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1.  Predictors of Percutaneous Catheter Drainage (PCD) after Abdominal Paracentesis Drainage (APD) in Patients with Moderately Severe or Severe Acute Pancreatitis along with Fluid Collections 
PLoS ONE  2015;10(2):e0115348.
Although we previously demonstrated abdominal paracentesis drainage (APD) preceding percutaneous catheter drainage (PCD) as the central step for treating patients with moderately severe (MSAP) or severe acute pancreatitis (SAP), the predictors leading to PCD after APD have not been studied.
Consecutive patients with MSAP or SAP were recruited between June 2011 and June 2013. As a step-up approach, all patients initially received medical management, later underwent ultrasound-guided APD before PCD, if necessary, followed by endoscopic necrosectomy through the path formed by PCD. APD primarily targeted fluid in the abdominal or pelvic cavities, whereas PCD aimed at (peri)pancreatic fluid.
Of the 92 enrolled patients, 40 were managed with APD alone and 52 received PCD after APD (14 required necrosectomy after initial PCD). The overall mortality was 6.5%. Univariate analysis showed that among the 20 selected parameters, 13 factors significantly affected PCD intervention after APD. Multivariate analysis revealed that infected (peri)pancreatic collections (P = -0.001), maximum extent of necrosis of more than 30% of the pancreas (P = -0.024), size of the largest necrotic peri(pancreatic) collection (P = -0.007), and reduction of (peri)pancreatic fluid collections by <50% after APD (P = -0.008) were all independent predictors of PCD.
Infected (peri)pancreatic collections, a largest necrotic peri(pancreatic) collection of more than 100 ml, and reduction of (peri)pancreatic fluid collections by <50% after APD could effectively predict the need for PCD in the early course of the disease.
PMCID: PMC4319763  PMID: 25659143
2.  Effects of Electroacupuncture Stimulation at “Zusanli” Acupoint on Hepatic NO Release and Blood Perfusion in Mice 
The study is to observe the influence of electroacupuncture (EA) stimulation at “Zusanli” (ST36) on the release of nitric oxide (NO) and blood perfusion (BP) in the liver and further explore whether the hepatic blood perfusion (HBP) changes were regulated by EA ST36 induced NO in nitric oxide synthase inhibited mice. The HBP change of the mice was detected by laser speckle perfusion imaging (LSPI) before and after being given interventions, and the NO in liver tissue was detected by nitric acid reductase in each group. The NO levels and HBP in the L-NAME group were significantly lower than those in the control group (P < 0.01). The NO level and HBP increase in EA group were significantly higher than those in control group (P < 0.05). The NO level in the L-NAME EA group was slightly higher than that in the L-NAME group. The HBP increase in the L-NAME EA group was not statistically significant. These results showed that EA could accelerate the synthesis of NO and thereby increase HBP via vasodilation in liver tissue.
PMCID: PMC4306412  PMID: 25649678
3.  Important Poisonous Plants in Tibetan Ethnomedicine 
Toxins  2015;7(1):138-155.
Tibetan ethnomedicine is famous worldwide, both for its high effectiveness and unique cultural background. Many poisonous plants have been widely used to treat disorders in the Tibetan medicinal system. In the present review article, some representative poisonous plant species are introduced in terms of their significance in traditional Tibetan medicinal practices. They are Aconitum pendulum, Strychnos nux-vomica, Datura stramonium and Anisodus tanguticus, for which the toxic chemical constituents, bioactivities and pharmacological functions are reviewed herein. The most important toxins include aconitine, strychnine, scopolamine, and anisodamine. These toxic plants are still currently in use for pain-reduction and other purposes by Tibetan healers after processing.
PMCID: PMC4303819  PMID: 25594733
poisonous plants; Tibetan ethnomedicine; toxins; aconitine; strychnine; scopolamine; anisodamine
4.  Universal Stem-Loop Primer Method for Screening and Quantification of MicroRNA 
PLoS ONE  2014;9(12):e115293.
RT-qPCR is the accepted technique for the quantification of microRNA (miR) expression: however, stem-loop RT-PCR, the most frequently used method for quantification of miRs, is time- and reagent-consuming as well as inconvenient for scanning. We established a new method called ‘universal stem-loop primer’ (USLP) with 8 random nucleotides instead of a specific sequence at the 3′ end of the traditional stem-loop primer (TSLP), for screening miR profile and to semi-quantify expression of miRs. Peripheral blood samples were cultured with phytohaemagglutinin (PHA), and then 87 candidate miRs were scanned in cultured T cells. By USLP, our study revealed that the expression of miR-150-5p (miR-150) decreased nearly 10-fold, and miR-155-5p (miR-155) increased more than 7-fold after treated with PHA. The results of the dissociation curve and gel electrophoresis showed that the PCR production of the USLP and TSLP were specificity. The USLP method has high precision because of its low ICV (ICV<2.5%). The sensitivity of the USLP is up to 103 copies/µl miR. As compared with the TSLP, USLP saved 75% the cost of primers and 60% of the test time. The USLP method is a simple, rapid, precise, sensitive, and cost-effective approach that is suitable for screening miR profiles.
PMCID: PMC4280144  PMID: 25548906
5.  Essential Structural and Functional Roles of the Cmr4 Subunit in RNA Cleavage by the Cmr CRISPR-Cas Complex 
Cell reports  2014;9(5):1610-1617.
The Cmr complex is the multi-subunit effector complex of the Type III-B CRISPR-Cas immune system. The Cmr complex recognizes a target RNA through base pairing with the integral CRISPR RNA (crRNA) and cleaves the target at multiple regularly spaced locations within the complementary region. To understand the molecular basis of the function of this complex, we have assembled information from electron microscopic and x-ray crystallographic structural studies and mutagenesis of a complete Pyrococcus furiosus Cmr complex. Our findings reveal that four helically-packed Cmr4 subunits, which comprise the backbone of the Cmr complex, act as a platform to support crRNA binding and target RNA cleavage. Interestingly, we found a hook-like structural feature associated with Cmr4 that is likely the site of target RNA binding and cleavage. Our results also elucidate analogies in the mechanisms of crRNA and target molecule binding by the distinct Cmr Type III-A and Cascade Type I-E complexes.
PMCID: PMC4269474  PMID: 25482566
6.  Cigarette Smoke Induces Systemic Defects in Cystic Fibrosis Transmembrane Conductance Regulator Function 
Rationale: Several extrapulmonary disorders have been linked to cigarette smoking. Smoking is reported to cause cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction in the airway, and is also associated with pancreatitis, male infertility, and cachexia, features characteristic of cystic fibrosis and suggestive of an etiological role for CFTR.
Objectives: To study the effect of cigarette smoke on extrapulmonary CFTR function.
Methods: Demographics, spirometry, exercise tolerance, symptom questionnaires, CFTR genetics, and sweat chloride analysis were obtained in smokers with and without chronic obstructive pulmonary disease (COPD). CFTR activity was measured by nasal potential difference in mice and by Ussing chamber electrophysiology in vitro. Serum acrolein levels were estimated with mass spectroscopy.
Measurements and Main Results: Healthy smokers (29.45 ± 13.90 mEq), smokers with COPD (31.89 ± 13.9 mEq), and former smokers with COPD (25.07 ± 10.92 mEq) had elevated sweat chloride levels compared with normal control subjects (14.5 ± 7.77 mEq), indicating reduced CFTR activity in a nonrespiratory organ. Intestinal current measurements also demonstrated a 65% decrease in CFTR function in smokers compared with never smokers. CFTR activity was decreased by 68% in normal human bronchial epithelial cells exposed to plasma from smokers, suggesting that one or more circulating agents could confer CFTR dysfunction. Cigarette smoke–exposed mice had decreased CFTR activity in intestinal epithelium (84.3 and 45%, after 5 and 17 wk, respectively). Acrolein, a component of cigarette smoke, was higher in smokers, blocked CFTR by inhibiting channel gating, and was attenuated by antioxidant N-acetylcysteine, a known scavenger of acrolein.
Conclusions: Smoking causes systemic CFTR dysfunction. Acrolein present in cigarette smoke mediates CFTR defects in extrapulmonary tissues in smokers.
PMCID: PMC3919073  PMID: 24040746
cystic fibrosis transmembrane conductance regulator; cigarette smoking; chronic obstructive pulmonary disease; acrolein
7.  Redox-Responsive, Core-Cross-Linked Micelles Capable of On-Demand, Concurrent Drug Release and Structure Disassembly 
Biomacromolecules  2013;14(10):3706-3712.
We developed camptothecin (CPT)-conjugated, core-cross-linked (CCL) micelles that are subject to redox-responsive cleavage of the built-in disulfide bonds, resulting in disruption of the micellar structure and rapid release of CPT. CCL micelles were prepared via co-precipitation of disulfide-containing CPT-poly(Tyrosine(alkynyl)-OCA) conjugate and monomethoxy poly(ethylene glycol)-b-poly(Tyrosine(alkynyl)-OCA), followed by cross-linking of the micellar core via azide–alkyne click chemistry. CCL micelles exhibited excellent stability under physiological conditions while underwent rapid dissociation in reduction circumstance, resulting in burst release of CPT. These redox-responsive CCL micelles showed enhanced cytotoxicity against human breast cancer cells in vitro.
PMCID: PMC4232441  PMID: 24003893
Core-cross-linked micelles; drug delivery; functional polyester; click chemistry; drug-polymer conjugate; on-demand drug release
8.  Epigenetics of hyper-responsiveness to allergen challenge following intrauterine growth retardation rat 
Respiratory Research  2014;15(1):137.
Epidemiological studies have revealed that intrauterine growth retardation (IUGR) or low birth weight is linked to the later development of asthma. Epigenetic regulatory mechanisms play an important role in the fetal origins of adult disease. However, little is known regarding the correlation between epigenetic regulation and the development of asthma following IUGR.
An IUGR and ovalbumin (OVA)-sensitization/challenge rat model was used to study whether epigenetic mechanisms play a role in the development of asthma following IUGR.
Maternal nutrient restriction increased histone acetylation levels of the endothelin-1 (ET-1) gene promoter in lung tissue of offspring, but did not cause significant alterations of DNA methylation. The effect was maintained until 10 weeks after birth. Furthermore, these epigenetic changes may have induced IUGR individuals to be highly sensitive to OVA challenge later in life, resulting in more significant changes related to asthma.
These findings suggest that epigenetic mechanisms might be closely associated with the development of asthma following IUGR, providing further insight for improved prevention of asthma induced by environmental factors.
PMCID: PMC4233040  PMID: 25391516
Allergen; Asthma; Epigenetics; Endothelin-1; Intrauterine growth retardation
9.  Herbal Insomnia Medications that Target GABAergic Systems: A Review of the Psychopharmacological Evidence 
Current Neuropharmacology  2014;12(3):289-302.
Insomnia is a common sleep disorder which is prevalent in women and the elderly. Current insomnia drugs mainly target the γ-aminobutyric acid (GABA) receptor, melatonin receptor, histamine receptor, orexin, and serotonin receptor. GABAA receptor modulators are ordinarily used to manage insomnia, but they are known to affect sleep maintenance, including residual effects, tolerance, and dependence. In an effort to discover new drugs that relieve insomnia symptoms while avoiding side effects, numerous studies focusing on the neurotransmitter GABA and herbal medicines have been conducted. Traditional herbal medicines, such as Piper methysticum and the seed of Zizyphus jujuba Mill var. spinosa, have been widely reported to improve sleep and other mental disorders. These herbal medicines have been applied for many years in folk medicine, and extracts of these medicines have been used to study their pharmacological actions and mechanisms. Although effective and relatively safe, natural plant products have some side effects, such as hepatotoxicity and skin reactions effects of Piper methysticum. In addition, there are insufficient evidences to certify the safety of most traditional herbal medicine. In this review, we provide an overview of the current state of knowledge regarding a variety of natural plant products that are commonly used to treat insomnia to facilitate future studies.
PMCID: PMC4023459  PMID: 24851093
Hypnotic; insomnia; natural products; sedatives; γ-aminobutyric acid.
10.  Bone Health History in Breast Cancer Patients on Aromatase Inhibitors 
PLoS ONE  2014;9(10):e111477.
A cross-sectional study was performed to assess bone health history among aromatase inhibitor (AI) users before breast cancer (BC) diagnosis, which may impact fracture risk after AI therapy and choice of initial hormonal therapy. A total of 2,157 invasive BC patients initially treated with an AI were identified from a prospective cohort study at Kaiser Permanente Northern California (KPNC). Data on demographic and lifestyle factors were obtained from in-person interviews, and bone health history and clinical data from KPNC clinical databases. The prevalence of osteoporosis and fractures in postmenopausal AI users was assessed, compared with 325 postmenopausal TAM users. The associations of bone health history with demographic and lifestyle factors in AI users were also examined. Among all initial AI users, 11.2% had a prior history of osteoporosis, 16.3% had a prior history of any fracture, and 4.6% had a prior history of major fracture. Postmenopausal women who were taking TAM as their initial hormonal therapy had significantly higher prevalence of prior osteoporosis than postmenopausal AI users (21.5% vs. 11.8%, p<0.0001). Among initial AI users, the associations of history of osteoporosis and fracture in BC patients with demographic and lifestyle factors were, in general, consistent with those known in healthy older women. This study is one of the first to characterize AI users and risk factors for bone morbidity before BC diagnosis. In the future, this study will examine lifestyle, molecular, and genetic risk factors for AI-induced fractures.
PMCID: PMC4213031  PMID: 25354083
11.  Selective Delivery of an Anticancer Drug with Aptamer-Functionalized Liposomes to Breast Cancer Cells in Vitro and in Vivo 
Selective targeting of cancer cells is a critical step in cancer diagnosis and therapy. To address this need, DNA aptamers have attracted significant attention as possible targeting ligands. However, while their use in targeting cancer cells in vitro has been reported, their effectiveness has rarely been established in vivo. Here we report the development of a liposomal drug delivery system for targeted anticancer chemotherapy. Liposomes were prepared containing doxorubicin as a payload, and functionalized with AS1411, a DNA aptamer with strong binding affinity for nucleolin. AS1411 aptamer-functionalized liposomes increased cellular internalization and cytotoxicity to MCF-7 breast cancer cells as compared to non-targeting liposomes. Furthermore, targeted liposomal doxorubicin improved antitumor efficacy against xenograft MCF-7 breast tumors in athymic nude mice, attributable to their enhanced tumor tissue penetration. This study suggests that AS1411 aptamer-functionalized liposomes can recognize nucleolin overexpressed on MCF-7 cell surface, and therefore enable drug delivery with high specificity and selectivity.
PMCID: PMC3800741  PMID: 24159374
DNA aptamer; cancer targeting; nucleolin; liposome; targeted drug delivery; breast cancer
12.  Subvoxel Accurate Graph Search Using Non-Euclidean Graph Space 
PLoS ONE  2014;9(10):e107763.
Graph search is attractive for the quantitative analysis of volumetric medical images, and especially for layered tissues, because it allows globally optimal solutions in low-order polynomial time. However, because nodes of graphs typically encode evenly distributed voxels of the volume with arcs connecting orthogonally sampled voxels in Euclidean space, segmentation cannot achieve greater precision than a single unit, i.e. the distance between two adjoining nodes, and partial volume effects are ignored. We generalize the graph to non-Euclidean space by allowing non-equidistant spacing between nodes, so that subvoxel accurate segmentation is achievable. Because the number of nodes and edges in the graph remains the same, running time and memory use are similar, while all the advantages of graph search, including global optimality and computational efficiency, are retained. A deformation field calculated from the volume data adaptively changes regional node density so that node density varies with the inverse of the expected cost. We validated our approach using optical coherence tomography (OCT) images of the retina and 3-D MR of the arterial wall, and achieved statistically significant increased accuracy. Our approach allows improved accuracy in volume data acquired with the same hardware, and also, preserved accuracy with lower resolution, more cost-effective, image acquisition equipment. The method is not limited to any specific imaging modality and readily extensible to higher dimensions.
PMCID: PMC4196762  PMID: 25314272
13.  Total isothiocyanate yield from raw cruciferous vegetables commonly consumed in the United States 
Journal of functional foods  2013;5(4):1996-2001.
Dietary isothiocyanates are a group of promising chemopreventive agents obtained primarily from cruciferous vegetables. Due to their potent chemopreventive and/or anti-cancer activities, there is a growing interest in assessing dietary isothiocyanate exposure and its impact on human health. Using the HPLC-based cyclocondensation assay, the current study measured total isothiocyanate yield from raw cruciferous vegetables. A total of 73 samples comprising nine types of cruciferous vegetables were analyzed. We observed a wide range of isothiocyanate content across the individual vegetables with an average level of 16.2 μmol/100g wet weight, ranging from 1.5 μmol in raw cauliflower to 61.3 μmol in raw mustard greens. The data represent the maximum amount of isothiocyanates released from the intake of raw cruciferous vegetables. Given that the vegetables assayed in this study include the most commonly consumed cruciferous vegetables in western diets, the data may be particularly useful in estimation of dietary isothiocyanate exposure in these populations. However, due to the variation observed within each vegetable, biomarkers such as urinary isothiocyanate level may be necessary for accurate estimation of individual exposure.
PMCID: PMC3891790  PMID: 24443655
Isothiocyanates; cruciferous vegetables; phytochemicals; glucosinolates; food composition; the United States
14.  Identification of Cryptotanshinone as an Inhibitor of Oncogenic Protein Tyrosine Phosphatase SHP2 (PTPN11) 
Journal of medicinal chemistry  2013;56(18):7212-7221.
Activating mutations of PTPN11 (encoding the SHP2 phosphatase) are associated with Noonan syndrome, childhood leukemias, and sporadic solid tumors. Virtual screening combined with experimental assays was performed to identify inhibitors of SHP2 from a database of natural products. This effort led to the identification of Cryptotanshinone as an inhibitor of SHP2. Cryptotanshinone inhibited SHP2 with an IC50 of 22.50 μM. Fluorescence titration experiments confirmed that it directly bound to SHP2. Enzymatic kinetic analyses showed that Cryptotanshinone was a mixed-type and irreversible inhibitor. This drug was further verified for its ability to block SHP2-mediated cell signaling and cellular functions. Furthermore, mouse myeloid progenitors and patient leukemic cells with the activating mutation E76K in PTPN11 were found to be sensitive to this inhibitor. Since Cryptotanshinone is used to treat cardiovascular diseases in Asian countries, this drug has a potential to be used directly or to be further developed to treat PTPN11-associated malignancies.
PMCID: PMC4159095  PMID: 23957426
15.  Targeting Protein Tyrosine Phosphatase SHP2 for the Treatment of PTPN11- Associated Malignancies 
Molecular cancer therapeutics  2013;12(9):1738-1748.
Activating mutations in PTPN11 (encoding SHP2), a protein tyrosine phosphatase (PTP) that plays an overall positive role in growth factor and cytokine signaling, are directly associated with the pathogenesis of Noonan syndrome and childhood leukemias. Identification of SHP2 selective inhibitors could lead to the development of new drugs that ultimately serve as treatments for PTPN11-associated diseases. As the catalytic core of SHP2 shares extremely high homology to those of SHP1 and other PTPs that play negative roles in cell signaling, to identify selective inhibitors of SHP2 using computer-aided drug design, we targeted a protein surface pocket that is adjacent to the catalytic site, is predicted to be important for binding to phosphopeptide substrates, and has structural features unique to SHP2. From computationally selected candidate compounds, #220–324 effectively inhibited SHP2 activity with an IC50 of 14 μM. Fluorescence titration experiments confirmed its direct binding to SHP2. This active compound was further verified for its ability to inhibit SHP2-mediated cell signaling and cellular function with minimal off-target effects. Furthermore, mouse myeloid progenitors with the activating mutation (E76K) in PTPN11 and patient leukemic cells with the same mutation were more sensitive to this inhibitor than wild-type cells. This study provides evidence that SHP2 is a “druggable” target for the treatment of PTPN11-associated diseases. Since the small molecule SHP2 inhibitor identified has a simple chemical structure, it represents an ideal lead compound for the development of novel anti-SHP2 drugs.
PMCID: PMC3769526  PMID: 23825065
PTPN11 (SHP2); Phosphatase; Inhibitor; Drug development; Leukemia
16.  Autologous serum eye drops for dry eye 
Theoretically, autologous serum eye drops (AS) have a potential advantage over traditional therapies based on the assumption that AS serve not only as a lacrimal substitute to provide lubrication, but also contain other biochemical components mimicking natural tears more closely. The application of AS in dry eye treatment has gained popularity as a second-line therapy in the treatment of dry eye. Published studies on the subject indicate that autologous serum could be an effective treatment for dry eye.
To evaluate the efficacy and safety of AS compared to artificial tears for treating dry eye.
Search methods
We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2013, Issue 3), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLD MEDLINE, (January 1950 to April 2013), EMBASE (January 1980 to April 2013), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to April 2013), the meta Register of Controlled Trials (mRCT) (, ( and the WHO International Clinical Trials Registry Platform (ICTRP) ( We also searched the Science Citation Index Expanded database (September 2013) and reference lists of included studies. We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 15 April 2013.
Selection criteria
We included randomized controlled trials (RCTs) in which AS was compared to artificial tears in the treatment of dry eye in adults.
Data collection and analysis
Two review authors independently screened all titles and abstracts and assessed full-text articles of potentially eligible trials. Two review authors extracted data and assessed the methodological quality and characteristics of the included trials.We contacted investigators for missing data. For both primary and secondary outcomes, we reported mean differences with corresponding 95% confidence intervals (CIs) for continuous outcomes.
Main results
We identified four eligible RCTs in which AS was compared with artificial tear treatment or saline in individuals (n = 72 participants) with dry eye of various etiologies (Sjögren’s syndrome-related dry eye, non-Sjögren’s syndrome dry eye and postoperative dry eye induced by laser-assisted in situ keratomileusis (LASIK)). The quality of the evidence provided by these trials was variable. A majority of the risk of bias domains were judged to have an unclear risk of bias in two trials owing to insufficient reporting of trial characteristics. One trial was considered to have a low risk of bias for most domains while another was considered to have a high risk of bias for most domains. Incomplete outcome reporting and heterogeneity in the participant populations and follow-up periods prevented the inclusion of these trials in a summary meta-analysis. For the primary outcome, improvement in participant-reported symptoms at one month, one trial (12 participants) showed no difference in participant-reported symptoms between 20% AS and artificial tears. Based on the results of two trials in 32 participants, 20% AS may provide some improvement in participant-reported symptoms compared to traditional artificial tears after two weeks of treatment. One trial also showed positive results with a mean difference in tear breakup time (TBUT) of 2.00 seconds (95% CI 0.99 to 3.01 seconds) between 20% AS and artificial tears after two weeks, which were not similar to findings from the other trials. Based on all other objective clinical assessments included in this review, AS was not associated with improvements in aqueous tear production measured by Schirmer’s test (two trials, 33 participants), ocular surface condition with fluorescein (four trials, 72 participants) or Rose Bengal staining (three trials, 60 participants), and epithelial metaplasia by impression cytology compared to artificial tears (one trial, 12 participants). Data on adverse effects were not reported by three of the included studies. In one study, there were no serious adverse events reported with the collection of and treatment with AS.
Authors’ conclusions
Overall there was inconsistency in the possible benefits of AS in improving participant-reported symptoms and TBUT and lack of effect based on other objective clinical measures. Well-planned, large, high-quality RCTs are warranted, in different severities of dry eye and using standardized questionnaires to measure participant-reported outcomes and objective clinical tests as well as objective biomarkers to assess the benefit of AS therapy for dry eye.
PMCID: PMC4007318  PMID: 23982997
17.  MAPKAP1 rs10118570 Polymorphism Is Associated with Anti-Infection and Anti-Hepatic Fibrogenesis in Schistosomiasis Japonica 
PLoS ONE  2014;9(8):e105995.
Chronic infection with Schistosoma japonicum is an important cause of hepatic fibrosis (HF). Human 9q33.3 is one of the most important loci for stress-related diseases. We examined the potential associations of 43 single-nucleotide polymorphisms (SNPs) with S. japonicum infection and HF in epidemic region in China. We identified a SNP (rs10118570 GG in mitogen-activated protein kinase associated protein 1, MAPKAP1) contributes to anti-infection (adjusted OR = 0.35) and anti-fibrogenesis (adjusted RR = 0.44) in the discovery study. Replicative and combined studies showed consistent protective quality for this genotype (replicative: adjusted OR = 0.37 for anti-infection, and adjusted RR = 0.40 for anti-fibrogenesis; Combined: adjusted OR = 0.45 for anti-infection, and adjusted RR = 0.42 for anti-fibrogenesis). Univariate and multivariate analysis in the discovery, replicative and combined studies, suggested that durations (years), splenomegaly, serum ALB and rs10118570 were independent predictors influencing the fibrogenesis. The analysis of gene-gene interaction showed rs10118570 functions independently. We conclude that MAPKAP1 may represent a novel anti-infection and anti-fibrogenesis genomic locus in chronic schistosomiasis japonica. And rs10118570 may be a potential biomarker and target for the treatment of this life-threatening ancient disease.
PMCID: PMC4143368  PMID: 25153992
18.  Comparison of pemetrexed plus cisplatin with gemcitabine plus docetaxel in refractory/metastatic osteosarcoma: Clinical outcomes from a retrospective database monitored in a single institute 
Oncology Letters  2014;8(5):2243-2248.
The prognosis for patients with relapsed/metastatic osteosarcoma is poor and the optimal treatment strategy remains to be refined. Whilst gemcitabine plus docetaxel combination treatment has already been demonstrated to have certain promising results in the treatment of osteosarcoma, the use of pemetrexed, a multi-targeted antifolate, remains controversial. In the present study, a retrospective investigation was conducted to evaluate the toxicity and efficacy of the pemetrexed plus cisplatin combination in relapsed/metastatic osteosarcoma. Comparison of this treatment with that of the gemcitabine plus docetaxel combination was also conducted. Clinical data from 39 patients suffering from refractory/metastatic osteosarcoma between January 2005 and May 2011 were reviewed retrospectively. Of these patients, 21 were administered the gemcitabine plus docetaxel combination, and 18 were provided the pemetrexed plus cisplatin combination. Treatment was continued until the occurrence of disease progression or unacceptable toxicity. In the gemcitabine plus docetaxel group, the overall response rate and disease control rate were found to be 9.5 and 28.5% respectively, compared with 5.5 and 33.3% respectively in the pemetrexed plus cisplatin group. The median progression-free survival (PFS) time was found to be 1.8 months for both the gemcitabine plus docetaxel and pemetrexed plus cisplatin groups. The median overall survival (OS) time was 6 months in the gemcitabine plus docetaxel group and 7 months in the pemetrexed plus cisplatin group. No statistically significant differences were recognized between the overall response rates, disease control rates, PFS times and OS times in the two groups. The two combinations appeared to be well tolerated. However, the incidence of grade 3/4 thrombocytopenia and leucopenia was higher in the gemcitabine plus docetaxel group than in the pemetrexed plus cisplatin group. The present study clearly demonstrated that both chemo-combinations were well-tolerated and exerted antitumor activity in patients with refractory/metastatic osteosarcoma. However, with regard to grade 3/4 toxicity, the pemetrexed plus cisplatin chemotherapy appears to be better tolerated.
PMCID: PMC4186569  PMID: 25289103
osteosarcoma; metastatic; gemcitabine; docetaxel; pemetrexed; cisplatin
19.  Effects of lentiviral infection of mesenchymal stem cells on the expression of octamer transcription factor 4 
Molecular Medicine Reports  2014;10(5):2249-2254.
The present study aimed to investigate the effects of lentiviral infection of human umbilical cord mesenchymal stem cells (hUCMSCs) on the expression of octamer transcription factor 4 (Oct4). hUCMSCs were infected with lentivirus carrying the green fluorescent protein gene (GFP) at different multiplicities of infection (MOI), and the optimal MOI was determined by flow cytometry; the proliferation of non-infected and GFP-carrying lentivirus-infected hUCMSCs was evaluated by the MTT assay; and the expression of the Oct4 gene was measured by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and immunofluorescence staining in hUCMSCs cultured in vitro for eight weeks. Positive GFP staining of hUCMSCs was estimated at >75% at 48 h following infection with the GFP-carrying lentivirus (MOI = 20); no effect on hUCMSC proliferation was detected by the MTT assay following the infection; immunofluorescence analysis detected positive Oct4 expression in the cell nuclei at two and eight weeks of culture, while the relative expression of Oct4 assessed by qRT-PCR was 0.9075±0.0124. The GFP gene carried by the lentivirus was successfully expressed in hUCMSCs and had no significant effect on Oct4 expression, which lays a solid foundation for future studies investigating gene functions via the use of exogenous markers.
PMCID: PMC4199401  PMID: 25174942
green fluorescent protein; lentivirus; human umbilical cord mesenchymal stem cells; octamer transcription factor 4
20.  Increased methylation of the MOR gene proximal promoter in primary sensory neurons plays a crucial role in the decreased analgesic effect of opioids in neuropathic pain 
Molecular Pain  2014;10:51.
The analgesic potency of opioids is reduced in neuropathic pain. However, the molecular mechanism is not well understood.
The present study demonstrated that increased methylation of the Mu opioid receptor (MOR) gene proximal promoter (PP) in dorsal root ganglion (DRG) plays a crucial role in the decreased morphine analgesia. Subcutaneous (s.c.), intrathecal (i.t.) and intraplantar (, not intracerebroventricular (i.c.v.) injection of morphine, the potency of morphine analgesia was significantly reduced in nerve-injured mice compared with control sham-operated mice. After peripheral nerve injury, we observed a decreased expression of MOR protein and mRNA, accompanied by an increased methylation status of MOR gene PP, in DRG. However, peripheral nerve injury could not induce a decreased expression of MOR mRNA in the spinal cord. Treatment with 5-aza-2′-deoxycytidine (5-aza-dC), inhibited the increased methylation of MOR gene PP and prevented the decreased expression of MOR in DRG, thereby improved systemic, spinal and periphery morphine analgesia.
Altogether, our results demonstrate that increased methylation of the MOR gene PP in DRG is required for the decreased morphine analgesia in neuropathic pain.
PMCID: PMC4137045  PMID: 25118039
Neuropathic pain; Epigenetics; Opioids
21.  A hierarchical model for probabilistic independent component analysis of multi-subject fMRI studies 
Biometrics  2013;69(4):970-981.
An important goal in fMRI studies is to decompose the observed series of brain images to identify and characterize underlying brain functional networks. Independent component analysis (ICA) has been shown to be a powerful computational tool for this purpose. Classic ICA has been successfully applied to single-subject fMRI data. The extension of ICA to group inferences in neuroimaging studies, however, is challenging due to the unavailability of a pre-specified group design matrix. Existing group ICA methods generally concatenate observed fMRI data across subjects on the temporal domain and then decompose multi-subject data in a similar manner to single-subject ICA. The major limitation of existing methods is that they ignore between-subject variability in spatial distributions of brain functional networks in group ICA. In this paper, we propose a new hierarchical probabilistic group ICA method to formally model subject-specific effects in both temporal and spatial domains when decomposing multi-subject fMRI data. The proposed method provides model-based estimation of brain functional networks at both the population and subject level. An important advantage of the hierarchical model is that it provides a formal statistical framework to investigate similarities and differences in brain functional networks across subjects, e.g., subjects with mental disorders or neurodegenerative diseases such as Parkinson’s as compared to normal subjects. We develop an EM algorithm for model estimation where both the E-step and M-step have explicit forms. We compare the performance of the proposed hierarchical model with that of two popular group ICA methods via simulation studies. We illustrate our method with application to an fMRI study of Zen meditation.
PMCID: PMC4130464  PMID: 24033125
Independent component analysis; Multi-subject imaging data; Functional magnetic resonance imaging (fMRI); Hierarchical model; Group inferences; Maximum likelihood estimation; EM algorithm
22.  Differential Expression of Heat Shock Transcription Factors and Heat Shock Proteins after Acute and Chronic Heat Stress in Laying Chickens (Gallus gallus) 
PLoS ONE  2014;9(7):e102204.
Heat stress due to high environmental temperature negatively influences animal performances. To better understand the biological impact of heat stress, laying broiler breeder chickens were subjected either to acute (step-wisely increasing temperature from 21 to 35°C within 24 hours) or chronic (32°C for 8 weeks) high temperature exposure. High temperature challenges significantly elevated body temperature of experimental birds (P<0.05). However, oxidation status of lipid and protein and expression of heat shock transcription factors (HSFs) and heat shock proteins (HSPs) 70 and 90 were differently affected by acute and chronic treatment. Tissue-specific responses to thermal challenge were also found among heart, liver and muscle. In the heart, acute heat challenge affected lipid oxidation (P = 0.05) and gene expression of all 4 HSF gene expression was upregulated (P<0.05). During chronic heat treatment, the HSP 70 mRNA level was increased (P<0.05) and HSP 90 mRNA (P<0.05) was decreased. In the liver, oxidation of protein was alleviated during acute heat challenge (P<0.05), however, gene expression HSF2, 3 and 4 and HSP 70 were highly induced (P<0.05). HSP90 expression was increased by chronic thermal treatment (P<0.05). In the muscle, both types of heat stress increased protein oxidation, but HSFs and HSPs gene expression remained unaltered. Only tendencies to increase were observed in HSP 70 (P = 0.052) and 90 (P = 0.054) gene expression after acute heat stress. The differential expressions of HSF and HSP genes in different tissues of laying broiler breeder chickens suggested that anti-heat stress mechanisms might be provoked more profoundly in the heart, by which the muscle was least protected during heat stress. In addition to HSP, HSFs gene expression could be used as a marker during acute heat stress.
PMCID: PMC4114549  PMID: 25072282
23.  Genetic variants in STAT4 and HLA-DQ genes confer risk of hepatitis B virus–related hepatocellular carcinoma 
Nature genetics  2012;45(1):72-75.
To identify genetic susceptibility loci for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) in the Chinese population, we carried out a genome-wide association study (GWAS) in 2,514 chronic HBV carriers (1,161 HCC cases and 1,353 controls) followed by a 2-stage validation among 6 independent populations of chronic HBV carriers (4,319 cases and 4,966 controls). The joint analyses showed that HCC risk was significantly associated with two independent loci: rs7574865 at STAT4, Pmeta = 2.48 × 10−10, odds ratio (OR) = 1.21; and rs9275319 at HLA-DQ, Pmeta = 2.72 × 10−17, OR = 1.49. The risk allele G at rs7574865 was significantly associated with lower mRNA levels of STAT4 in both the HCC tissues and nontumor tissues of 155 individuals with HBV-related HCC (Ptrend = 0.0008 and 0.0002, respectively). We also found significantly lower mRNA expression of STAT4 in HCC tumor tissues compared with paired adjacent nontumor tissues (P = 2.33 × 10−14).
PMCID: PMC4105840  PMID: 23242368
24.  Multi-locus phylogeny of lethal amanitas: Implications for species diversity and historical biogeography 
Lethal amanitas (Amanita section Phalloideae) are a group of wild, fatal mushrooms causing many poisoning cases worldwide. However, the diversity and evolutionary history of these lethal mushrooms remain poorly known due to the limited sampling and insufficient gene fragments employed for phylogenetic analyses. In this study, five gene loci (nrLSU, ITS, rpb2, ef1-α and β-tubulin) with a widely geographic sampling from East and South Asia, Europe, North and Central America, South Africa and Australia were analysed with maximum-likelihood, maximum-parsimony and Bayesian inference methods. Biochemical analyses were also conducted with intention to detect amatoxins and phalloidin in 14 representative samples.
Lethal amanitas were robustly supported to be a monophyletic group after excluding five species that were provisionally defined as lethal amanitas based on morphological studies. In lethal amanitas, 28 phylogenetic species were recognised by integrating molecular phylogenetic analyses with morphological studies, and 14 of them represented putatively new species. The biochemical analyses indicated a single origin of cyclic peptide toxins (amatoxins and phalloidin) within Amanita and suggested that this kind of toxins seemed to be a synapomorphy of lethal amanitas. Molecular dating through BEAST and biogeographic analyses with LAGRANGE and RASP indicated that lethal amanitas most likely originated in the Palaeotropics with the present crown group dated around 64.92 Mya in the early Paleocene, and the East Asia–eastern North America or Eurasia–North America–Central America disjunct distribution patterns were primarily established during the middle Oligocene to Miocene.
The cryptic diversity found in this study indicates that the species diversity of lethal amanitas is strongly underestimated under the current taxonomy. The intercontinental sister species or sister groups relationships among East Asia and eastern North America or Eurasia–North America–Central America within lethal amanitas are best explained by the diversification model of Palaeotropical origin, dispersal via the Bering Land Bridge, followed by regional vicariance speciation resulting from climate change during the middle Oligocene to the present. These findings indicate the importance of both dispersal and vicariance in shaping the intercontinental distributions of these ectomycorrhizal fungi.
PMCID: PMC4094918  PMID: 24950598
Amanita; Biogeography; Lethal substances; Phylogenetic species; Molecular clock; Synapomorphy
25.  A Nationwide Survey of Mild Cognitive Impairment and Dementia, Including Very Mild Dementia, in Taiwan 
PLoS ONE  2014;9(6):e100303.
An increasing population of dementia patients produces substantial societal impacts. We assessed the prevalence of mild cognitive impairment (MCI) and all-cause dementia, including very mild dementia (VMD), in Taiwan. In a nationwide population-based cross-sectional survey, participants were selected by computerized random sampling from all 19 Taiwan counties and were enrolled between December 2011 and March 2013. Cases were identified through in-person interviews based on the National Institute on Aging-Alzheimer’s Association clinical criteria. Demographic data and histories involving mental status and function in daily living were collected. The principal objective assessments were the Taiwanese Mental Status Examination and Clinical Dementia Rating. In all, 10,432 people aged 65 years or older (mean age 76.2±6.7, 52.3% women) were interviewed. The age-adjusted prevalence of all-cause dementia was 8.04% (95% CI 7.47–8.61), including a 3.25% (95% CI 2.89–3.61) prevalence of VMD; that of MCI was 18.76% (95% CI 17.91–19.61). Women had a higher prevalence than men of both all-cause dementia (9.71% vs. 6.36%) and MCI (21.63% vs. 15.57%). MCI affects a considerable portion of the population aged 65 and above in Taiwan. The inclusion of VMD yields dementia prevalence rates higher than those previously reported from Taiwan. Old age, female gender, and a low educational level are significant associated factors.
PMCID: PMC4062510  PMID: 24940604

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