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1.  Anesthesia for stem cell transplantation in autistic children: A prospective, randomized, double-blind comparison of propofol and etomidate following sevoflurane inhalation 
The objective of the present study was to comparatively investigate the feasibility and safety of etomidate and propofol use following sevoflurane inhalation in autistic children during the intrathecal transplantation of stem cells. The patients selected were 60 autistic children with American Society of Anesthesiologists physical status I, who were aged between two and 12 years and scheduled for stem cell transplantation. The children received an inhalation induction of 8% sevoflurane, followed by intravenous injection of etomidate (0.2 mg/kg) in group E and propofol (2 mg/kg) in group P (n=30/group). Supplemental doses of 0.1 mg/kg etomidate or 1 mg/kg propofol were used until a deep sedation was obtained. The heart rate (HR), mean arterial pressure, oxygen saturation, respiratory rate, Ramsay sedation score (RSS) and recovery time were monitored continuously. Following anesthesia, blood pressure and HR measurements were significantly decreased in group P compared with the baseline (P<0.01) and group E values at the same time-points (P<0.05). The occurrence of adverse effects, such as respiratory depression, bradycardia, hypotension and pain on injection, was significantly higher in group P than that in group E, whereas the incidence of myoclonus in group E was significantly higher than that in group P (P<0.01). No significant differences in anesthesia induction, surgery duration, recovery time, RSS and physician satisfaction were observed between the two groups. In conclusion, sevoflurane-etomidate combinations resulted in more stable hemodynamic responses and relatively fewer adverse effects compared with propofol injection following sevoflurane inhalation and may therefore be more suitable for the induction of short-term anesthesia in autistic children during stem cell transplantation.
PMCID: PMC4316962  PMID: 25667673
sevoflurane; propofol; etomidate; autism; stem cell transplantation
2.  The TCR γδ Repertoire and Relative Gene Expression Characteristics of T-ALL Cases with Biclonal Malignant Vδ1 and Vδ2 T Cells 
DNA and Cell Biology  2014;33(1):49-56.
Despite significant improvement in our understanding of T-cell acute lymphoblastic leukemia (T-ALL) biology and pathogenesis, many questions remain unanswered. In previous studies, we found a T-ALL case with two malignant T-cell clones with Vδ1Dδ2Dδ3Jδ1 and Vδ2Dδ3Jδ2 rearrangements. In this study, we further characterized T-ALL cases with two malignant clones containing Vδ1Dδ3Jδ1 and Vδ2Dδ1Jδ1 rearrangements using fine-tiling array comparative genomic hybridization, ligation-mediated polymerase chain reaction (LM-PCR), sequencing, and reverse transcription polymerase chain reaction (RT-PCR) analysis. We further analyzed the distribution and clonality of the T-cell receptor (TCR) Vγ and Vδ subfamily T cells in the two T-ALL cases by RT-PCR and GeneScan. Monoclonal Vδ1 and Vδ2 subfamilies were confirmed in both samples, the Vδ3 through Vδ7 subfamilies could not be detected in the T-ALL samples, whereas the oligoclonal Vδ8 subfamily could be identified. Based on the clinical finding that both of the T-ALL cases with two malignant T-cell clones had a poor outcome, we attempted to compare the expression pattern of genes related to T-cell activation and proliferation between cases with the malignant Vδ1 and Vδ2 T-cell clones and T-ALL cases with a mono-malignant Vα T-cell clone. We selected two T-ALL cases with VαJα rearrangements and analyzed the expression level of Notch1, TAL1, and the CARMA-BCL10-MALT-A20-NF-κB pathway genes by real-time PCR. A20 had significantly higher expression in the biclonal compared with the monoclonal T-ALL group (p=0.0354), and there was a trend toward higher expression for the other genes in the biclonal group with the exception of TAL1, although the differences were not statistically significant. In conclusion, we identified two T-ALL cases with biclonal malignant T-cell clones and described the characteristics of the biclonal T-ALL subtype and its gene expression pattern. Thus, our findings may improve the understanding of biclonal T-ALL.
PMCID: PMC3880916  PMID: 24329526
3.  Myoclonic epilepsy with ragged-red fibers: A case report 
Myoclonic epilepsy with ragged-red fibers is a maternally inherited disease that is characterized by myoclonic epilepsy, cerebellar ataxia and progressive muscular weakness. The present study reports the case of a 25-year-old male who presented with paroxysmal left upper limb tics and weakness for two years. Neurological examination revealed intact cranial nerves, decreased deep tendon reflexes and decreased sensation of touch, pain and vibration. The gait of the patient was broad and he was unable to walk in a straight line. Local cortical atrophy was also observed in the left temporal-occipital cortex on a magnetic resonance imaging scan. The muscle biopsy revealed ragged-red fibers. Therefore, the present study hypothesized that imaging observations and follow-up examinations are important in patients with myoclonic epilepsy.
PMCID: PMC4280940  PMID: 25574211
myoclonia; epilepsy; mitochondrial encephalomyopathy
4.  Characteristics of CARMA1-BCL10-MALT1-A20-NF-κB expression in T cell-acute lymphocytic leukemia 
Knowledge of the oncogenic signaling pathways of T-cell acute lymphoblastic leukemia (T-ALL) remains limited. Constitutive aberrant activation of the nuclear factor kappa B (NF-κB) signaling pathway has been detected in various lymphoid malignancies and plays a key role in the development of these carcinomas. The zinc finger-containing protein, A20, is a central regulator of multiple NF-κB-activating signaling cascades. A20 is frequently inactivated by deletions and/or mutations in several B-and T-cell lymphoma subtypes. However, few A20 mutations and polymorphisms have been reported in T-ALL. Thus, it is of interest to analyze the expression characteristics of A20 and its regulating factors, including upstream regulators and the CBM complex, which includes CARMA1, BCL10, and MALT1.
The expression levels of CARMA1, BCL10, MALT1, A20, and NF-κB were detected in peripheral blood mononuclear cells (PBMCs) from 21 patients with newly diagnosed T-ALL using real-time PCR, and correlations between the aberrant expression of these genes in T-ALL was analyzed. Sixteen healthy individuals, including 10 males and 6 females, served as controls.
Significantly lower A20 expression was found in T-ALL patients (median: 4.853) compared with healthy individuals (median: 8.748; P = 0.017), and significantly increased expression levels of CARMA1 (median: 2.916; P = 0.034), BCL10 (median: 0.285; P = 0.033), and MALT1 (median: 1.201; P = 0.010) were found in T-ALL compared with the healthy individuals (median: 1.379, 0.169, and 0.677, respectively). In contrast, overexpression of NF-κB (median: 0.714) was found in T-ALL compared with healthy individuals (median: 0.335; P = 0.001). A negative correlation between the MALT1 and A20 expression levels and a positive correlation between CARMA1 and BCL10 were found in T-ALL and healthy individuals. However, no negative correlation was found between A20 and NF-κB and the MALT1 and NF-κB expression level in the T-ALL group.
We characterized the expression of the CARMA-BCL10-MALT1-A20-NF-κB pathway genes in T-ALL. Overexpression of CARMA-BCL10-MALT in T-ALL may contribute to the constitutive cleavage and inactivation of A20, which enhances NF-κB signaling and may be related to T-ALL pathogenesis.
PMCID: PMC4228272  PMID: 25384343
A20; CARMA1-BCL10-MALT1; T-cell acute lymphoblastic leukemia
5.  Neuroprotective effect of lovastatin by inhibiting NMDA receptor1 in 6-hydroxydopamine treated PC12 cells 
In addition to original role of lowering cholesterol, statins display multiple neuroprotective mechanisms. In this study, 6-Hydroxydopamine (6-OHDA)-treated pheochromocytoma-12 (PC12) cells were used to investigate the neuroprotective nature of lovastatin. After incubation with 6-OHDA and/or lovastatin, test kits were used to detect the levels of LDH and glutamate, which were released from PC12 cells exposed to different culture media. The mRNA levels of TNF-α, and NMDAR1 were determined by RT-PCR and the protein levels were analyzed by western blot. Our results show that lovastatin significantly decreased both the mRNA and the protein levels of TNF-α and NMDAR1. ELISA assays revealed increased lactate dehydrogenase (LDH) and glutamate binding activity in 6-OHDA-lesioned PC12 cells, and this increase could be prevented by lovastatin. Our results suggest that lovastatin induces neuroprotection by inhibiting NMDAR1 and TNF-α. The data provide direct evidence of the potential application of lovastatin for the treatment of parkinson’s diseases.
PMCID: PMC4238522  PMID: 25419363
Parkinson’s disease; lovastatin; NMDA receptor1; TNF-α
6.  Assessment of Mouse Germinal Vesicle Stage Oocyte Quality by Evaluating the Cumulus Layer, Zona Pellucida, and Perivitelline Space 
PLoS ONE  2014;9(8):e105812.
To improve the outcome of assisted reproductive technology (ART) for patients with ovulation problems, it is necessary to retrieve and select germinal vesicle (GV) stage oocytes with high developmental potential. Oocytes with high developmental potential are characterized by their ability to undergo proper maturation, fertilization, and embryo development. In this study, we analyzed morphological traits of GV stage mouse oocytes, including cumulus cell layer thickness, zona pellucida thickness, and perivitelline space width. Then, we assessed the corresponding developmental potential of each of these oocytes and found that it varies across the range measured for each morphological trait. Furthermore, by manipulating these morphological traits in vitro, we were able to determine the influence of morphological variation on oocyte developmental potential. Manually altering the thickness of the cumulus layer showed strong effects on the fertilization and embryo development potentials of oocytes, whereas manipulation of zona pellucida thickness effected the oocyte maturation potential. Our results provide a systematic detailed method for selecting GV stage oocytes based on a morphological assessment approach that would benefit for several downstream ART applications.
PMCID: PMC4140848  PMID: 25144310
7.  Risk factors associated with early and late HAT after adult liver transplantation 
World Journal of Gastroenterology : WJG  2014;20(30):10545-10552.
AIM: To identify risk factors that might contribute to hepatic artery thrombosis (HAT) after liver transplantation (LT).
METHODS: The perioperative and follow-up data of a total of 744 liver transplants, performed from February 1999 to July 2010, were retrospectively reviewed. HAT developed in 20 patients (2.7%). HAT was classified as early (occurring in fewer than 30 d post LT) or late (occurring more than 30 d post LT). Early HAT developed in 14 patients (1.9%). Late HAT developed in 6 patients (0.8%). Risk factors associated with HAT were analysed using the χ2 test for univariate analysis and logistic regression for multivariate analysis.
RESULTS: Lack of ABO compatibility, recipient/donor weight ratio ≥ 1.15, complex arterial reconstruction, duration time of hepatic artery anastomosis > 80 min, duration time of operation > 10 h, dual grafts, number of units of blood received intraoperatively ≥ 7, number of units of fresh frozen plasma (FFP) received intraoperatively ≥ 6, postoperative blood transfusion and postoperative FFP use were significantly associated with early HAT in the univariate analysis (P < 0.1). After logistic regression, independent risk factors associated with early HAT were recipient/donor weight ratio ≥ 1.15 (OR = 4.499), duration of hepatic artery anastomosis > 80 min (OR = 5.429), number of units of blood received intraoperatively ≥ 7 (OR = 4.059) and postoperative blood transfusion (OR = 6.898). Graft type (whole/living-donor/split), duration of operation > 10 h, retransplantation, rejection reaction, recipients with diabetes preoperatively and recipients with a high level of blood glucose or diabetes postoperatively were significantly associated with late HAT in the univariate analysis (P < 0.1). After logistic regression, the independent risk factors associated with early HAT were duration of operation > 10 h (OR = 6.394), retransplantation (OR = 21.793) and rejection reactions (OR = 16.936).
CONCLUSION: Early detection of these risk factors, strict surveillance protocols by Doppler ultrasound and prophylactic anticoagulation for recipients at risk might be determined prospectively.
PMCID: PMC4130865  PMID: 25132774
Liver transplantation; Hepatic artery thrombosis; Risk factors; Complication; Blood transfusion
8.  Antisense knockdown of pyruvate dehydrogenase kinase promotes the neutral lipid accumulation in the diatom Phaeodactylum tricornutum 
Microbial Cell Factories  2014;13(1):100.
Microalgae have been an emerging biofuel resource; however, the germplasm improvement has been slow due to the lack of molecular tools. Pyruvate dehydrogenase kinase (PDK) deactivates the pyruvate dehydrogenase complex (PDC) which catalyzes the oxidative decarboxylation of pyruvate. Acetyl-CoA production via PDC is important in plant tissues that are active in fatty acid synthesis.
A 1261-bp cDNA of a putative PDK gene (PtPDK) was cloned from a diatom Phaeodactylum tricornutum, and PtPDK antisense knockdown transgenic diatoms were generated. Both PtPDK transcript abundance and enzyme activity were reduced significantly due to antisense knockdown of PtPDK. Neutral lipid content of transgenic diatom cells increased up to 82% as determined by Nile red staining, and fatty acid composition was not altered. Transgenic cells showed slightly lower growth rate but similar cell size with the wild type, hence retaining similar biomass productivity.
This work first obtained a successful engineered diatom regulating a key gene involved in lipid metabolism. Our findings also provide powerful indications in enhancing microalgal lipid production by metabolic engineering for biofuel industry.
PMCID: PMC4251698  PMID: 25106441
Microalga; Pyruvate dehydrogenase kinase; Antisense; Lipid; Biofuel
9.  Rapid Diagnosis of Childhood Pulmonary Tuberculosis by Xpert MTB/RIF Assay Using Bronchoalveolar Lavage Fluid 
BioMed Research International  2014;2014:310194.
In order to evaluate the diagnostic accuracy of the Xpert MTB/RIF assay on childhood pulmonary tuberculosis (PTB) using bronchoalveolar lavage fluid (BALF), we evaluated the sensitivity, specificity, positive predictive value, and negative predictive value of Xpert MTB/RIF assay using BALF in comparison with acid-fast bacilli (AFB) microscopy and Mycobacterium tuberculosis (MTB) culture for diagnosing childhood PTB using Chinese “composite clinical reference standard” (CCRS) as reference standard. Two hundred fifty-five children with suspected PTB were enrolled at Beijing Children's Hospital from September 2010 to July 2013. Compared with Chinese CCRS, the sensitivity of AFB microscopy, MTB culture, and Xpert MTB/RIF assay was 8.4%, 28.9%, and 53.0%, respectively. The specificity of three assays was all 100%. Xpert MTB/RIF assay could detect 33.9% of cases with negative MTB culture, and 48.7% of cases with negative AFB microscopy. Younger age (<3 years), absence of BCG scar, and contact with TB patient were found significantly associated with a positive result of Xpert MTB/RIF assay. In conclusion, Xpert MTB/RIF assay using BALF can assist in diagnosing childhood PTB much faster when fiberoptic bronchoscopy is necessary according to the chest radiograph.
PMCID: PMC4140106  PMID: 25165698
10.  Tanshinone IIA Downregulates HMGB1 and TLR4 Expression in a Spinal Nerve Ligation Model of Neuropathic Pain 
Fifty-four Sprague-Dawley rats weighing 200~240 g were randomly divided into sham-operated group (sham group), vehicle-treated SNL group (model group), and Tan IIA-treated SNL group (Tan IIA group). Tan IIA was administered intraperitoneally to rats in the Tan IIA-treated group at a dose of 30 mg/kg daily for 14 days after SNL surgery. Paw withdrawal mechanical thresholds (PWTs) and paw withdrawal thermal latencies (PWLs) were measured. High-mobility group box 1 (HMGB1) and Toll-like Receptor 4 (TLR4) mRNA and protein expression in the spinal cord were measured. Tumour necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-10 (IL-10) in the spinal cord were measured, too. Both the mechanical and heat pain thresholds were significantly decreased. After Tan IIA treatment, HMGB1, and TLR4 mRNA and protein levels, the expression of TNF-α and IF-1β was reduced significantly. In conclusion, Tanshinone IIA reversed SNL-induced thermal hyperalgesia and mechanical allodynia and downregulated HMGB1 and TLR4 levels and inhibited the HMGB1-TLR4 pathway. Tanshinone IIA inhibited TNF-α and IL-1β expression but not IF-10 expression in the spinal cords of SNL rats. These results indicate that Tanshinone IIA inhibited SNL-induced neuropathic pain via multiple effects, and targeting the HMGB1-TLR4 pathway could serve as the basis of new antinociceptive agents.
PMCID: PMC4120799  PMID: 25120576
11.  The Good Pain Management (GPM) Ward Program in China and its impact on Chinese cancer patients: the SYSUCC experience 
Chinese Journal of Cancer  2014;33(7):323-329.
To improve cancer pain management, the Medical Oncology Department of Sun Yat-sen University Cancer Center (SYSUCC) launched the Good Pain Management (GPM) Ward Program, which has been recognized by the Chinese Ministry of Health and promoted throughout the nation. This retrospective case-control study was designed to evaluate the effectiveness of the program. Patients diagnosed with malignant solid tumors with bone metastasis were eligible. Patients who were admitted 6 months before the initiation of the GPM program were used as the control group, and patients admitted 6 months after the initiation of the program were used as the GPM group. The pain-reporting rate and pain management index (PMI) were calculated. The pain levels before and after pain management were compared. A total of 475 patients (244 in the control group and 231 in the GPM group) were analyzed. The pain-reporting rate of the GPM group was significantly higher than that of the control group (62.8% vs. 37.7%, P < 0.001). The PMI of the GPM group was significantly higher than that of the control group (0.083 vs. -0.261, P < 0.001). Therefore, the GPM Ward Program improved the pain management of cancer patients and provided experience for improving cancer pain management in the future.
PMCID: PMC4110464  PMID: 24874643
Good pain management; cancer pain management; pain-reporting rate; pain management index
12.  Interventional therapy for human breast cancer in nude mice with 131I gelatin microspheres (131I-GMSs) following intratumoral injection 
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.
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.
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.
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.
PMCID: PMC4083354  PMID: 24958442
131I; Gelatin microspheres; Breast neoplasms; Intratumoral injection; Treatment outcome; Biodistribution
13.  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.
PMCID: PMC4009118  PMID: 24955421
14.  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.
PMCID: PMC3981565  PMID: 24782598
15.  7.0T nuclear magnetic resonance evaluation of the amyloid beta (1–40) animal model of Alzheimer's disease: comparison of cytology verification 
Neural Regeneration Research  2014;9(4):430-435.
3.0T magnetic resonance spectroscopic imaging is a commonly used method in the research of brain function in Alzheimer's disease. However, the role of 7.0T high-field magnetic resonance spectroscopic imaging in brain function of Alzheimer's disease remains unclear. In this study, 7.0T magnetic resonance spectroscopy showed that in the hippocampus of Alzheimer's disease rats, the N-acetylaspartate wave crest was reduced, and the creatine and choline wave crest was elevated. This finding was further supported by hematoxylin-eosin staining, which showed a loss of hippocampal neurons and more glial cells. Moreover, electron microscopy showed neuronal shrinkage and mitochondrial rupture, and scanning electron microscopy revealed small size hippocampal synaptic vesicles, incomplete synaptic structure, and reduced number. Overall, the results revealed that 7.0T high-field nuclear magnetic resonance spectroscopy detected the lesions and functional changes in hippocampal neurons of Alzheimer's disease rats in vivo, allowing the possibility for assessing the success rate and grading of the amyloid beta (1–40) animal model of Alzheimer's disease.
PMCID: PMC4146198  PMID: 25206831
nerve regeneration; Alzheimer's disease; Aβ1–40; high-field functional magnetic resonance; nuclear magnetic resonance spectroscopy; neuropathology; N-acetylaspartate; creatine; choline; hippocampus; NSFC grant; neural regeneration
16.  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.
PMCID: PMC3935012  PMID: 23816558
NSCLC; platinum-based doublet chemotherapy; correlation; EGFR-TKIs; overall survival
17.  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.
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.
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.
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.
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.
PMCID: PMC3900682  PMID: 24466311
18.  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.
PMCID: PMC3880695  PMID: 24454500
19.  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.
PMCID: PMC3917744  PMID: 24649095
acute pancreatitis; systemic inflammatory reaction syndrome; cytokine; methylprednisolone; cyclophosphamide; methotrexate
20.  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.
PMCID: PMC3885003  PMID: 24454178
21.  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.
PMCID: PMC3828386  PMID: 24244479
22.  Energetic factors determining the binding of type I inhibitors to c-Met kinase: experimental studies and quantum mechanical calculations 
Acta Pharmacologica Sinica  2013;34(11):1475-1483.
To decipher the molecular interactions between c-Met and its type I inhibitors and to facilitate the design of novel c-Met inhibitors.
Based on the prototype model inhibitor 1, four ligands with subtle differences in the fused aromatic rings were synthesized. Quantum chemistry was employed to calculate the binding free energy for each ligand. Symmetry-adapted perturbation theory (SAPT) was used to decompose the binding energy into several fundamental forces to elucidate the determinant factors.
Binding free energies calculated from quantum chemistry were correlated well with experimental data. SAPT calculations showed that the predominant driving force for binding was derived from a sandwich π–π interaction with Tyr-1230. Arg-1208 was the differentiating factor, interacting with the 6-position of the fused aromatic ring system through the backbone carbonyl with a force pattern similar to hydrogen bonding. Therefore, a hydrogen atom must be attached at the 6-position, and changing the carbon atom to nitrogen caused unfavorable electrostatic interactions.
The theoretical studies have elucidated the determinant factors involved in the binding of type I inhibitors to c-Met.
PMCID: PMC4006466  PMID: 24056705
receptor tyrosine kinase; type I c-Met inhibitor; cancer; quantum chemistry; protein-ligand interaction; symmetry-adapted perturbation theory (SAPT)
23.  A Rat Model of Hemidystonia Induced by 3-Nitropropionic Acid  
PLoS ONE  2013;8(10):e79199.
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.
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.
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.
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.
PMCID: PMC3806852  PMID: 24194961
24.  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.
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.
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.
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.
PMCID: PMC3851874  PMID: 24106772
Estrogen; Neuroprotection; Ischemia; Middle carotid artery occlusion (MCAO); Oxygen and glucose deprivation (OGD)
25.  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.
PMCID: PMC3790242  PMID: 23856644
embryonic stem cell; haploid cells; monkey

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