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1.  Interventional therapy for human breast cancer in nude mice with 131I gelatin microspheres (131I-GMSs) following intratumoral injection 
Introduction
The aim of this study was to investigate the effects of 131I gelatin microspheres (131I-GMS) on human breast cancer cells (MCF-7) in nude mice and the biodistribution of 131I-GMSs following intratumoral injections.
Methods
A total of 20 tumor-bearing mice were divided into a treatment group and control group and received intratumoral injections of 2.5 mci 131I-GMSs and nonradioactive GMSs, respectively. Tumor size was measured once per week. Another 16 mice received intratumoral injections of 0.4 mci 131I-GMSs and were subjected to single photon emission computed tomography (SPECT) scans and tissue radioactivity concentration measurements on day 1, 4, 8 and 16 postinjection. The 20 tumor-bearing mice received intratumoral injections of 0.4 mci [131I] sodium iodide solution and were subjected to SPECT scans and intratumoral radioactivity measurements at 1, 6, 24, 48 and 72 h postinjection. The tumors were collected for histological examination.
Results
The average tumor volume in the 131I-GMSs group on post-treatment day 21 decreased to 86.82 ± 63.6%, while it increased to 893.37 ± 158.12% in the control group (P < 0.01 vs. the 131I-GMSs group). 131I-GMSs provided much higher intratumoral retention of radioactivity, resulting in 19.93 ± 5.24% of the injected radioactivity after 16 days, whereas the control group retained only 1.83 ± 0.46% of the injected radioactivity within the tumors at 1 h postinjection.
Conclusions
131I-GMSs suppressed the growth of MCF-7 in nude mice and provided sustained intratumoral radioactivity retention. The results suggest the potential of 131I-GMSs for clinical applications in radiotherapy for breast cancer.
doi:10.1186/1748-717X-9-144
PMCID: PMC4083354  PMID: 24958442
131I; Gelatin microspheres; Breast neoplasms; Intratumoral injection; Treatment outcome; Biodistribution
2.  MicroRNA-222 Expression and Its Prognostic Potential in Non-Small Cell Lung Cancer 
The Scientific World Journal  2014;2014:908326.
Overexpression of miR-222 has been found in several types of cancers; however, the expression of miR-222 in non-small cell lung cancer (NSCLC) and its prognostic values are unclear. This study aimed to investigate whether the miR-222 expression level is related to clinicopathological factors and prognosis of NSCLC. Through a prospective study, 100 pairs of NSCLC tissues and adjacent normal tissues were examined by quantitative reverse-transcription polymerase chain reaction. The correlation between miR-222 expression and clinicopathological features was analyzed, and the significance of miR-222 as a prognostic factor and its relationship with survival were determined. Results showed that the expression levels of miR-222 were significantly elevated in the NSCLC tissue compared with that in adjacent normal tissue. In addition, Cox's proportional hazards model analysis confirmed that miR-222 high expression level was an independent predictor of poor prognosis. In conclusion, miR-222 overexpression is involved in the poor prognosis of NSCLC and can be used as a biomarker for selection of cases requiring especial attention.
doi:10.1155/2014/908326
PMCID: PMC4009118  PMID: 24955421
3.  Protective Effect of Cytosolic Phospholipase A2 Inhibition against Inflammation and Degeneration by Promoting Regulatory T Cells in Rats with Experimental Autoimmune Encephalomyelitis 
Mediators of Inflammation  2014;2014:890139.
Cytosolic phospholipase A2 (cPLA2) is the rate-limiting enzyme that initiates the production of various inflammatory mediators. Previous studies have shown that inhibiting cPLA2 exerts a neuroprotective effect on experimental autoimmune encephalomyelitis (EAE) by ameliorating the severity of the disease and influencing Th1 and Th17 responses. However, it remains unclear whether treatment with a cPLA2 inhibitor will influence the regulatory T cells (Tregs) that play a critical role in maintaining immune homeostasis and preventing autoimmune diseases. In this study, the cPLA2 inhibitor AX059 reduced the onset and progression of EAE in Lewis rats. In addition, this effect was accompanied by activation of Tregs and alterations in the expression of their various cytokines. The study therefore demonstrated that Tregs are involved in the immunomodulatory effect mediated by cPLA2 inhibition. These findings may have clinical application in the treatment of multiple sclerosis.
doi:10.1155/2014/890139
PMCID: PMC3981565  PMID: 24782598
4.  The impact of both platinum-based chemotherapy and EGFR-TKIs on overall survival of patients with advanced non-small cell lung cancer 
Chinese Journal of Cancer  2014;33(2):105-114.
Both platinum-based doublet chemotherapy (PBC) and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) prolong the survival of patients with advanced non-small cell lung cancer (NSCLC). In early studies, most patients underwent PBC as first-line treatment, but not all patients could afford EGFR-TKIs as second-line treatment. To understand the impact of PBC and EGFR-TKIs on NSCLC prognosis, we evaluated the association between the receipt of both regimens and overall survival (OS). Using MEDLINE and EMBASE, we identified prospective, randomized, controlled phase III clinical trials in advanced NSCLC that met the inclusion criteria: in general population with advanced NSCLC, the percentage of patients treated with both PBC and EGFR-TKIs was available in the trial and OS was reported. After collecting data from the selected trials, we correlated the percentage of patients treated with both PBC and EGFR-TKIs with the reported OS, using a weighted analysis. Fifteen phase III clinical trials—involving 11,456 adult patients in 32 arms—were included in the analysis, including 6 trials in Asian populations and 9 in non-Asian (predominantly Caucasian) populations. The OS was positively correlated with the percentage of patients treated with both PBC and EGFR-TKIs (r = 0.797, P < 0.001). The correlation was obvious in the trials in Asian populations (r = 0.936, P < 0.001) but was not statistically significant in the trials in predominantly Caucasian populations (r = 0.116, P = 0.588). These results suggest that treatment with PBC and EGFR-TKIs may provide a survival benefit to patients with advanced NSCLC, highlighting the importance of having both modalities available for therapy.
doi:10.5732/cjc.012.10274
PMCID: PMC3935012  PMID: 23816558
NSCLC; platinum-based doublet chemotherapy; correlation; EGFR-TKIs; overall survival
5.  Quantitative Assessment of the Influence of TP63 Gene Polymorphisms and Lung Cancer Risk: Evidence Based on 93,751 Subjects 
PLoS ONE  2014;9(1):e87004.
Background
Several genome-wide association studies on lung cancer (LC) have reported similar findings of a new susceptibility locus, 3q28. After that, a number of studies reported that the rs10937405, and rs4488809 polymorphism in chromosome 3q28 has been implicated in LC risk. However, the studies have yielded contradictory results.
Methods
PubMed, ISI web of science, EMBASE and the Chinese National Knowledge Infrastructure databases were systematically searched to identify relevant studies. Data were abstracted independently by two reviewers. A meta-analysis was performed to examine the association between rs10937405, rs4488809 polymorphism at 3q28 and susceptibility to LC. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. Heterogeneity and publication bias were also tested.
Results
A total of 9 studies including 35,961 LC cases and 57,790 controls were involved in this meta-analysis. An overall random-effects per-allele OR of1.19 (95% CI: 1.14–1.25; P<10−5) and 1.19 (95% CI: 1.13–1.25; P<10−5) was found for the rs10937405 and rs4488809 polymorphism respectively. Similar results were also observed using dominant or recessive genetic model. After stratified by ethnicity, significant associations were found among East Asians (per-allele OR = 1.22, 95% CI: 1.17–1.27; P<10−5); whereas no significant associations were found among Caucasians for rs10937405. In the sub-group analysis by sample size, significantly increased risks were found for these polymorphisms in all genetic models. When analyzed according to histological type, the effects of rs10937405, and rs4488809 at 3q28 on the risk of lung cancer were significant mostly for lung adenocarcinoma.
Conclusions
Our findings demonstrated that rs10937405-G allele and rs4488809-G allele might be risk-conferring factors for the development of lung cancer, especially for East Asian populations.
doi:10.1371/journal.pone.0087004
PMCID: PMC3900682  PMID: 24466311
6.  Randomized Clinical Trial: The Clinical Effects of Herb-Partitioned Moxibustion in Patients with Diarrhoea-Predominant Irritable Bowel Syndrome 
Objective. To explore the efficacy of Herb-partitioned moxibustion in treating IBS-D patients. Method. 210 IBS-D patients were randomly assigned on a 3 : 3 : 2 basis to group HM, group FM, or group PB for 4-week treatment. The change of GSRS total score at weeks 4 and 8, the changes of GSRS specific scores, and adverse events were evaluated. Results. Patients in group HM and group FM had lower GSRS total score at week 4 (1.98 ± 0.303, 2.93 ± 0.302 versus 3.73 ± 0.449) and at week 8 (2.75 ± 0.306, 3.56 ± 0.329 versus 4.39 ± 2.48) as compared with patients' score in group PB. However, there was no significant difference of GSRS total score between group HM and group FM. The effect of HM was significantly greater than that of orally taking PB in ameliorating the symptoms of rugitus (0.38 versus 0.59, P < 0.05), abdominal pain (0.28 versus 0.57, P < 0.01), abdominal distension (0.4 versus 0.7, P < 0.01), and increased passage of stools (0.06 versus 0.25, P < 0.01) at the end of treatment period. In the follow-up period, patients' therapeutic effect in group HM remained greater than that in group FM (in abdominal pain, abdominal distension, and increased passage of stools) and that in group PB (in loose stools). Conclusions. HM appears to be a promising, efficacious, and well-tolerated treatment for patients with IBS-D.
doi:10.1155/2013/605460
PMCID: PMC3880695  PMID: 24454500
7.  The regulatory role of immunosuppressants on immune abnormalities in acute pancreatitis 
Biomedical Reports  2013;2(2):193-198.
The uncontrolled progression of the inflammatory cascade is the main cause underlying the development of multiple organ dysfunction syndrome (MODS) in acute pancreatitis. In this study, we investigated the effects of several immunosuppressants on mitigating the systemic inflammatory reaction syndrome (SIRS) and the compensatory anti-inflammatory response syndrome (CARS) associated with acute pancreatitis. A total of 93 male Sprague Dawley rats were divided into 5 groups: group 1 was the sham group and group 2 underwent laparoscopic intrapancreatic duct injection of sodium taurocholate to induce pancreatitis. The remaining 3 groups were the same as group 2, with the addition of methylprednisolone, cyclophosphamide or methotrexate treatment (metastab, CTX or MTX groups, respectively). Following establishment of the acute pancreatitis model, the serum levels of inflammatory and anti-inflammatory cytokines in groups 2, 3, 4 and 5 were found to be significantly elevated. Following immunosuppressant administration, the levels of all inflammatory and anti-inflammatory cytokines investigated in groups 3, 4 and 5 were decreased compared to those in group 2. The pancreatic amylase levels and pancreatic wet weight (PWW) were also decreased in groups 3, 4 and 5 compared to those in group 2. Therefore, immunosuppressants may reduce inflammation-related cytokine levels in acute pancreatitis and relieve disease progression.
doi:10.3892/br.2013.208
PMCID: PMC3917744  PMID: 24649095
acute pancreatitis; systemic inflammatory reaction syndrome; cytokine; methylprednisolone; cyclophosphamide; methotrexate
8.  Poly[di-μ9-citrato-tetra­sodiumzinc] 
In the title compound, [Na4Zn(C6H5O7)2]n, the ZnII ion lies on an inversion center and is coordinated by six O atoms from two citrate ligands, forming a distorted octa­hedral geometry. There are two crystallographically independent Na+ cations in the asymmetric unit. One Na+ cation exhibits a distorted square-pyramidal geometry defined by five O atoms from four citrate ligands. The other Na+ cation is surrounded by six O atoms from five citrate ligands in a distorted octa­hedral geometry. The Na+ cations are bridged by citrate carboxyl­ate groups, forming a layer parallel to (100). The layers are further assembled into a three-dimensional network with the [Zn(citrate)2]4− building units as ‘pillars’; O—H⋯O hydrogen bonds also stabilize the structure.
doi:10.1107/S1600536813030067
PMCID: PMC3885003  PMID: 24454178
9.  High-Frequency Stimulation of Nucleus Accumbens Changes in Dopaminergic Reward Circuit 
PLoS ONE  2013;8(11):e79318.
Deep brain stimulation (DBS) of the nucleus accumbens (NAc) is a potential remedial therapy for drug craving and relapse, but the mechanism is poorly understood. We investigated changes in neurotransmitter levels during high frequency stimulation (HFS) of the unilateral NAc on morphine-induced rats. Sixty adult Wistar rats were randomized into five groups: the control group (administration of saline), the morphine-only group (systematic administration of morphine without electrode implantation), the morphine-sham-stimulation group (systematic administration of morphine with electrode implantation but not given stimulation), the morphine-stimulation group (systematic administration of morphine with electrode implantation and stimulation) and the saline-stimulation group (administration of saline with electrode implantation and stimulation). The stimulation electrode was stereotaxically implanted into the core of unilateral NAc and microdialysis probes were unilaterally lowered into the ipsilateral ventral tegmental area (VTA), NAc, and ventral pallidum (VP). Samples from microdialysis probes in the ipsilateral VTA, NAc, and VP were analyzed for glutamate (Glu) and γ-aminobutyric acid (GABA) by high-performance liquid chromatography (HPLC). The levels of Glu were increased in the ipsilateral NAc and VP of morphine-only group versus control group, whereas Glu levels were not significantly changed in the ipsilateral VTA. Furthermore, the levels of GABA decreased significantly in the ipsilateral NAc, VP, and VTA of morphine-only group when compared with control group. The profiles of increased Glu and reduced GABA in morphine-induced rats suggest that the presence of increased excitatory neurotransmission in these brain regions. The concentrations of the Glu significantly decreased while the levels of GABA increased in ipsilateral VTA, NAc, and VP in the morphine-stimulation group compared with the morphine-only group. No significant changes were seen in the morphine-sham stimulation group compared with the morphine-only group. These findings indicated that unilateral NAc stimulation inhibits the morphine-induced rats associated hyperactivation of excitatory neurotransmission in the mesocorticolimbic reward circuit.
doi:10.1371/journal.pone.0079318
PMCID: PMC3828386  PMID: 24244479
10.  A Rat Model of Hemidystonia Induced by 3-Nitropropionic Acid  
PLoS ONE  2013;8(10):e79199.
Objective
Secondary dystonia commonly presents as hemidystonia and is often refractory to current treatments. We aimed to establish an inducible rat model of hemidystonia utilizing 3-nitropropionic acid (3-NP) and to determine the pathophysiology of this model.
Methods
Two different doses of 3-NP were stereotactically administered into the ipsilateral caudate putamen (CPu) of Wistar rats. Behavioral changes and alterations in the neurotransmitter levels in the basal ganglia were analyzed. We also performed an electromyogram, 7.0-T magnetic resonance imaging and transmission electron microscopy examination to determine the pathophysiology of the model.
Results
In the CPu region, 3-NP produced mitochondrial cristae rupture, axonal degeneration, increased excitatory synaptic vesicles and necrosis. The extracellular concentrations of excitatory amino acids increased, whereas the inhibitory amino acids decreased in the CPu. Furthermore, an imbalance of neurotransmitters was found in other regions of the basal ganglia with the exception of the external globus pallidus. This study demonstrated that 3-NP administration results in CPu damage, and combined with a neurotransmitter imbalance in the basal ganglia, it produces specific neurobehavioral changes in rats. Right limb (contralateral side of CPu lesion) and trunk dystonic postures, shortened step length and ipsiversive dystonic posturing were observed in these rats. Furthermore, EMG recordings confirmed that co-contraction of the agonist and antagonist muscles could be seen for several seconds in right limbs.
Conclusions
Stereotactic injection of 3-NP into the ipsilateral CPu of rats established an inducible model for hemidystonia. This effect might result from an imbalance of neurotransmitter levels, which induce dysfunctional activity of the basal ganglia mainly via the cortico-striato-GPi direct pathway. Symptoms in this model were present for 1 week. Activation of the cortico-striato-GPe indirect pathway and rebalance of neurotransmitters may lead to recovery. This rat model may be a suitable tool used to understand and further investigate the pathophysiology of dystonia.
doi:10.1371/journal.pone.0079199
PMCID: PMC3806852  PMID: 24194961
11.  The effects of different doses of estradiol (E2) on cerebral ischemia in an in vitro model of oxygen and glucose deprivation and reperfusion and in a rat model of middle carotid artery occlusion 
BMC Neuroscience  2013;14:118.
Background
Because neuroprotective effects of estrogen remain controversial, we aimed to investigate the effect of different doses of estradiol (E2) on cerebral ischemia using both in vivo and in vitro experiments.
Results
PC12 cells were cultured at physiological (10 nM and 20 nM) or pharmacological (10 μM and 20 μM) dosages of E2 for 24 hours (h). The results of 5-bromodeoxyuridine (Brdu) incorporation and flow cytometric analysis showed that physiological doses of E2 enhanced cell proliferation and pharmacological doses of E2 inhibited cell proliferation. After the cells were exposed to oxygen and glucose deprivation (OGD) for 4 h and reperfusion for 20 h, the results of 3-(4, 5-dimethylthiazol-2-yl) 2, 5-diphenyl tetrazolium bromide (MTT) assay, lactate dehydrogenase (LDH) release assay, flow cytometric analysis and Western blot analysis showed that physiological doses of E2 enhanced cell viability, reduced cell apoptosis and decreased the expression of pro-apoptotic protein caspase-3. In contrast, pharmacological doses of E2 decreased cell viability and induced cell apoptosis. In vivo, adult ovariectomized (OVX) female rats received continuous subcutaneous injection of different doses of E2 for 4 weeks. Transient cerebral ischemia was induced for 2 h using the middle cerebral artery occlusion (MCAO) technique, followed by 22 h of reperfusion. The results of Garcia test, 2, 3, 5-triphenyltetrazolium chloride (TTC) staining showed that 6 μg/kg and 20 μg/kg E2 replacement induced an increase in neurological deficit scores, a decrease in the infarct volume and a reduction in the expression of caspase-3 when compared to animals in the OVX group without E2 treatment. However, 50 μg/kg E2 replacement treatment decreased neurological deficit scores, increased the infarct volume and the expression of caspase-3 when compared to animals in the control group and 6 up/kg or 20 μg/kg E2 replacement group.
Conclusion
We conclude that physiological levels of E2 exhibit neuroprotective effects on cerebral ischemia; whereas, pharmacological or supraphysiological doses of E2 have damaging effects on neurons after cerebral ischemia.
doi:10.1186/1471-2202-14-118
PMCID: PMC3851874  PMID: 24106772
Estrogen; Neuroprotection; Ischemia; Middle carotid artery occlusion (MCAO); Oxygen and glucose deprivation (OGD)
12.  Generation of haploid embryonic stem cells from Macaca fascicularis monkey parthenotes 
Cell Research  2013;23(10):1187-1200.
Recent success in the derivation of haploid embryonic stem cells (haESCs) from mouse via parthenogenesis and androgenesis has enabled genetic screening in mammalian cells and generation of gene-modified animals. However, whether haESCs can be derived from primates remains unknown. Here, we report the derivation of haESCs from parthenogenetic blastocysts of Macaca fascicularis monkeys. These cells, termed as PG-haESCs, are pluripotent and can differentiate to cells of three embryonic germ layers in vitro or in vivo. Interestingly, the haploidy of one monkey PG-haESC line (MPH1) is more stable compared with that of the other one (MPH2), as shown by the existence of haploid cells for more than 140 days without fluorescence-activated cell sorting (FACS) enrichment of haploid cells. Importantly, transgenic monkey PG-haESC lines can be generated by lentivirus- and piggyBac transposon-mediated gene transfer. Moreover, genetic screening is feasible in monkey PG-haESCs. Our results demonstrate that PG-haESCs can be generated from monkeys, providing an ideal tool for genetic analyses in primates.
doi:10.1038/cr.2013.93
PMCID: PMC3790242  PMID: 23856644
embryonic stem cell; haploid cells; monkey
13.  Serum leptin, adiponectin and endometrial cancer risk in Chinese women 
Journal of Gynecologic Oncology  2013;24(4):336-341.
Objective
To investigate the relationship between serum concentrations of leptin or adiponectin, and endometrial carcinoma in Chinese women.
Methods
We conducted a case-control study of a total of 516 Chinese women to detect the relationships between serum concentrations of leptin or adiponectin, and endometrial carcinoma in Chinese women. The study subject constituted 206 cases of endometrial cancer and 310 normal controls.
Results
Patients with endometrial carcinoma had higher serum leptin concentrations than controls (28.8±2.2 ug/L vs. 19.8±1.4 ug/L; p<0.001). The adiponectin levels in patients were lower than in controls with borderline statistical significance (2,330.7±180.5 ug/L vs. 2,583.9±147.2 ug/L; p=0.078). Logistic regression analysis confirmed the associations between leptin or adiponectin, and endometrial carcinoma after adjustment for age, body mass index, fasting insulin, serum glucose, cholesterol, triglycerides, and high-density lipoprotein cholesterol (odds ratio for the top tertile vs. the bottom tertile: leptin 2.05; 95% confidence interval [CI], 1.28 to 3.29; p<0.001; adiponectin 0.52; 95% CI, 0.32 to 0.83; p<0.001).
Conclusion
Increased leptin or decreased adiponectin levels are associated with endometrial carcinoma.
doi:10.3802/jgo.2013.24.4.336
PMCID: PMC3805914  PMID: 24167669
Adiponectin; Endometrial carcinoma; Insulin resistance; Leptin
14.  Controlling Cellular Uptake of Nanoparticles with pH-Sensitive Polymers 
Scientific Reports  2013;3:2804.
The major challenge in cancer therapy is to efficiently translocate drug molecules into cancer tumors without doing any damage to healthy tissues. Since there exist pH gradients between tumor and normal tissues, pH-sensitive materials may have great potential to overcome such challenge. Here, we report one new type of pH-responsive drug delivery system where pH-sensitive polymers are introduced to control the cellular uptake of nanoparticles under different pH environments through dissipative particle dynamics simulations. Interestingly, the behavior of cellular uptake of nanoparticles here exhibits “smart” pH-responsive properties: for lower and higher pH, the nanoparticles can be taken up by cell membranes, while for pH in middle range, the endocytosis is blocked. Further, it is found that receptor-ligand interactions as well as surface charge property of nanoparticles and membranes can also have important impacts on the endocytosis. The present study may give some significant insights into future stimulus-responsive medical materials design.
doi:10.1038/srep02804
PMCID: PMC3786291  PMID: 24076598
15.  catena-Poly[[tri­aqua­copper(II)]-μ-5-carb­oxy­benzene-1,3-di­carboxyl­ato-κ2 O 1:O 3] 
In the title complex, [Cu(C9H4O6)(H2O)3]n, the CuII cation exhibits a distorted square-pyramidal coordination geometry involving five O atoms from two monodentate 5-carb­oxy­benzene-1,3-di­carboxyl­ate anions and three water mol­ecules. The 5-carb­oxy­benzene-1,3-di­carboxyl­ate anions bridge CuII cations into zigzag polymeric chains running along the b-axis direction. These chains are further linked by O—H⋯O hydrogen bonds between coordinating water mol­ecules or carboxyl groups and carboxylate groups into a three-dimensional supra­molecular architecture. In the crystal, π–π stacking is observed between parallel benzene rings of adjacent chains, the centroid–centroid distances being 3.584 (3) and 3.684 (3) Å.
doi:10.1107/S1600536813024781
PMCID: PMC3790349  PMID: 24098171
16.  Quantitative Assessment of the Influence of Cytochrome P450 1A2 Gene Polymorphism and Colorectal Cancer Risk 
PLoS ONE  2013;8(8):e71481.
Cytochrome P450 1A2 (CYP1A2) encodes a member of the cytochrome P450 superfamily of enzymes, which play a central role in activating and detoxifying many carcinogens and endogenous compounds thought to be involved in the development of colorectal cancer (CRC). The CYP1A2*C (rs2069514) and CYP1A2*F (rs762551) polymorphism are two of the most commonly studied polymorphisms of the gene for their association with risk of CRC, but the results are conflicting. To derive a more precise estimation of the relationship between CYP1A2 and genetic risk of CRC, we performed a comprehensive meta-analysis which included 7088 cases and 7568 controls from 12 published case-control studies. In a combined analysis, the summary per-allele odds ratio for CRC was 0.91 (95% CI: 0.83–1.00, P = 0.04), and 0.91 (95% CI: 0.68–1.22, P = 0.53), for CYP1A2 *F and *C allele, respectively. In the subgroup analysis by ethnicity, significant associations were found in Asians for CYP1A2*F and CYP1A2*C, while no significant associations were detected among Caucasian populations. Similar results were also observed using dominant genetic model. Potential sources of heterogeneity were explored by subgroup analysis and meta-regression. No significant heterogeneity was detected in most of comparisons. This meta-analysis suggests that the CYP1A2 *F and *C polymorphism is a protective factor against CRC among Asians.
doi:10.1371/journal.pone.0071481
PMCID: PMC3741149  PMID: 23951174
17.  Anti-angiogenic effect of the total flavonoids in Scutellaria barbata D. Don 
Background
Angiogenesis is closely related to the growth, invasion and metastasis of tumors, also considered as the key target of anticancer therapy. Scutellaria barbata D. Don (S. barbata), a traditional Chinese medicine, is being used to treat various diseases, including cancer. However, the antitumor molecular mechanism of S. barbata was still unclear. This study aimed to investigate the inhibitory effects of the total flavones in S. barbata (TF-SB) on angiogenesis.
Methods
Human umbilical vein endothelial cells (HUVECs) were treated with various concentrations of TF-SB. Cell viability was examined using the MTT assay. The scratch assay was used to detect the migration of HUVECs after treatment with TF-SB. The ability of HUVECs to form network structures in vitro was demonstrated using the tube formation assay. The chick embryo chorioallantoic membrane assay was performed to detect the in vivo anti-angiogenic effect. The expression of VEGF was measured by the enzyme-linked immunosorbent.
Results
Results showed that TF-SB inhibited the proliferation and migration of HUVECs in a dose- dependent manner. Simultaneously, TF-SB significantly suppressed HUVEC angiogenesis in vitro and in vivo. Furthermore, VEGF was downregulated in both HUVECs and MHCC97-H cells after TF-SB treatment.
Conclusion
TF-SB could suppress the process of angiogenesis in vitro and in vivo. TF-SB potentially suppresses angiogenesis in HUVECs by regulating VEGF. These findings suggested that TF-SB may serve as a potent anti-angiogenic agent.
doi:10.1186/1472-6882-13-150
PMCID: PMC3717098  PMID: 23815868
Scutellaria Barbata; Angiogenesis; Hepatocellular Carcinoma; Human Umbilical Vein Endothelial Cells
18.  Adverse Reactions Due to Directly Observed Treatment Strategy Therapy in Chinese Tuberculosis Patients: A Prospective Study 
PLoS ONE  2013;8(6):e65037.
Background
More than 1 million tuberculosis (TB) patients are receiving directly observed treatment strategy (DOTS) therapy in China every year. As to the profile of adverse drug reactions (ADRs) due to DOTS therapy, no consensus has been reached. There is no report regarding ADRs due to DOTS therapy with a large Chinese TB population. This study aimed to determine the incidence and prognosis of ADRs due to DOTS therapy, and to evaluate their impact on anti-TB treatment in China.
Methods
A prospective population-based cohort study was performed during 2007–2008. Sputum smear positive pulmonary TB patients who received DOTS therapy were included and followed up for six to nine months in 52 counties of four regions in China. The suspected ADRs were recorded and reviewed by Chinese State Food and Drug Administration.
Results
A total of 4304 TB patients were included in this study. 649 patients (15.08%) showed at least one ADR and 766 cases in total were detected. The incidence (count) of ADR based on affected organ was: liver dysfunction 6.34% (273), gastrointestinal disorders 3.74% (161), arthralgia 2.51% (108), allergic reactions 2.35% (101), neurological system disorders 2.04% (88), renal impairment 0.07% (3) and others 0.05% (2). Most cases of ADRs (95%) had a good clinical outcome, while two with hepatotoxicity and one with renal impairment died. Compared with patients without ADRs, patients with ADRs were more likely to have positive smear test results at the end of the intensive phase (adjusted OR, 2.00; 95%CI, 1.44–2.78) and unsuccessful anti-TB outcomes (adjusted OR, 2.58; 95%CI, 1.43–4.68).
Conclusions
The incidence of ADRs due to DOTS therapy was 15.08%. Those ADRs had a substantial impact on TB control in China. This highlighted the importance of developing strategies to ameliorate ADRs both to improve the quality of patient care and to control TB safely.
doi:10.1371/journal.pone.0065037
PMCID: PMC3672195  PMID: 23750225
19.  Proteomics to reveal metabolic network shifts towards lipid accumulation following nitrogen deprivation in the diatom Phaeodactylum tricornutum 
The marine diatom Phaeodactylum tricornutum is attracting considerable interest as a candidate for biofuel production due to its fast growth and high lipid content. Nitrogen deficiency can increase the lipid content in certain microalgae species, including P. tricornutum. However, the molecular basis of such changes remains unclear without analyzing metabolism at the proteomic level. We attempted to systematically analyze protein expression level changes of P. tricornutum upon N deprivation. We observed translational level changes that could overall redirect the metabolic network from carbon flux towards lipid accumulation. N deprivation led to an increase in the expression of genes involved in nitrogen assimilation and fatty acid biosynthesis and a concomitant decrease in photosynthesis and lipid catabolism enzymes. These molecular level changes are consistent with the observed physiological changes, e.g., in photosynthesis rate and saturated lipid content. Our results provide information at the proteomic level of the key enzymes involved in carbon flux towards lipid accumulation in P. tricornutum and suggest candidates for genetic manipulation in microalgae breeding for biodiesel production.
doi:10.1007/s10811-013-0050-3
PMCID: PMC3918386  PMID: 24600163
Lipid accumulation; Nitrogen deprivation; Diatom; Biofuel
20.  Molecular and cellular mechanisms of neutral lipid accumulation in diatom following nitrogen deprivation 
Background
Nitrogen limitation can induce neutral lipid accumulation in microalgae, as well as inhibiting their growth. Therefore, to obtain cultures with both high biomass and high lipid contents, and explore the lipid accumulation mechanisms, we implemented nitrogen deprivation in a model diatom Phaeodactylum tricornutum at late exponential phase.
Results
Neutral lipid contents per cell subsequently increased 2.4-fold, both the number and total volume of oil bodies increased markedly, and cell density rose slightly. Transcriptional profile analyzed by RNA-Seq showed that expression levels of 1213 genes (including key carbon fixation, TCA cycle, glycerolipid metabolism and nitrogen assimilation genes) increased, with a false discovery rate cut-off of 0.001, under N deprivation. However, most light harvesting complex genes were down-regulated, extensive degradation of chloroplast membranes was observed under an electron microscope, and photosynthetic efficiency declined. Further identification of lipid classes showed that levels of MGDG and DGDG, the main lipid components of chloroplast membranes, dramatically decreased and triacylglycerol (TAG) levels significantly rose, indicating that intracellular membrane remodeling substantially contributed to the neutral lipid accumulation.
Conclusions
Our findings shed light on the molecular mechanisms of neutral lipid accumulation and the key genes involved in lipid metabolism in diatoms. They also provide indications of possible strategies for improving microalgal biodiesel production.
doi:10.1186/1754-6834-6-67
PMCID: PMC3662598  PMID: 23642220
Microalga; Nitrogen deprivation; Lipid; Membrane remodeling; Transcriptomics
21.  The characteristic expression pattern of BMI-1 and SALL4 genes in placenta tissue and cord blood 
Introduction
SALL4 and BMI-1 are important factors in hematopoiesis. Placental tissue (PT) and umbilical cord blood (CB) are rich in hematopoietic stem/progenitor cells (HSCs/HPCs), but their SALL4 and BMI-1 expression levels remain unknown.
Methods
Real-time PCR was used to determine the expression level of these genes in PT and CB from ten cases, and ten healthy donors were used as controls.
Results
A significantly higher BMI-1 and SALL4 gene expression level was found in PT (median: 17.548 and 34.362, respectively) than in cord blood mononuclear cells (CBMCs) (median: 2.071 and 11.300, respectively) (P = 0.0001 and P = 0.007) and healthy peripheral blood mononuclear cells (PBMCs) (median: 0.259 and 0.384, respectively) (P = 0.001 and P <0.0001), and their expression level was lower in PBMCs than in CBMCs (P = 0.029 and P = 0.002). A positive correlation between the BMI-1 and SALL4 genes was found in the PT and CB groups, while there was no significant correlation between these genes in the healthy group. There was also no significant correlation between the expression level of each gene in PT and CB.
Conclusions
These results describe the characteristic features of the BMI-1 and SALL4 gene expression pattern in placental tissue and cord blood. Placental tissue with higher expression level of both genes may be considered as a potential resource for SALL4-related HPC expansion.
doi:10.1186/scrt199
PMCID: PMC3706899  PMID: 23632167
BMI-1 gene; Cord blood; Placenta; Real-time PCR; SALL4 gene
22.  Prevalence of Hypertension in Chinese Cities: A Meta-Analysis of Published Studies 
PLoS ONE  2013;8(3):e58302.
Background
Hypertension has been recognized as a health concern for developing countries. However, there are no current nationwide surveys on the prevalence of hypertension in China (the latest nationwide survey was ten years ago). The goal of this study was to estimate the pooled prevalence of hypertension in Chinese cities.
Methods
We systematically reviewed published epidemiologic studies on the prevalence of hypertension in Chinese cities through meta-analysis. We searched for studies published between January 2002 and June 2012 using PubMed and two Chinese electronic publication libraries. The keywords ‘hypertension’ and ‘prevalence’ were used. Before pooling prevalence of hypertension, all raw prevalence data was age adjusted to the 2010 China standard population. Prevalence estimates were stratified by sex and geographic area.
Results
27 studies were identified with of a total of 195,027 study participants. The overall pooled prevalence of hypertension was 21.5% (19.4%, 23.6%). Subgroup analyses showed the following results north 25.8% (21.6%, 30.0%), south 20.4% (18.6%, 22.2%); male 22.2% (19.3%, 25.1%), female 19.9% (17.6%, 22.1%); large cities 18.9% (15.7%, 22.1%), medium-sized cities 24.6% (19.9%, 29.4%), small cities 20.6% (17.5%, 23.7%); study years in 2002–2006, 21.9% (18.9%, 24.8%), and study year in 2007–2011, 20.6% (17.3%, 23.9%).
Conclusions
Comparing data from several previous national hypertension surveys, the prevalence of hypertension is higher in cities than the Chinese national average. Subgroup studies also found a higher prevalence of hypertension in northern cities and among males. Also, the prevalence of hypertension in medium-sized and small cities is likely to increase faster than in large cities.
doi:10.1371/journal.pone.0058302
PMCID: PMC3590128  PMID: 23484011
23.  Cytochrome P450 2E1 Gene Polymorphisms/Haplotypes and Anti-Tuberculosis Drug-Induced Hepatitis in a Chinese Cohort 
PLoS ONE  2013;8(2):e57526.
Objective
The pathogenic mechanism of anti-tuberculosis (anti-TB) drug-induced hepatitis is associated with drug metabolizing enzymes. No tagging single-nucleotide polymorphisms (tSNPs) of cytochrome P450 2E1(CYP2E1) in the risk of anti-TB drug-induced hepatitis have been reported. The present study was aimed at exploring the role of tSNPs in CYP2E1 gene in a population-based anti-TB treatment cohort.
Methods and Design
A nested case-control study was designed. Each hepatitis case was 14 matched with controls by age, gender, treatment history, disease severity and drug dosage. The tSNPs were selected by using Haploview 4.2 based on the HapMap database of Han Chinese in Beijing, and detected by using TaqMan allelic discrimination technology.
Results
Eighty-nine anti-TB drug-induced hepatitis cases and 356 controls were included in this study. 6 tSNPs (rs2031920, rs2070672, rs915908, rs8192775, rs2515641, rs2515644) were genotyped and minor allele frequencies of these tSNPs were 21.9%, 23.0%, 19.1%, 23.6%, 20.8% and 44.4% in the cases and 20.9%, 22.7%, 18.9%, 23.2%, 18.2% and 43.2% in the controls, respectively. No significant difference was observed in genotypes or allele frequencies of the 6 tSNPs between case group and control group, and neither of haplotypes in block 1 nor in block 2 was significantly associated with the development of hepatitis.
Conclusion
Based on the Chinese anti-TB treatment cohort, we did not find a statistically significant association between genetic polymorphisms of CYP2E1 and the risk of anti-TB drug-induced hepatitis. None of the haplotypes showed a significant association with the development of hepatitis in Chinese TB population.
doi:10.1371/journal.pone.0057526
PMCID: PMC3583841  PMID: 23460870
24.  Ascorbic acid enhances the cardiac differentiation of induced pluripotent stem cells through promoting the proliferation of cardiac progenitor cells 
Cell Research  2011;22(1):219-236.
Generation of induced pluripotent stem cells (iPSCs) has opened new avenues for the investigation of heart diseases, drug screening and potential autologous cardiac regeneration. However, their application is hampered by inefficient cardiac differentiation, high interline variability, and poor maturation of iPSC-derived cardiomyocytes (iPS-CMs). To identify efficient inducers for cardiac differentiation and maturation of iPSCs and elucidate the mechanisms, we systematically screened sixteen cardiomyocyte inducers on various murine (m) iPSCs and found that only ascorbic acid (AA) consistently and robustly enhanced the cardiac differentiation of eleven lines including eight without spontaneous cardiogenic potential. We then optimized the treatment conditions and demonstrated that differentiation day 2-6, a period for the specification of cardiac progenitor cells (CPCs), was a critical time for AA to take effect. This was further confirmed by the fact that AA increased the expression of cardiovascular but not mesodermal markers. Noteworthily, AA treatment led to approximately 7.3-fold (miPSCs) and 30.2-fold (human iPSCs) augment in the yield of iPS-CMs. Such effect was attributed to a specific increase in the proliferation of CPCs via the MEK-ERK1/2 pathway by through promoting collagen synthesis. In addition, AA-induced cardiomyocytes showed better sarcomeric organization and enhanced responses of action potentials and calcium transients to β-adrenergic and muscarinic stimulations. These findings demonstrate that AA is a suitable cardiomyocyte inducer for iPSCs to improve cardiac differentiation and maturation simply, universally, and efficiently. These findings also highlight the importance of stimulating CPC proliferation by manipulating extracellular microenvironment in guiding cardiac differentiation of the pluripotent stem cells.
doi:10.1038/cr.2011.195
PMCID: PMC3351910  PMID: 22143566
induced pluripotent stem cells; ascorbic acid; cardiomyocytes; cardiac progenitor cells
25.  Systematic Review and Meta-Analysis on the Association between Outpatient Statins Use and Infectious Disease-Related Mortality 
PLoS ONE  2012;7(12):e51548.
Background
To update and refine systematic literature review on the association between outpatient statins use and mortality in patients with infectious disease.
Materials and Methods
We searched articles published before September 31, 2012, on the association between statins and infectious disease-related mortality through electronic databases. Eligible articles were analyzed in Review Manager 5.1. We conducted stratification analysis by study design, infection types, clinical outcomes and study locations.
Results
The pooled odds ratio (OR) for death (statins use vs. no use) across the 41 included studies was 0.71 (95% confidence interval: 0.64, 0.78). The corresponding pooled ORs were 0.58 (0.38, 0.90), 0.66 (0.57, 0.75), 0.71 (0.57, 0.89) and 0.83 (0.67, 1.04) for the case-control study, retrospective cohort studies, prospective cohort studies and RCTs; 0.40 (0.20, 0.78), 0.61 (0.41, 0.90), 0.69 (0.62, 0.78) and 0.86 (0.68, 1.09) for bacteremia, sepsis, pneumonia and other infections; 0.62 (0.534, 0.72), 0.68 (0.53, 0.89), 0.71 (0.61, 0.83) and 0.86 (0.70, 1.07) for 30-day, 90-day, in-hospital and long-term (>1 year) mortality, respectively.
Conclusions
Outpatient statins use is associated with a lower risk of death in patients with infectious disease in observational studies, but in a less extent in clinical trials. This association also varies considerably by infection types and clinical outcomes.
doi:10.1371/journal.pone.0051548
PMCID: PMC3524177  PMID: 23284711

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