men.
PMCID: PMC4440739  PMID: 25996772
23.  Coverage, use and maintenance of bed nets and related influence factors in Kachin Special Region II, northeastern Myanmar 
Malaria Journal  2015;14:212.
Myanmar is one of the 31 highest burden malaria countries worldwide. Scaling up the appropriate use of insecticide-treated nets (ITNs) is a national policy for malaria prevention and control. However, the data on use, influencing factors and maintenance of bed nets is still lack among the population in Kachin Special Region II (KR2), Northeastern Myanmar.
The study combined a quantitative household questionnaire survey and qualitative direct observation of households. A Chi-squared test was used to compare the percentages of ownership, coverage, and rates of use of bed nets. Additionally, multivariate logistic regression analysis (MVLRA) was used to analyse factors that influence the use of bed nets. Finally, covariance compared the mean calibrated hole indexes (MCHI) across potential influence variables.
The bed net to person ratio was 1:1.96 (i.e., more than one net for every two people). The long-lasting insecticidal net (LLIN) to person ratio was 1: 2.52. Also, the percentage of households that owned at least one bed net was 99.7 % (666/688). Some 3262 (97.3 %) residents slept under bed nets the prior night, 2551 (76.1 %) of which slept under ITNs/LLINs the prior night (SUITNPN). The poorest families, those with thatched roofing, those who use agriculture as their main source of family income, household heads who knew that mosquitoes transmit malaria and those who used bed nets to prevent malaria, were significantly more likely to be in the SUITNPN group. However, residents in lowlands, and foothills were significantly less likely to be SUITNPNs. Finally, head of household attitude towards fixing bed nets influenced MCHI (F = 8.09, P = 0.0046).
The coverage and usage rates of bed nets were high, especially among children, and pregnant women. Family wealth index, geographical zones, household roofing, source of family income, household head’s knowledge of malaria transmission and of using bed nets as tools for malaria prevention are all independent factors which influence use of ITNs/LLINs in KR2. Maintaining high coverage, and use rate of bed nets should be a priority for the war-torn population of KR2 to ensure equity and human rights.
PMCID: PMC4457094  PMID: 25990715
Malaria; Bed net; Insecticide-treated nets (ITNs); War-torn population; Kachin Special Region II; Myanmar
24.  Application of Combined Two-Dimensional and Three-Dimensional Transvaginal Contrast Enhanced Ultrasound in the Diagnosis of Endometrial Carcinoma 
BioMed Research International  2015;2015:292743.
Objective. The goal of this study was to explore the clinical value of combining two-dimensional (2D) and three-dimensional (3D) transvaginal contrast-enhanced ultrasounds (CEUS) in diagnosis of endometrial carcinoma (EC). Methods. In this prospective diagnostic study, transvaginal 2D and 3D CEUS were performed on 68 patients with suspected EC, and the results of the obtained 2D-CEUS and 3D-CEUS images were compared with the gold standard for statistical analysis. Results. 2D-CEUS benign endometrial lesions showed the normal uterine perfusion phase while EC cases showed early arrival and early washout of the contrast agent and nonuniform enhancement. The 3D-CEUS images differed in central blood vessel manifestation, blood vessel shape, and vascular pattern between benign and malignant endometrial lesions (P < 0.05). Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of transvaginal 2D-CEUS and 2D-CEUS combined with 3D-CEUS for diagnosis of benign and malignant endometrial lesions were 76.9%, 73.8%, 64.5%, 83.8%, and 75.0% and 84.6%, 83.3%, 75.9%, 89.7%, and 83.8%, respectively. Conclusion. 3D-CEUS is a useful supplement to 2D-CEUS and can clearly reveal the angioarchitecture spatial relationships between vessels and depth of myometrial invasion in EC. The combined use of 2D and 3D-CEUS can offer direct, accurate, and comprehensive diagnosis of early EC.
PMCID: PMC4450230  PMID: 26090396
25.  Associations of genetic polymorphisms of TLR5, TLR9 and transduction molecules in MyD88 signaling pathway with systemic lupus erythematosus in Zhuang and Han ethnics of Guangxi province, China 
Objectives: To discuss the associations of SNPs of TLR5, TLR9 and transduction molecules in MyD88 signaling pathway with systemic lupus erythematosus (SLE) risk in Zhuang and Han ethnics and to compare the difference between the two ethnics. Methods: PCR and direct sequencing method were used to detect gene polymorphisms of TLR5, TLR9 and transduction molecules in MyD88 signaling pathway in 77 patients with SLE and 72 healthy controls, in order to explore their relationships with SLE incidence and compare the differences in genotypes and allele frequencies between groups. Results: TLR5 rs5744168 gene polymorphism was unrelated with SLE susceptibility of Guangxi Zhuang and Han. Among the Han population, there was a statistically significant difference in TLR9 rs352140 genotype frequency between SLE group and control group (P = 0.043). In the Han and Zhuang populations, there were no significant differences in MyD88 rs7744 genotype and allele frequencies (all P > 0.05) between SLE group and control group; but there was a statistically significant difference in allele frequencies between the case group and the control group (P = 0.033). For TRAF6 rs5030472, GA + AA genotype frequency of Zhuang SLE group was significantly higher than that of control group and the difference was statistically significant (P = 0.006); an allele frequency was also significantly higher. IRF5 rs2004640 GG/TT genotype and the corresponding G allele frequencies of Zhuang SLE group were significantly higher than that of control group, with statistically significant differences (P = 0.008 and P = 0.000, respectively). Conclusion: TLR5 rs5744168 gene polymorphism may have no correlation with SLE susceptibility in Guangxi Zhuang and Han populations; TLR9 rs352140 gene polymorphism may be associated with SLE susceptibility in Guangxi Han population, while TRAF6 rs5030472 and IRF5 rs2004640 gene polymorphisms may relate to SLE susceptibility in Guangxi Zhuang population.
PMCID: PMC4509288  PMID: 26221343
Zhuang nationality; Han nationality; SLE; TLR5; TLR9

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