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1.  Laparoscopic-endoscopic cooperative surgery for gastric submucosal tumors 
AIM: To assess the feasibility, safety, and advantages of minimally invasive laparoscopic-endoscopic cooperative surgery (LECS) for gastric submucosal tumors (SMT).
METHODS: We retrospectively analyzed 101 consecutive patients, who had undergone partial, proximal, or distal gastrectomy using LECS for gastric SMT at Peking Union Medical College Hospital from June 2006 to April 2013. All patients were followed up by visit or telephone. Clinical data, surgical approach, pathological features such as the size, location, and pathological type of each tumor; and follow-up results were analyzed. The feasibility, safety and effectiveness of LECS for gastric SMT were evaluated, especially for patients with tumors located near the cardia or pylorus.
RESULTS: The 101 patients included 43 (42.6%) men and 58 (57.4%) women, with mean age of 51.2 ± 13.1 years (range, 14-76 years). The most common symptom was belching. Almost all (n = 97) patients underwent surgery with preservation of the cardia and pylorus, with the other four patients undergoing proximal or distal gastrectomy. The mean distance from the lesion to the cardia or pylorus was 3.4 ± 1.3 cm, and the minimum distance from the tumor edge to the cardia was 1.5 cm. Tumor pathology included gastrointestinal stromal tumor in 78 patients, leiomyoma in 13, carcinoid tumors in three, ectopic pancreas in three, lipoma in two, glomus tumor in one, and inflammatory pseudotumor in one. Tumor size ranged from 1 to 8.2 cm, with 65 (64.4%) lesions < 2 cm, 32 (31.7%) > 2 cm, and four > 5 cm. Sixty-six lesions (65.3%) were located in the fundus, 21 (20.8%) in the body, 10 (9.9%) in the antrum, three (3.0%) in the cardia, and one (1.0%) in the pylorus. During a median follow-up of 28 mo (range, 1-69 mo), none of these patients experienced recurrence or metastasis. The three patients who underwent proximal gastrectomy experienced symptoms of regurgitation and belching.
CONCLUSION: Laparoscopic-endoscopic cooperative surgery is feasible and safe for patients with gastric submucosal tumor. Endoscopic intraoperative localization and support can help preserve the cardia and pylorus during surgery.
PMCID: PMC3769911  PMID: 24039367
Laparoscopic-endoscopic cooperative surgery; Gastric submucosal tumor; Minimally invasive surgery; Laparoscopy; Endoscopy
2.  Leaf cDNA-AFLP analysis of two citrus species differing in manganese tolerance in response to long-term manganese-toxicity 
BMC Genomics  2013;14:621.
Very little is known about manganese (Mn)-toxicity-responsive genes in citrus plants. Seedlings of ‘Xuegan’ (Citrus sinensis) and ‘Sour pummelo’ (Citrus grandis) were irrigated for 17 weeks with nutrient solution containing 2 μM (control) or 600 μM (Mn-toxicity) MnSO4. The objectives of this study were to understand the mechanisms of citrus Mn-tolerance and to identify differentially expressed genes, which might be involved in Mn-tolerance.
Under Mn-toxicity, the majority of Mn in seedlings was retained in the roots; C. sinensis seedlings accumulated more Mn in roots and less Mn in shoots (leaves) than C. grandis ones and Mn concentration was lower in Mn-toxicity C. sinensis leaves compared to Mn-toxicity C. grandis ones. Mn-toxicity affected C. grandis seedling growth, leaf CO2 assimilation, total soluble concentration, phosphorus (P) and magenisum (Mg) more than C. sinensis. Using cDNA-AFLP, we isolated 42 up-regulated and 80 down-regulated genes in Mn-toxicity C. grandis leaves. They were grouped into the following functional categories: biological regulation and signal transduction, carbohydrate and energy metabolism, nucleic acid metabolism, protein metabolism, lipid metabolism, cell wall metabolism, stress responses and cell transport. However, only 7 up-regulated and 8 down-regulated genes were identified in Mn-toxicity C. sinensis ones. The responses of C. grandis leaves to Mn-toxicity might include following several aspects: (1) accelerating leaf senescence; (2) activating the metabolic pathway related to ATPase synthesis and reducing power production; (3) decreasing cell transport; (4) inhibiting protein and nucleic acid metabolisms; (5) impairing the formation of cell wall; and (6) triggering multiple signal transduction pathways. We also identified many new Mn-toxicity-responsive genes involved in biological and signal transduction, carbohydrate and protein metabolisms, stress responses and cell transport.
Our results demonstrated that C. sinensis was more tolerant to Mn-toxicity than C. grandis, and that Mn-toxicity affected gene expression far less in C. sinensis leaves. This might be associated with more Mn accumulation in roots and less Mn accumulation in leaves of Mn-toxicity C. sinensis seedlings than those of C. grandis seedlings. Our findings increase our understanding of the molecular mechanisms involved in the responses of plants to Mn-toxicity.
PMCID: PMC3847489  PMID: 24034812
cDNA-AFLP; Citrus grandis; Citrus sinensis; Leaves; Manganese
3.  Bone Marrow Injury Induced via Oxidative Stress in Mice by Inhalation Exposure to Formaldehyde 
PLoS ONE  2013;8(9):e74974.
Formaldehyde, a ubiquitous environmental pollutant has been classified as a human leukemogen. However, toxicity of formaldehyde in bone marrow, the target site of leukemia induction, is still poorly understood.
Methodology/Principal Findings
To investigate bone marrow toxicity (bone marrow pathology, hematotoxicity) and underlying mechanisms (oxidative stress, inflammation, apoptosis) in formaldehyde-exposed mice. Male Balb/c mice were exposed to formaldehyde (0, 0.5, and 3.0 mg/m3) by nose-only inhalation for 8 hours/day, over a two week period designed to simulate a factory work schedule, with an exposure-free “weekend” on days 6 and 7, and were sacrificed on the morning of day 13. Counts of white blood cells, red blood cells and lymphocytes were significantly (p<0.05) decreased at 0.5 mg/m3 (43%, 7%, and 39%, respectively) and 3.0 mg/m3 (52%, 27%, and 43%, respectively) formaldehyde exposure, while platelet counts were significantly increased by 109% (0.5 mg/m3) and 67% (3.0 mg/m3). Biomarkers of oxidative stress (reactive oxygen species, glutathione depletion, cytochrome P450 1A1 and glutathione s-transferase theta 1 expression), inflammation (nuclear factor kappa-B, tomour necrosis factor alpha, interleukin-1 beta), and apoptosis (activity of cysteine-aspartic acid protease 3) in bone marrow tissues were induced at one or both formaldehyde doses mentioned above.
Exposure of mice to formaldehyde by inhalation induced bone marrow toxicity, and that oxidative stress, inflammation and the consequential apoptosis jointly constitute potential mechanisms of such induced toxicity.
PMCID: PMC3770590  PMID: 24040369
4.  Increased rate of sporadic and recurrent rare genic copy number variants in Parkinson's disease among Ashkenazi Jews 
To date, only one genome-wide study has assessed the contribution of copy number variants (CNVs) to Parkinson's disease (PD). We conducted a genome-wide scan for CNVs in a case–control dataset of Ashkenazi Jewish (AJ) origin (268 PD cases and 178 controls). Using high-confidence CNVs, we examined the global genome wide burden of large (≥100 kb) and rare (≤1% in the dataset) CNVs between cases and controls. A total of 986 such CNVs were observed in our dataset of 432 subjects. Overall global burden analyses did not reveal significant differences between cases and controls in CNV rate, distribution of deletions or duplications or number of genes affected by CNVs. Overall deletions (total CNV size and ≥2× frequency) were found 1.4 times more often in cases than in controls (P = 0.019). The large CNVs (≥500 kb) were also significantly associated with PD (P = 0.046, 1.24-fold higher in cases than in controls). Global burden was elevated for rare CNV regions. Specifically, for OVOS2 on Chr12p11.21, CNVs were observed only in PD cases (n = 7) but not in controls (P = 0.028) and this was experimentally validated. A total of 81 PD cases carried a rare genic CNV that was absent in controls. Ingenuity pathway analysis (IPA) identified ATXN3, FBXW7, CHCHD3, HSF1, KLC1, and MBD3 in the same disease pathway with known PD genes.
PMCID: PMC3782064  PMID: 24073418
Ashkenazi Jews; candidate genes; case–control study; CNV; Parkinson's disease
5.  Polo-Like Kinase 1 Inhibits the Activity of Positive Transcription Elongation Factor of RNA Pol II b (P-TEFb) 
PLoS ONE  2013;8(8):e72289.
Polo-like kinase 1 (Plk1) is a highly conserved Ser/Thr kinase in eukaryotes and plays a critical role in various aspects of the cell cycle. Plk1 exerts its multiple functions by phosphorylating its substrates. In this study, we found that Plk1 can interact with cyclin T1/Cdk9 complex-the main form of the positive transcription elongation complex b (P-TEFb), and its C-terminal polo-box domain is responsible for the binding. Further analysis indicated that Plk1 could phosphorylate cyclin T1 at Ser564 and inhibit the kinase activity of cyclin T1/Cdk9 complex on phosphorylation of the C-terminal domain (CTD) of RNA polymerase II. By taking the approach of luciferase assay, we demonstrated that over-expression of both wild type Plk1 and constitutively active form of Plk1 inhibits the P-TEFb dependent HIV-1 LTR transcription, while knockdown of Plk1 increases the HIV-1 LTR transcription. Consistently, the data from the HIV-1 pseudovirus reporter assay indicated that Plk1 blocks the gene expression of HIV-1 pseudovirus. Taken together, our results revealed that Plk1 negatively regulates the RNA polymerase II-dependent transcription through inhibiting the activity of cyclin T1/Cdk9 complex.
PMCID: PMC3745420  PMID: 23977272
6.  Portal for Families Overcoming Neurodevelopmental Disorders (PFOND): Implementation of a Software Framework for Facilitated Community Website Creation by Nontechnical Volunteers 
JMIR Research Protocols  2013;2(2):e25.
The Portal for Families Overcoming Neurodevelopmental Disorders (PFOND) provides a structured Internet interface for the sharing of information with individuals struggling with the consequences of rare developmental disorders. Large disease-impacted communities can support fundraising organizations that disseminate Web-based information through elegant websites run by professional staff. Such quality resources for families challenged by rare disorders are infrequently produced and, when available, are often dependent upon the continued efforts of a single individual.
The project endeavors to create an intuitive Web-based software system that allows a volunteer with limited technical computer skills to produce a useful rare disease website in a short time period. Such a system should provide access to emerging news and research findings, facilitate community participation, present summary information about the disorder, and allow for transient management by volunteers who are likely to change periodically.
The prototype portal was implemented using the WordPress software system with both existing and customized supplementary plug-in software modules. Gamification scoring features were implemented in a module, allowing editors to measure progress. The system was installed on a Linux-based computer server, accessible across the Internet through standard Web browsers.
A prototype PFOND system was implemented and tested. The prototype system features a structured organization with distinct partitions for background information, recent publications, and community discussions. The software design allows volunteer editors to create a themed website, implement a limited set of topic pages, and connect the software to dynamic RSS feeds providing information about recent news or advances. The prototype was assessed by a fraction of the disease sites developed (8 out of 27), including Aarskog-Scott syndrome, Aniridia, Adams-Oliver syndrome, Cat Eye syndrome, Kabuki syndrome, Leigh syndrome, Peters anomaly, and Rothmund-Thomson syndrome. The editor progress score was used to measure performance for a portion of sites.
The PFOND system provides a convenient and structured Internet resource for the facilitated creation of information resources for families confronted by rare disorders. The system empowers volunteers to participate in the creation of quality content, while allowing for the inevitable turnover of contributors over time. The next phase of PFOND development will focus on volunteer participation in system development and community engagement.
PMCID: PMC3742411  PMID: 23920006
medical informatics; medical genetics; inborn genetic disease; rare disease; social media; consumer participation
7.  Hepatitis B Virus mRNA-Mediated miR-122 Inhibition Upregulates PTTG1-Binding Protein, Which Promotes Hepatocellular Carcinoma Tumor Growth and Cell Invasion 
Journal of Virology  2013;87(4):2193-2205.
As the most abundant liver-specific microRNA, miR-122 is involved in diverse aspects of hepatic function and neoplastic transformation. Our previous study showed that miR-122 levels are significantly decreased in hepatitis B virus (HBV)-infected patients, which may facilitate viral replication and persistence (S. Wang, L. Qiu, X. Yan, W. Jin, Y. Wang, L. Chen, E. Wu, X. Ye, G. F. Gao, F. Wang, Y. Chen, Z. Duan, and S. Meng, Hepatology 55:730–741, 2012). Loss of miR-122 expression in patients with hepatitis B enhances hepatitis B virus replication through cyclin G1-modulated P53 activity.). In this study, we provide evidence that all HBV mRNAs harboring an miR-122 complementary site act as sponges to bind and sequester endogenous miR-122, indicating that the highly redundant HBV transcripts are involved in HBV-mediated miR-122 suppression. We next identified pituitary tumor-transforming gene 1 (PTTG1) binding factor (PBF) as a target of miR-122 and demonstrated that HBV replication causes an obvious increase in PBF levels. Furthermore, we observed that the miR-122 levels were decreased and PBF was upregulated in chronic hepatitis B (CHB) and hepatocellular carcinoma (HCC). Overexpression and knockdown studies both revealed that PBF enhances proliferation and invasion of HCC cells, and silencing PBF resulted in a dramatic reduction of HCC tumor growth in vivo. Mechanistic analysis demonstrated that PBF interacts with PTTG1 and facilitates PTTG1 nuclear translocation, subsequently increasing its transcriptional activities. Therefore, we identified a novel HBV mRNA-miR-122-PBF regulatory pathway that facilitates malignant hepatocyte growth and invasion in CHB which may contribute to CHB-induced HCC development and progression. Our work underscores the reciprocal interplay of host miRNA sequestration and depletion by viral mRNAs, which may contribute to chronic-infection-related cancer.
PMCID: PMC3571498  PMID: 23221562
8.  Real-world utilization patterns and outcomes of colesevelam hcl in the ge electronic medical record 
In randomized controlled trials (RCTs), colesevelam HCI, added to other anti-diabetic therapy, reduced hemoglobin A1C by approximately 0.3% to 0.4% over 16- to 26-weeks compared with an increase of approximately 0.1% to 0.2% for placebo, for a placebo-adjusted treatment effect of approximately 0.5%. Evidence on real-world effectiveness is unknown. This retrospective cohort study examined A1C changes following colesevelam HCL initiation in patients with diabetes, regardless of concomitant anti-diabetic medication use.
2000–2011 GE Centricity electronic medical records data were used to identify patients with type 2 diabetes mellitus (T2DM) aged 18 or older initiating colesevelam HCL. The sample was further restricted to uncontrolled patients with database activity ≥ 395 days before and after colesevelam HCL initiation, A1C > 7% during 90 days prior to starting colesevelam HCL, without prior use of bile acid sequestrants, and with at least one A1C result between 42 to 210 days after initiation. Three overlapping time intervals were created for A1C measurement, including 16-weeks, 26-weeks, and 52-weeks following therapy initiation. The last observed A1C lab measurement during each interval was used to define change from baseline. Mean change in A1C was examined using paired t-tests. Sensitivity analyses considered only patients who remained on colesevelam HCL through each respective measurement period, as well as the effect of concomitant diabetes medications.
Of 1,709,393 patients in the GE database with T2DM, 1,747 met inclusion criteria. The cohort was 58% female, 38% age ≥ 65, and the majority was white. For the 16-week endpoint (N = 1,385), A1C dropped from a mean of 8.22% to 7.75% (mean change −0.47%; P < 0.0001). For the 26- and 52-week endpoints (N = 1,747), A1C dropped from a mean of 8.25% to 7.81% (mean change −0.44%; P < 0.0001) and 8.25% to 7.79% (mean change −0.46%; P < 0.0001), respectively. Sensitivity analyses showed that A1C reductions were of similar direction and magnitude for patients who remained on treatment, and for the subgroups of patients stratified by receipt of concomitant T2DM treatments.
The 0.44% to 0.47% A1C reduction observed in this study was similar to the reduction observed in RCTs, supporting the real-world effectiveness of colesevelam HCL in reducing A1C.
PMCID: PMC3750408  PMID: 23866087
9.  The Immunity-related GTPase Irgm3 Relieves Endoplasmic Reticulum Stress Response during Coxsackievirus B3 Infection via a PI3K/Akt Dependent Pathway 
Cellular microbiology  2011;14(1):133-146.
The IRG protein Irgm3 preserves cell survival during coxsackievirus B3 (CVB3) infection. However, the molecular mechanisms are not clear. Here, we examined the effect of Irgm3 expression on ER stress triggered by pharmacological agents or CVB3 infection. In Tet-On/Irgm3 HeLa cells, Irgm3 expression suppressed either chemical- or CVB3-induced upregulation of glucose-regulated protein78. Further, Irgm3 strongly inhibited the activation of both the PERK and ATF6 pathways of ER stress responses, which further led to the diminished phosphorylation of eIF2α, reduced cleavage/activation of transcription factor SREBP1 and attenuated induction of proapoptotic genes CHOP and GADD34. These data were further supported by experiments using Irgm3 knockout mouse embryonic fibroblasts, in which the ER stress induced by CVB3 was not relieved due to the lack of Irgm3 expression. In addition, the tunicamycin-triggered ER stress promoted the subsequent CVB3 infection. The effect of Irgm3 on ER stress and CVB3 infection was diminished by the PI3K inhibitor, LY294002, while inhibitors of ERK, JNK and p38 had no effect. These data were further corroborated by transfection of cells with a dominant negative Akt. Taken together, these data suggest that Irgm3 relieves the ER stress response via a PI3K/Akt dependent mechanism, which contributes to host defense against CVB3 infection.
PMCID: PMC3691006  PMID: 21981022
10.  A comparative study of axis-line-distance technique and Cobb method on assessing the curative effect on scoliosis 
European Spine Journal  2011;21(6):1075-1081.
To compare the axis-line-distance technique (ALDT) and Cobb method for therapeutic evaluation of scoliosis.
Fifty-seven patients with scoliosis were treated in our hospital, 47 underwent conservative bracing therapy and 10 underwent surgery. Based on 171 full-spine X-ray images obtained from these 57 cases before treatment, during conservative treatment or surgery, and at final follow-up after removing the brace or after surgery, two radiologists independently measured and calculated the correction rate during treatment and at final follow-up and the rate of correction loss after treatment with the ALDT and Cobb methods. Paired t-test and correlation analysis were performed.
Based on the ALDT, the lateral deviations of the apical vertebrae before treatment, during treatment, and at final follow-up were 31 ± 14 mm, 16 ± 8 mm, and 20 ± 8 mm, respectively; the correction rates during treatment and at final follow-up were 48.7 ± 21.2% and 37.6 ± 14.2%, respectively, and the rate of correction loss after treatment was 11.3 ± 6.5%. The Cobb angles of scoliosis before treatment, during treatment, and at final follow-up were 34 ± 14°, 19 ± 7°, and 22 ± 6°, respectively; the correction rates during treatment and at final follow-up were 44.4 ± 17.3% and 33.9 ± 14.4%, respectively, and the rate of correction loss after treatment was 11.4 ± 4.3%. Calculation of the correction rate during treatment differed significantly between the two radiologists when using the Cobb method (P < 0.05); their calculations of the correction rate and rate of correction loss were not different (P > 0.05). The measurement data of the two radiologists using the Cobb method showed a weak to moderate correlation (r = 0.49, 0.57, and 0.51, respectively). When using the ALDT, there were no significant differences between the radiologists in their measurements of the correction rate during and after treatment (P > 0.05) or in the rate of correction loss. The measurement data of the two radiologists using the ALDT showed a good to excellent correlation (r = 0.92, 0.93, and 0.90, respectively).
The ALDT is better than the Cobb method for therapeutic evaluation of scoliosis during treatment and at follow-up visits.
PMCID: PMC3366122  PMID: 22105310
Scoliosis; Radiography; Curative effect assessment; Measurement
11.  Recurrent Pyogenic Cholangitis: Disease Characteristics and Patterns of Recurrence 
ISRN Surgery  2013;2013:536081.
Recurrent pyogenic cholangitis (RPC) is characterized by repeated infections of the biliary system with the formation of stones and strictures. The management aims are to treat acute cholangitis, clear the biliary ductal debris and calculi, and eliminate predisposing factors of bile stasis. Operative options include hepatectomy and biliary drainage procedures or a combination of both; nonoperative options include endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic cholangiography (PTC) guided procedures. This current study compares the operative and the nonoperative management outcomes in patients with RPC in 80 consecutive patients. In addition, we aim to evaluate our approach to the management of RPC over the past decade, according to the various degrees of severity and extent of the disease, and identify the patterns of recurrence in this complex clinical condition. Initial failure rate in terms of residual stone of operative compared with nonoperative treatment was 10.2% versus 32.3% (P = 0.020). Long-term failure rate for operative compared with non-operative treatment was 20.4% versus 61.3% (P = 0.010). Based on multivariate logistic regression, the only significant factors associated with failure were bilaterality of disease (OR: 8.101, P = 0.007) and nonoperative treatment (OR: 26.843, P = 0.001). The median time to failure of the operative group was 48 months as compared to 20 months in the nonoperative group (P < 0.010). Thus operative treatment is a durable option in long-term resolution of disease. Hepatectomy is the preferred option to prevent recurrent disease. However, biliary drainage procedures are also an effective treatment option. The utility of nonoperative treatment can achieve a reasonable duration of disease free interval with minimal complications, albeit inferior to operative management.
PMCID: PMC3677639  PMID: 23762626
12.  Incidence and costs of bleeding-related complications in French hospitals following surgery for various diagnoses 
Limited information is available on the epidemiology and economics of bleeding during surgery in France.
The objective of this study was to examine the incidence, costs and length of stay (LOS) of bleeding-related complications during various surgical procedures.
A retrospective DRG (diagnosis-related group) analysis was conducted using the French National database PMSI (Programme Médicalisé des Systèmes d’Informations). Patients undergoing surgery during 2008 were identified according to their DRG classifications and those with at least one episode of secondary haemostasis and blood transfusion (according to French procedure codes) were designated as ‘with bleeding’ (WB). The analysis focussed on DRGs where ≥10% of patients presenting with bleeding and compared them to patients who did not require blood transfusions (i.e. without bleeding: WoB).
Hospital LOS and costs (age and gender adjusted) were compared between WB and WoB patients within each DRG. Hospitalisation periods exceeding the LOS average (derived from the PMSI database) were compared using multivariate logistic regression adjusted for patient characteristics.
Amongst all 88 different surgical DRGs recognised by the French database 24 (totalling 321,657 hospitalisations) yielded WB rates ≥10% (range 10.3–25.3%). The highest DRG rates were for transplantations, cardiac and major orthopaedic surgery, vascular and solid organ surgery.
The average LOS for the WB population (adjusted for age, gender, number of procedures and secondary diagnoses) were 3.38 days (26.5%) longer than for the WoB population (p < 0.001). The average adjusted LOS costs for a WB patient were estimated at €12,087, and for a WoB patient €10,086 i.e. 19.9% higher than for WB patients (p < 0.001). The overall mean LOS was exceeded by 42.3% of WB patients compared to 37.0% of WoB patients (p < 0.001). Also, WB patients were more likely to exceed the average LOS than were WoB patients (Odds Ratio (OR) = 1.09, p < 0.001), after adjusting for patient characteristics.
The present study for France demonstrates a significant increase of hospital LOS and associated costs following post-surgical bleeding, supporting the need for blood conservation strategies.
PMCID: PMC3668216  PMID: 23692862
Bleeding; Surgery; France; Costs; Incidence rate
13.  Role of Transient Receptor Potential Ion Channels and Evoked Levels of Neuropeptides in a Formaldehyde-Induced Model of Asthma in Balb/c Mice 
PLoS ONE  2013;8(5):e62827.
Asthma is a complex pulmonary inflammatory disease characterized by the hyper-responsiveness, remodeling and inflammation of airways. Formaldehyde is a common indoor air pollutant that can cause asthma in people experiencing long-term exposure. The irritant effect and adjuvant effect are the two possible pathways of formaldehyde promoted asthma.
Methodology/Principal Findings
To explore the neural mechanisms and adjuvant effect of formaldehyde, 48 Balb/c mice in six experimental groups were exposed to (a) vehicle control; (b) ovalbumin; (c) formaldehyde (3.0 mg/m3); (d) ovalbumin+formaldehyde (3.0 mg/m3); (e) ovalbumin+formaldehyde (3.0 mg/m3)+HC-030031 (transient receptor potential ankyrin 1 antagonist); (f) ovalbumin+formaldehyde (3.0 mg/m3)+ capsazepine (transient receptor potential vanilloid 1 antagonist). Experiments were conducted after 4 weeks of combined exposure and 1-week challenge with aerosolized ovalbumin. Airway hyper-responsiveness, pulmonary tissue damage, eosinophil infiltration, and increased levels of interleukin-4, interleukin-6, interleukin-1β, immunoglobulin E, substance P and calcitonin gene-related peptide in lung tissues were found in the ovalbumin+formaldehyde (3.0 mg/m3) group compared with the values seen in ovalbumin -only immunized mice. Except for interleukin-1β levels, other changes in the levels of biomarker could be inhibited by HC-030031 and capsazepine.
Formaldehyde might be a key risk factor for the rise in asthma cases. Transient receptor potential ion channels and neuropeptides have important roles in formaldehyde promoted-asthma.
PMCID: PMC3650028  PMID: 23671638
14.  Sodium Butyrate Stimulates Expression of Fibroblast Growth Factor 21 in Liver by Inhibition of Histone Deacetylase 3 
Diabetes  2012;61(4):797-806.
Fibroblast growth factor 21 (FGF21) stimulates fatty acid oxidation and ketone body production in animals. In this study, we investigated the role of FGF21 in the metabolic activity of sodium butyrate, a dietary histone deacetylase (HDAC) inhibitor. FGF21 expression was examined in serum and liver after injection of sodium butyrate into dietary obese C57BL/6J mice. The role of FGF21 was determined using antibody neutralization or knockout mice. FGF21 transcription was investigated in liver and HepG2 hepatocytes. Trichostatin A (TSA) was used in the control as an HDAC inhibitor. Butyrate was compared with bezafibrate and fenofibrate in the induction of FGF21 expression. Butyrate induced FGF21 in the serum, enhanced fatty acid oxidation in mice, and stimulated ketone body production in liver. The butyrate activity was significantly reduced by the FGF21 antibody or gene knockout. Butyrate induced FGF21 gene expression in liver and hepatocytes by inhibiting HDAC3, which suppresses peroxisome proliferator–activated receptor-α function. Butyrate enhanced bezafibrate activity in the induction of FGF21. TSA exhibited a similar set of activities to butyrate. FGF21 mediates the butyrate activity to increase fatty acid use and ketogenesis. Butyrate induces FGF21 transcription by inhibition of HDAC3.
PMCID: PMC3314370  PMID: 22338096
15.  Key Role of Group V Secreted Phospholipase A2 in Th2 Cytokine and Dendritic Cell-Driven Airway Hyperresponsiveness and Remodeling 
PLoS ONE  2013;8(2):e56172.
Previous work has shown that disruption of the gene for group X secreted phospholipase A2 (sPLA2-X) markedly diminishes airway hyperresponsiveness and remodeling in a mouse asthma model. With the large number of additional sPLA2s in the mammalian genome, the involvement of other sPLA2s in the asthma model is possible – in particular, the group V sPLA2 (sPLA2-V) that like sPLA2-X is highly active at hydrolyzing membranes of mammalian cells.
Methodology and Principal Findings
The allergen-driven asthma phenotype was significantly reduced in sPLA2-V-deficient mice but to a lesser extent than observed previously in sPLA2-X-deficient mice. The most striking difference observed between the sPLA2-V and sPLA2-X knockouts was the significant impairment of the primary immune response to the allergen ovalbumin (OVA) in the sPLA2-V−/− mice. The impairment in eicosanoid generation and dendritic cell activation in sPLA2-V−/− mice diminishes Th2 cytokine responses in the airways.
This paper illustrates the diverse roles of sPLA2s in the immunopathogenesis of the asthma phenotype and directs attention to developing specific inhibitors of sPLA2-V as a potential new therapy to treat asthma and other allergic disorders.
PMCID: PMC3581544  PMID: 23451035
16.  Reduced FAF1 Expression and Helicobacter Infection: Correlations with Clinicopathological Features in Gastric Cancer 
Background. This study aimed to investigate possible associations between FAF1 expression and aspects of gastric cancer, in particular its clinical characteristics and Helicobacter infection. Materials and Methods. RT-PCR and immunohistochemistry were used to analyze expression of FAF1 mRNA and protein in 40 gastric cancer patients. H. pylori infection was detected by three staining protocols. Results. The expression level of FAF1 mRNA was significantly lower in gastric cancer tissue than in normal gastric mucosa from the same patient (P < 0.05). FAF1 mRNA expression was significantly lower in stage IV gastric cancer than in stage I+II or IIIA+IIIB (P = 0.004) and also significantly lower in gastric cancer with distant metastasis. FAF1 mRNA expression was higher in well-differentiated cancer than in poorly-differentiated cancer (0.39 ± 0.06 versus 0.19 ± 0.06, t = 9.966, P < 0.01). FAF1 protein was detected in 15 of 40 (37.5%) cancerous tissue samples and in 29 of 40 (72.5%) corresponding normal tissue samples (P < 0.01). FAF1 mRNA expression was lower in H. pylori-positive cancerous tissue samples than in H. pylori-negative ones (P < 0.05). Conclusions. Downregulation of FAF1 expression may be related to the carcinogenesis and progression of gastric cancer, and H. pylori infection during gastric carcinogenesis may downregulate FAF1 expression.
PMCID: PMC3530185  PMID: 23304123
17.  Identification and Characterization of Three Novel Nuclear Export Signals in the Influenza A Virus Nucleoprotein 
Journal of Virology  2012;86(9):4970-4980.
The nuclear export of the influenza A virus ribonucleoprotein (vRNP) is crucial for virus replication. As a major component of the vRNP, nucleoprotein (NP) alone can also be shuttled out of the nucleus by interacting with chromosome region maintenance 1 (CRM1) and is therefore hypothesized to promote the nuclear export of the vRNP. In the present study, three novel nuclear export signals (NESs) of the NP—NES1, NES2, and NES3—were identified as being responsible for mediating its nuclear export. The nuclear export of NES3 was CRM1 dependent, whereas that of NES1 or NES2 was CRM1 independent. Inactivation of these NESs led to an overall nuclear accumulation of NP. Mutation of all three NP-NESs significantly impaired viral replication. Based on structures of influenza virus NP oligomers, these three hydrophobic NESs are found present on the surface of oligomeric NPs. Functional studies indicated that oligomerization is also required for nuclear export of NP. Together, these results suggest that the nuclear export of NP is important for virus replication and relies on its NESs and oligomerization.
PMCID: PMC3347336  PMID: 22345439
18.  Gastrodin Inhibits Allodynia and Hyperalgesia in Painful Diabetic Neuropathy Rats by Decreasing Excitability of Nociceptive Primary Sensory Neurons 
PLoS ONE  2012;7(6):e39647.
Painful diabetic neuropathy (PDN) is a common complication of diabetes mellitus and adversely affects the patients’ quality of life. Evidence has accumulated that PDN is associated with hyperexcitability of peripheral nociceptive primary sensory neurons. However, the precise cellular mechanism underlying PDN remains elusive. This may result in the lacking of effective therapies for the treatment of PDN. The phenolic glucoside, gastrodin, which is a main constituent of the Chinese herbal medicine Gastrodia elata Blume, has been widely used as an anticonvulsant, sedative, and analgesic since ancient times. However, the cellular mechanisms underlying its analgesic actions are not well understood. By utilizing a combination of behavioral surveys and electrophysiological recordings, the present study investigated the role of gastrodin in an experimental rat model of STZ-induced PDN and to further explore the underlying cellular mechanisms. Intraperitoneal administration of gastrodin effectively attenuated both the mechanical allodynia and thermal hyperalgesia induced by STZ injection. Whole-cell patch clamp recordings were obtained from nociceptive, capsaicin-sensitive small diameter neurons of the intact dorsal root ganglion (DRG). Recordings from diabetic rats revealed that the abnormal hyperexcitability of neurons was greatly abolished by application of GAS. To determine which currents were involved in the antinociceptive action of gastrodin, we examined the effects of gastrodin on transient sodium currents (INaT) and potassium currents in diabetic small DRG neurons. Diabetes caused a prominent enhancement of INaT and a decrease of potassium currents, especially slowly inactivating potassium currents (IAS); these effects were completely reversed by GAS in a dose-dependent manner. Furthermore, changes in activation and inactivation kinetics of INaT and total potassium current as well as IAS currents induced by STZ were normalized by GAS. This study provides a clear cellular basis for the peripheral analgesic action of gastrodin for the treatment of chronic pain, including PDN.
PMCID: PMC3382466  PMID: 22761855
19.  IRES-Dependent Translational Control during Virus-Induced Endoplasmic Reticulum Stress and Apoptosis 
Many virus infections and stresses can induce endoplasmic reticulum (ER) stress response, a host self-defense mechanism against viral invasion and stress. During this event, viral and cellular gene expression is actively regulated and often encounters a switching of the translation initiation from cap-dependent to internal ribosome-entry sites (IRES)-dependent. This switching is largely dependent on the mRNA structure of the 5′ untranslated region (5′ UTR) and on the particular stress stimuli. Picornaviruses and some other viruses contain IRESs within their 5′ UTR of viral genome and employ an IRES-driven mechanism for translation initiation. Recently, a growing number of cellular genes involved in growth control, cell cycle progression and apoptosis were also found to contain one or more IRES within their long highly structured 5′ UTRs. These genes initiate translation usually by a cap-dependent mechanism under normal physiological conditions; however, in certain environments, such as infection, starvation, and heat shock they shift translation initiation to an IRES-dependent modality. Although the molecular mechanism is not entirely understood, a number of studies have revealed that several cellular biochemical processes are responsible for the switching of translation initiation to IRES-dependent. These include the cleavage of translation initiation factors by viral and/or host proteases, phosphorylation (inactivation) of host factors for translation initiation, overproduction of homologous proteins of cap-binding protein eukaryotic initiation factors (eIF)4E, suppression of cap-binding protein eIF4E expression by specific microRNA, activation of enzymes for mRNA decapping, as well as others. Here, we summarize the recent advances in our understanding of the molecular mechanisms for the switching of translation initiation, particularly for the proteins involved in cell survival and apoptosis in the ER stress pathways during viral infections.
PMCID: PMC3307021  PMID: 22461781
internal ribosome-entry site; endoplasmic reticulum stress; microRNA; apoptosis; picornavirus; translation control; coxsackievirus
20.  An MRI-based Atlas and Database of the Developing Mouse Brain 
NeuroImage  2010;54(1):80-89.
The advent of mammalian gene engineering and genetically modified mouse models has led to renewed interest in developing resources for referencing and quantitative analysis of mouse brain anatomy. In this study, we used diffusion tensor imaging (DTI) for quantitative characterization of anatomical phenotypes in the developing mouse brain. As an anatomical reference for neuroscience research using mouse models, this paper presents DTI based atlases of ex vivo C57BL/6 mouse brains at several developmental stages. The atlas complements existing histology and MRI-based atlases by providing users access to three-dimensional, high-resolution images of the developing mouse brain, with distinct tissue contrasts and segmentations of major gray matter and white matter structures. The usefulness of the atlas and database was demonstrated by quantitative measurements of the development of major gray matter and white matter structures. Population average images of the mouse brain at several postnatal stages were created using large deformation diffeomorphic metric mapping and their anatomical variations were quantitatively characterized. The atlas and database enhance our ability to examine the neuroanatomy in normal or genetically engineered mouse strains and mouse models of neurological diseases.
PMCID: PMC2962762  PMID: 20656042
21.  A Rare Case of Septic Deep Vein Thrombosis in the Inferior Vena Cava and the Left Iliac Vein in an Intravenous Drug Abuser 
Annals of Vascular Diseases  2012;5(3):389-392.
The patient was a 41 year-old Chinese female, a known intravenous drug abuser (IVDA), who presented with a left inguinal discharging sinus. A computed tomography (CT) scan showed inflammation in the left groin involving the left femoral vein and resulting in thrombus within the iliac veins extending to the distal portion of the inferior vena cava.
Septic deep vein thrombosis is a well-recognized complication in intravenous drug abusers (IVDA) when large proximal veins are used for drug injection. Life threatening complications such as septic pulmonary embolism and right sided infective endocarditis may result.
The aims of treatment are to prevent the septic thrombus from further embolisation and also to remove the thrombus. Treatment options include catheter directed thrombolysis, mechanical thrombectomy, endovascular treatment, surgical thrombectomy and excision of the involved venous segment.
PMCID: PMC3595840  PMID: 23555542
inferior vena cava (IVC); septic; deep vein thrombosis (DVT)
22.  Cyclophilin E Functions as a Negative Regulator to Influenza Virus Replication by Impairing the Formation of the Viral Ribonucleoprotein Complex 
PLoS ONE  2011;6(8):e22625.
The nucleoprotein (NP) of influenza A virus is a multifunctional protein that plays a critical role in the replication and transcription of the viral genome. Therefore, examining host factors that interact with NP may shed light on the mechanism of host restriction barriers and the tissue tropism of influenza A virus. Here, Cyclophilin E (CypE), a member of the peptidyl-propyl cis-trans isomerase (PPIase) family, was found to bind to NP and inhibit viral replication and transcription.
Methodology/Principal Findings
In the present study, CypE was found to interact with NP but not with the other components of the viral ribonucleoprotein complex (vRNP): PB1, PB2, and PA. Mutagenesis data revealed that the CypE domain comprised of residues 137–186 is responsible for its binding to NP. Functional analysis results indicated that CypE is a negative regulator in the influenza virus life cycle. Furthermore, knock-down of CypE resulted in increased levels of three types of viral RNA, suggesting that CypE negatively affects viral replication and transcription. Moreover, up-regulation of CypE inhibited the activity of influenza viral polymerase. We determined that the molecular mechanism by which CypE negatively regulates influenza virus replication and transcription is by interfering with NP self-association and the NP-PB1 and NP-PB2 interactions.
CypE is a host restriction factor that inhibits the functions of NP, as well as viral replication and transcription, by impairing the formation of the vRNP. The data presented here will help us to better understand the molecular mechanisms of host restriction barriers, host adaptation, and tissue tropism of influenza A virus.
PMCID: PMC3160840  PMID: 21887220
23.  Expression of the Norrie disease gene (Ndp) in developing and adult mouse eye, ear, and brain 
Gene expression patterns : GEP  2010;11(1-2):151-155.
The Norrie disease gene (Ndp) codes for a secreted protein, Norrin, that activates canonical Wnt signaling by binding to its receptor, Frizzled-4. This signaling system is required for normal vascular development in the retina and for vascular survival in the cochlea. In mammals, the pattern of Ndp expression beyond the retina is poorly defined due to the low abundance of Norrin mRNA and protein. Here we characterize Ndp expression during mouse development by studying a knock-in mouse that carries the coding sequence of human placental alkaline phosphatase (AP) inserted at the Ndp locus (NdpAP). In the CNS, NdpAP expression is apparent by E10.5 and is dynamic and complex. The anatomically delimited regions of NdpAP expression observed prenatally in the CNS are replaced postnatally by widespread expression in astrocytes in the forebrain and midbrain, Bergman glia in the cerebellum, and Müller glia in the retina. In the developing and adult cochlea, NdpAP expression is closely associated with two densely vascularized regions, the stria vascularis and a capillary plexus between the organ of Corti and the spiral ganglion. These observations suggest the possibility that Norrin may have developmental and/or homeostatic functions beyond the retina and cochlea.
PMCID: PMC3061303  PMID: 21055480
Norrin; Norrie disease; Frizzled-4; mouse; brain development; vascular development
24.  Targeted Delivery of Mutant Tolerant Anti-Coxsackievirus Artificial MicroRNAs Using Folate Conjugated Bacteriophage Phi29 pRNA 
PLoS ONE  2011;6(6):e21215.
Myocarditis is the major heart disease in infants and young adults. It is very commonly caused by coxsackievirus B3 (CVB3) infection; however, no specific treatment or vaccine is available at present. RNA interference (RNAi)-based anti-viral therapy has shown potential to inhibit viral replication, but this strategy faces two major challenges; viral mutational escape from drug suppression and targeted delivery of the reagents to specific cell populations.
Methodology/Principal Findings
In this study, we designed artificial microRNAs (AmiRs) targeting the 3′untranslated region (3′UTR) of CVB3 genome with mismatches to the central region of their targeting sites. Antiviral evaluation showed that AmiR-1 and AmiR-2 reduced CVB3 (Kandolf and CG strains) replication approximately 100-fold in both HeLa cells and HL-1 cardiomyoctes. To achieve specific delivery, we linked AmiRs to the folate-conjugated bacterial phage packaging RNA (pRNA) and delivered the complexes into HeLa cells, a folate receptor positive cancer cells widely used as an in vitro model for CVB3 infection, via folate-mediated specific internalization. We found that our designed pRNA-AmiRs conjugates were tolerable to target mutations and have great potential to suppress viral mutational escape with little effect on triggering interferon induction.
This study provides important clues for designing AmiRs targeting the 3′UTR of viral genome. It also proves the feasibility of specific deliver of AmiRs using conjugated pRNA vehicles. These small AmiRs combined with pRNA-folate conjugates could form a promising system for antiviral drug development.
PMCID: PMC3115994  PMID: 21698212
25.  Cyclin T1/CDK9 Interacts with Influenza A Virus Polymerase and Facilitates Its Association with Cellular RNA Polymerase II▿  
Journal of Virology  2010;84(24):12619-12627.
Influenza virus RNA-dependent RNA polymerase scavenges the 5′ cap from host pre-mRNA to prime viral transcription initiation. It is also well established that viral RNA-dependent RNA polymerase (vRNP) associates with cellular RNA polymerase II (Pol II), on which viral replication depends. Here we report that cyclin T1/CDK9 can interact with influenza virus polymerase and facilitate its association with cellular Pol II. The immunodepletion of cyclin T1/CDK9 totally abolished the association of vRNP with the C-terminal domain (CTD) Ser-2-phosphorylated form of RNA polymerase II. Further studies showed that overexpression of cyclin T1/CDK9 increased the transcription activity of vRNP, while knockdown of cyclin T1/CDK9 impaired viral replication. Our results suggest that cyclin T1/CDK9 serves as an adapter to mediate the interaction of vRNP and RNA Pol II and promote viral transcription.
PMCID: PMC3004352  PMID: 20943989

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