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1.  Spatial analysis of visceral leishmaniasis in the oases of the plains of Kashi Prefecture, Xinjiang Uygur Autonomous Region, China 
Parasites & Vectors  2016;9:148.
Kashi Prefecture of Xinjiang is one of the most seriously affected areas with anthroponotic visceral leishmaniasis in China. A better understanding of space distribution features in this area was needed to guide strategies to eliminate visceral leishmaniasis from highly endemic areas. We performed a spatial analysis using the data collected in Bosh Klum Township in Xinjiang China.
Based on the report of endemic diseases between 1990 and 2005, three villages with a high number of visceral leishmaniasis cases in Bosh Klum Township were selected. We conducted a household survey to collect the baseline data of kala-azar patients using standard case definitions. The geographical information was recorded with GIS equipment. A binomial distribution fitting test, runs test, and Scan statistical analysis were used to assess the space distribution of the study area.
The result of the binomial distribution fitting test showed that the distribution of visceral leishmaniasis cases in local families was inconsistent (χ2 = 53.23, P < 0.01). The results of runs test showed that the distribution of leishmaniasis infected families along the channel was not random in the group of more than five infected families. The proportion of this kind of group in all infected families was 63.84 % (113 of 177). In the Scan statistical analysis, spatial aggregation was analyzed by poisson model, which found 3 spatial distribution areas 1) Zone A was located in a center point of 76.153447°E, 39.528477°N within its 1.11 mile radius, where the cumulative life-incidence of leishmaniasis was 1.95 times as high as that in surrounding areas (P < 0.05); 2) Zone B was located in a center point of 76.111968°E, 39.531895°N within its 0.54 mile radius, where the cumulative life-incidence of leishmaniasis was 1.82 times as high as that in surrounding areas (P < 0.01); and 3) Zone C was located in a center point of 76.195427°E, 39.563835°N within its 0.68 mile radius, where the cumulative life-incidence of leishmaniasis was 1.31 times as high as that in surrounding areas (P < 0.05).
The spatial distribution of visceral leishmaniasis-infected families was clustered. Thus, the proper use of this finding would be an improvement in highly endemic areas, which could help identify the types of endemic areas and population at high risk and carry out appropriate measures to prevent and control VL in this area as well.
PMCID: PMC4791776  PMID: 26979847
Xinjiang, China; Visceral leishmaniasis; Familial aggregation; Spatial aggregation
2.  Control of Methicillin-Resistant Staphylococcus aureus Pneumonia Utilizing TLR2 Agonist Pam3CSK4 
PLoS ONE  2016;11(3):e0149233.
The spread of methicillin-resistant Staphylococcus aureus (MRSA) is a critical health issue that has drawn greater attention to the potential use of immunotherapy. Toll-like receptor 2 (TLR2), a pattern recognition receptor, is an essential component in host innate defense system against S. aureus infection. However, little is known about the innate immune response, specifically TLR2 activation, against MRSA infection. Here, we evaluate the protective effect and the mechanism of MRSA murine pneumonia after pretreatment with Pam3CSK4, a TLR2 agonist. We found that the MRSA-pneumonia mouse model, pretreated with Pam3CSK4, had reduced bacteria and mortality in comparison to control mice. As well, lower protein and mRNA levels of TNF-α, IL-1β and IL-6 were observed in lungs and bronchus of the Pam3CSK4 pretreatment group. Conversely, expression of anti-inflammatory cytokine IL-10, but not TGF-β, increased in Pam3CSK4-pretreated mice. Our additional studies showed that CXCL-2 and CXCL1, which are necessary for neutrophil recruitment, were less evident in the Pam3CSK4-pretreated group compared to control group, whereas the expression of Fcγ receptors (FcγⅠ/Ⅲ) and complement receptors (CR1/3) increased in murine lungs. Furthermore, we found that increased survival and improved bacterial clearance were not a result of higher levels of neutrophil infiltration, but rather a result of enhanced phagocytosis and bactericidal activity of neutrophils in vitro and in vivo as well as increased robust oxidative activity and release of lactoferrin. Our cumulative findings suggest that Pam3CSK4 could be a novel immunotherapeutic candidate against MRSA pneumonia.
PMCID: PMC4790907  PMID: 26974438
3.  Total glucosides of paeony for rheumatoid arthritis: a protocol for a systematic review 
BMJ Open  2016;6(3):e010116.
Total glucosides of paeony (TGP) is a natural plant extract, which is widely used in China for treating rheumatoid arthritis (RA). Many relevant randomised controlled trials (RCTs) of TGP for RA are available, but they have not been systematically reviewed. This systematic review aims to examine the effectiveness and safety of TGP in patients with RA.
Methods and analyses
We will search for RCTs of TGP in the treatment of RA, performed up until February 2016, in PubMed, Embase, Cochrane Central Register of Controlled Trials, and four Chinese databases (Chinese Biomedical Database, China National Knowledge Infrastructure, Wanfang Database and Chinese Scientific Journal Database). Trial registers and reference lists of retrieved articles will also be searched to identify potential articles. RCTs comparing TGP with placebo, no treatment, or disease-modifying antirheumatic drugs for patients with RA will be retrieved. The primary outcomes will be disease improvement and disease remission. The secondary outcomes will be surrogate outcomes, symptoms, adverse effects, and quality of life. Two reviewers will independently extract data on participants, interventions, comparisons, outcomes, etc. The methodological quality of each included study will be evaluated using the Cochrane risk of bias tool, and the strength of evidence on prespecified outcomes will be assessed in accordance with the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Review Manager 5.3 software will be used for data analyses. Meta-analyses will be performed if the data are sufficiently homogeneous, both statistically and clinically. Possible publication bias will also be checked using funnel plots once the number of included studies is sufficient.
Ethics and dissemination
Ethics approval is not required, as this study will not involve patients. The results of this study will be submitted to a peer-reviewed journal for publication, to inform both clinical practice and further research.
Trial registration number
PMCID: PMC4785289  PMID: 26962036
4.  Impact of non-oncological factors on tumor recurrence after liver transplantation in hepatocellular carcinoma patients 
World Journal of Gastroenterology  2016;22(9):2749-2759.
Hepatocellular carcinoma (HCC) is the most common primary neoplasm of the liver and is one of the leading causes of cancer-related death worldwide. Liver transplantation (LT) has become one of the best curative therapeutic options for patients with HCC, although tumor recurrence after LT is a major and unaddressed cause of mortality. Furthermore, the factors that are associated with recurrence are not fully understood, and most previous studies have focused on the biological properties of HCC, such as the number and size of the HCC nodules, the degree of differentiation, the presence of hepatic vascular invasion, elevated serum levels of alpha-fetoprotein, and the tumor stage outside of the Milan criteria. Thus, little attention has been given to factors that are not directly related to HCC (i.e., “non-oncological factors”), which have emerged as predictors of tumor recurrence. This review was performed to assess the effects of non-oncological factors on tumor recurrence after LT. The identification of these factors may provide new research directions and clinical strategies for the prophylaxis and surveillance of tumor recurrence after LT, which can help reduce recurrence and improve patient survival.
PMCID: PMC4777997  PMID: 26973413
Liver transplantation; Immunosuppressive agents; Hepatocellular carcinoma; Recurrence; Living donor; Deceased donor
5.  The coexistence of carotid and lower extremity atherosclerosis further increases cardio-cerebrovascular risk in type 2 diabetes 
Both carotid and lower limb atherosclerosis are associated with increased cardiovascular and cerebrovascular risks. However, it is still unclear whether the concomitant presence of carotid and lower extremity atherosclerosis further increases the cardiovascular and cerebrovascular risks. Therefore, our aim is to investigate whether the coexistence of carotid and lower extremity atherosclerosis was associated with higher cardiovascular and cerebrovascular risks in patients with type 2 diabetes.
This cross-sectional study was performed in 2830 hospitalized patients with type 2 diabetes. Based on carotid and lower limb Doppler ultrasound results, the patients were divided into three groups including 711 subjects without atherosclerosis, 999 subjects with either carotid or lower limb atherosclerosis, and 1120 subjects with both carotid and lower limb atherosclerosis. And we compared the clinical characteristics and prevalence of both cardio-cerebrovascular events (CCBVEs) and self-reported cardio- cerebrovascular diseases (CCBVDs) among the three groups.
After adjusting for age, sex, and duration of diabetes, there were significant increases in the prevalence of both CCBVEs (3.8 vs. 11.8 vs. 26.4 %, p < 0.001 for trend) and self-reported CCBVDs (6.9 vs. 19.9 vs. 36.5 %, p < 0.001 for trend) across the three groups (diabetics without atherosclerosis, diabetics with either carotid or lower limb atherosclerosis, and diabetics with both carotid and lower extremity atherosclerosis). A fully adjusted logistic regression analysis also revealed that compared with those without atherosclerosis, those with either carotid or lower limb atherosclerosis had higher risk of CCBVEs (OR 1.724, 95 % CI 1.001–2.966) and self-reported CCBVDs (OR 1.705, 95 % CI 1.115–2.605), and those with concomitant presence of carotid and lower extremity atherosclerosis had the highest risk of CCBVEs (OR 2.869, 95 % CI 1.660–4.960) and self-reported CCBVDs (2.147, 95 % CI 1.388–3.320)(p < 0.001 for trend in CCBVEs and p = 0.002 for trend in CCBVDs, respectively).
Either carotid or lower limb atherosclerosis was obviously related to increased cardio-cerebrovascular risk in type 2 diabetes. The concomitant presence of carotid and lower extremity atherosclerosis further increased cardio-cerebrovascular risk in patients with type 2 diabetes. The combined application of carotid and lower extremity ultrasonography may help identify type 2 diabetics with higher cardio-cerebrovascular risk.
PMCID: PMC4779218  PMID: 26944724
Type 2 diabetes; Carotid atherosclerosis; Lower limb atherosclerosis; Cardio-cerebrovascular events; Self-reported cardio-cerebrovascular diseases
6.  Effects of Dendritic Cells from Hepatitis B Virus Transgenic Mice-Stimulated Autologous Lymphocytes on Hepatitis B Virus Replication: A Study on the Impact of Specific Sensitized Effector Cells on In Vitro Virus Replication 
Viral Immunology  2015;28(2):85-92.
The objective of this study was to explore the effects of dendritic cells (DCs) from hepatitis B virus (HBV) transgenic mice-stimulated autologous lymphocytes on in vitro HBV replication. DCs from HBV transgenic mice were induced to maturity by lipopolysaccharide, followed by incubation with hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (HBcAg) in vitro. Mature DCs and autologous lymphocytes were co-stimulated to form specific sensitized immune effector cells (IEC), which were then co-cultured with the human hepatoma cell line HepG2.2.15. Changes in morphology and activity of hepatocytes were then observed, as well as analysis of changes in liver enzyme, and HBV DNA and inflammatory cytokine levels in the culture supernatant. Intracellular HBV DNA and covalently closed circular DNA (cccDNA) concentration were measured by real-time polymerase chain reaction. Co-stimulation by mature DCs and IEC showed no impact on the morphology and liver enzyme expression level of HepG2.2.15 cells, but the supernatant HBV DNA and intracellular HBV DNA and cccDNA levels decreased significantly compared with those cells co-cultured with immature DCs. Secretion of inflammatory cytokines in the supernatant showed that when HBV DNA was highly expressed, the concentration of IFN-γ and IL-2 decreased, while IL-10 increased. Contrastingly, when HBV DNA had low expression, the concentration of IFN-γ and IL-2 increased and IL-10 decreased. Co-stimulation of HBV-related antigen-induced mature DCs and autologous lymphocytes showed inhibitory effects on ex vivo HBV replication, and cytokines were suggested to mediate this effect.
PMCID: PMC4333252  PMID: 25343622
7.  Recurrent bilateral spontaneous pneumothorax secondary to lung adenocarcinoma with epidermal growth factor receptor mutation 
Thoracic Cancer  2015;7(2):257-260.
A 42‐year‐old female patient was admitted for recurrent bilateral spontaneous pneumothorax. High resolution computed tomography showed bilateral pneumothorax and numerous round and oval, thin‐walled lung cysts. Microscopically, each small cyst was composed of distended subpleural alveolar spaces. Tumor cells, characteristic of acinar adenocarcinoma, obstructed and narrowed the terminal bronchioles. There was no tumor necrosis or mucin production. This suggested check‐valve as a possible mechanism of the thin‐walled cysts and pneumothorax. Genetic analysis suggested that the tumors were positive for epidermal growth factor receptor mutation L858R in exon 21. Bilateral spontaneous pneumothorax and thin‐walled cysts in association with lung cancer is rarely reported and may be confused with cystic benign lung lesions.
PMCID: PMC4773303  PMID: 27042232
Epidermal growth factor receptor; lung cancer; lung cysts; pneumothorax
8.  Crosstalk between Wnt/β-catenin and Hedgehog/Gli signaling pathways in colon cancer and implications for therapy  
Cancer Biology & Therapy  2015;16(1):1-7.
Wnt/β-catenin and Hedgehog/Gli signalings play key roles in multiple biogenesis such as embryonic development and tissue homeostasis. Dysregulations of these 2 pathways are frequently found in most cancers, particularly in colon cancer. Their crosstalk has been increasingly appreciated as an important mechanism in regulating colon cancer progression. Our studies into the link between Wnt/β-catenin and Hedgehog/Gli signalings in colon cancer revealed several possible crosstalk points and suggested potential therapeutic strategies for colon cancer.
PMCID: PMC4622601  PMID: 25692617
β-catenin; colon cancer; crosstalk; Gli; Hedgehog/Gli signaling; therapeutic targets; Wnt/β-catenin signaling
9.  Specific cell surface labeling of GPCRs using split GFP 
Scientific Reports  2016;6:20568.
Specific cell surface labeling is essential for visualizing the internalization processes of G-protein coupled receptors (GPCRs) and for gaining mechanistic insight of GPCR functions. Here we present a rapid, specific, and versatile labeling scheme for GPCRs at living-cell membrane with the use of a split green fluorescent protein (GFP). Demonstrated with two GPCRs, GPR17 and CysLT2R, we show that two β-stands (β-stands 10 and 11) derived from a superfolder GFP (sfGFP) can be engineered to one of the three extracellular loop of a GPCR. The complementary fragment of sfGFP has nine β-strands (β-stands 1-9) that carries the mature fluorophore, and can be proteolytically derived from the full-length sfGFP. Separately the GFP fragments are non-fluorescent, but become fluorescent upon assembly, thus allowing specific labeling of the target proteins. The two GFP fragments rapidly assemble and the resulting complex is extremely tight under non-denaturing conditions, which allows real-time and quantitative assessment of the internalized GPCRs. We envision that this labeling scheme will be of great use for labeling other membrane proteins in various biological and pharmacological applications.
PMCID: PMC4746647  PMID: 26857153
10.  A new cascade halosulfonylation of 1,7-enynes toward 3,4-dihydroquinolin-2(1H)-ones via sulfonyl radical-triggered addition/6-exo-dig cyclization 
A new cascade three-component halosulfonylation of 1,7-enynes for efficient synthesis of densely functionalized 3,4-dihydroquinolin-2(1H)-ones has been established from readily accessible arylsulfonyl hydrazides and NIS (or NBS). The reaction pathway involves in situ-generated sulfonyl radical-triggered α,β-conjugated addition/6-exo-dig cyclization/radical coupling sequence, resulting in continuous multiple bond-forming events including C–S, C-C and C-I (or C-Br) bonds to rapidly build up molecular complexity.
PMCID: PMC4724266  PMID: 26680370
11.  Eliciting cytotoxic T lymphocytes against human laryngeal cancer-derived antigens: evaluation of dendritic cells pulsed with a heat-treated tumor lysate and other antigen-loading strategies for dendritic-cell-based vaccination 
Dendritic cells (DCs) have been used successfully in clinical pilot studies. However, tumor-specific immunity and clinical responses were only induced in certain cancer patients. It has been well documented that immunotherapy efficacy can be optimized for responses using antigen pulsing.
The human laryngeal squamous cell cancer (LSCC) cell line SNU899 was used to evaluate the in vitro anti-tumor efficacy of three different preparations of dendritic cell (DC) vaccines consisting of either whole tumor cells or their derivatives including: i) DCs pulsed with a tumor cell supernatant (DC-TCS), ii) DCs pulsed with whole-cell tumor stressed lysate (DC-TSL), and iii) DCs pulsed with irradiated tumor cells (DC-ITC).
Our results showed that DC-TSL is an effective source of tumor-associated antigens (TAAs) for pulsing DCs. DC-TSL induced the highest expansion of TAA-specific T cells, the strongest Th1 cytokine response, and the most potent cytotoxic T lymphocyte (CTL) activity. DC-TCS and DC-ITC inhibited T cell activation but induced a certain extent of CTL activity.
These data suggest that DC-TSL is a more potent inducer of antitumor immunity against laryngeal cancer than other antigen-loading strategies using whole tumor cell materials. This strategy provides an alternative approach for DC-based immunotherapy for laryngeal cancer.
PMCID: PMC4722756  PMID: 26795730
Antigen loading; Antigen presentation; Dendritic cells; Tumor immunity; Laryngeal cancer; Tumor lysate
12.  Coupling of soil prokaryotic diversity and plant diversity across latitudinal forest ecosystems 
Scientific Reports  2016;6:19561.
The belowground soil prokaryotic community plays a cardinal role in sustaining the stability and functions of forest ecosystems. Yet, the nature of how soil prokaryotic diversity co-varies with aboveground plant diversity along a latitudinal gradient remains elusive. By establishing three hundred 400-m2 quadrats from tropical rainforest to boreal forest in a large-scale parallel study on both belowground soil prokaryote and aboveground tree and herb communities, we found that soil prokaryotic diversity couples with the diversity of herbs rather than trees. The diversity of prokaryotes and herbs responds similarly to environmental factors along the latitudinal gradient. These findings revealed that herbs provide a good predictor of belowground biodiversity in forest ecosystems, and provide new perspective on the aboveground and belowground interactions in forest ecosystems.
PMCID: PMC4726043  PMID: 26781165
13.  Markedly improving asymmetric oxidation of 1-(4-methoxyphenyl) ethanol with Acetobacter sp. CCTCC M209061 cells by adding deep eutectic solvent in a two-phase system 
Enantiopure (S)-1-(4-methoxyphenyl) ethanol {(S)-MOPE} can be employed as an important synthon for the synthesis of cycloalkyl [b] indoles with the treatment function for general allergic response. To date, the biocatalytic resolution of racemic MOPE through asymmetric oxidation in the biphasic system has remained largely unexplored. Additionally, deep eutectic solvents (DESs), as a new class of promising green solvents, have recently gained increasing attention in biocatalysis for their excellent properties and many successful examples in biocatalytic processes. In this study, the biocatalytic asymmetric oxidation of MOPE to get (S)-MOPE using Acetobacter sp. CCTCC M209061 cells was investigated in different two-phase systems, and adding DES in a biphasic system was also explored to further improve the reaction efficiency of the biocatalytic oxidation.
Of all the examined water-immiscible organic solvents and ionic liquids (ILs), 1-butyl-3-methylimidazolium hexafluorophoshpate ([C4MIM][PF6]) afforded the best results, and consequently was selected as the second phase of a two-phase system for the asymmetric oxidation of MOPE with immobilized Acetobacter sp. CCTCC M209061 cells. For the reaction performed in the [C4MIM][PF6]/buffer biphasic system, under the optimized conditions, the initial reaction rate, the maximum conversion and the residual substrate e.e. recorded 97.8 μmol/min, 50.5 and >99.9 % after 10 h reaction. Furthermore, adding the DES [ChCl][Gly] (10 %, v/v) to the aqueous phase, the efficiency of the biocatalytic oxidation was rose markedly. The optimal substrate concentration and the initial reaction rate were significantly increased to 80 mmol/L and 124.0 μmol/min, respectively, and the reaction time was shortened to 7 h with 51.3 % conversion. The immobilized cell still retained over 72 % of its initial activity after 9 batches of successive reuse in the [C4MIM][PF6]/[ChCl][Gly]-containing buffer system. Additionally, the efficient biocatalytic process was feasible up to a 500-mL preparative scale.
The biocatalytic asymmetric oxidation of MOPE with Acetobacter sp. CCTCC M209061 cells was successfully conducted in the [C4MIM][PF6]-containing biphasic system with high conversion and enantioselectivity, and the reaction efficiency was further enhanced by adding [ChCl][Gly] to the reaction system. The efficient biocatalytic process was promising for the preparation of enantiopure (S)-MOPE.
PMCID: PMC4711044  PMID: 26758368
Asymmetric oxidation; Immobilized Acetobacter sp. CCTCC M209061 cells; MOPE; Biphasic system, DES
14.  Time series analysis of the association between ambient temperature and cerebrovascular morbidity in the elderly in Shanghai, China 
Scientific Reports  2016;6:19052.
Research on the association between ambient temperature and cerebrovascular morbidity is scarce in China. In this study, we applied mixed generalized additive model (MGAM) to daily counts of cerebrovascular disease of Shanghai residents aged 65 years or older from 2007–2011, stratified by gender. Weighted daily mean temperature up to lags of one week was smoothed by natural cubic spline, and was added into the model to assess both linear and nonlinear effects of temperature. We found that when the mean temperature increased by 1 °C, the male cases of cerebrovascular disease reduced by 0.95% (95% Confidence Interval (CI): 0.80%, 1.10%) or reduced by 0.34% (95% CI: −0.68, 1.36%) in conditions of temperature was below or above 27 °C. However, for every 1 °C increase in temperature, the female cases of cerebrovascular disease increased by 0.34% (95% CI: −0.26%, 0.94%) or decreased by 0.92% (95% CI: 0.72, 1.11%) in conditions of temperature was below or above 8 °C, respectively. Temperature and cerebrovascular morbidity is negatively associated in Shanghai. MGAM is recommended in assessing the association between environmental hazards and health outcomes in time series studies.
PMCID: PMC4707484  PMID: 26750421
15.  Toll-Like Receptors and Dectin-1, a C-Type Lectin Receptor, Trigger Divergent Functions in CNS Macrophages 
The Journal of Neuroscience  2015;35(27):9966-9976.
Spinal cord injury (SCI) activates macrophages, endowing them with both reparative and pathological functions. The mechanisms responsible for these divergent functions are unknown but are likely controlled through stochastic activation of different macrophage receptor subtypes. Various danger-associated molecular patterns released from dying cells in the injured spinal cord likely activate distinct subtypes of macrophage pattern recognition receptors, including bacterial toll-like receptors (TLRs) and fungal C-type lectin receptors (e.g., dectin-1). To determine the in vivo consequences of activating these receptors, ligands specific for TLR2 or dectin-1 were microinjected, alone or in combination, into intact spinal cord. Both ligands elicit a florid macrophage reaction; however, only dectin-1 activation causes macrophage-mediated demyelination and axonal injury. Coactivating TLR2 reduced the injurious effects of dectin-1 activation. When injected into traumatically injured spinal cord, TLR2 agonists enhance the endogenous macrophage reaction while conferring neuroprotection. Indeed, dieback of axons was reduced, leading to smaller lesion volumes at the peak of the macrophage response. Moreover, the density of NG2+ cells expressing vimentin increased in and near lesions that were enriched with TLR2-activated macrophages. In dectin-1-null mutant (knock-out) mice, dieback of corticospinal tract axons also is reduced after SCI. Collectively, these data support the hypothesis that the ability of macrophages to create an axon growth-permissive microenvironment or cause neurotoxicity is receptor dependent and it may be possible to exploit this functional dichotomy to enhance CNS repair.
SIGNIFICANCE STATEMENT There is a growing appreciation that macrophages exert diverse functions in the injured and diseased CNS. Indeed, both macrophage-mediated repair and macrophage-mediated injury occur, and often these effector functions are elicited simultaneously. Understanding the mechanisms governing the reparative and pathological properties of activated macrophages is at the forefront of neuroscience research. In this report, using in vitro and in vivo models of relevance to traumatic spinal cord injury (SCI), new data indicate that stochastic activation of toll-like and c-type lectin receptors on macrophages causes neuroprotection or neurotoxicity, respectively. Although this manuscript focuses on SCI, these two innate immune receptor subtypes are also involved in developmental processes and become activated in macrophages that respond to various neurological diseases.
PMCID: PMC4495245  PMID: 26156997
dieback; microglia; neuroinflammation; regeneration; TLR2; zymosan
16.  MicroRNA-26a suppresses epithelial-mesenchymal transition in human hepatocellular carcinoma by repressing enhancer of zeste homolog 2 
Our previous study reported that microRNA-26a (miR-26a) inhibited tumor progression by inhibiting tumor angiogenesis and intratumoral macrophage infiltration in hepatocellular carcinoma (HCC). The direct roles of miR-26a on tumor cell invasion remain poorly understood. In this study, we aim to explore the mechanism of miR-26a in modulating epithelial-mesenchymal transition (EMT) in HCC.
In vitro cell morphology and cell migration were compared between the hepatoma cell lines HCCLM3 and HepG2, which were established in the previous study. Overexpression and down-regulation of miR-26a were induced in these cell lines, and Western blot and immunofluorescence assays were used to detect the expression of EMT markers. Xenograft nude mouse models were used to observe tumor growth and pulmonary metastasis. Immunohistochemical assays were conducted to study the relationships between miR-26a expression and enhancer of zeste homolog 2 (EZH2) and E-cadherin expression in human HCC samples.
Down-regulation of miR-26a in HCCLM3 and HepG2 cells resulted in an EMT-like cell morphology and high motility in vitro and increased in tumor growth and pulmonary metastasis in vivo. Through down-regulation of EZH2 expression and up-regulation of E-cadherin expression, miR-26a inhibited the EMT process in vitro and in vivo. Luciferase reporter assay showed that miR-26a directly interacted with EZH2 messenger RNA (mRNA). Furthermore, the expression of miR-26a was positively correlated with E-cadherin expression and inversely correlated with EZH2 expression in human HCC tissue.
miR-26a inhibited the EMT process in HCC by down-regulating EZH2 expression.
PMCID: PMC4702409  PMID: 26733151
microRNA-26a (miR-26a); Hepatocellular carcinoma (HCC); Enhancer of zeste homolog 2 (EZH2); Epithelial-mesenchymal transition (EMT)
17.  A Retrospective Research of the Characteristic of Hypertriglyceridemic Pancreatitis in Beijing, China 
Aim. To investigate the characteristic of hypertriglyceridemic- (HTG-) induced pancreatitis (HTG pancreatitis). Methods. We reviewed 126 cases of HTG pancreatitis and 168 cases of biliary pancreatitis as control. Results. The HTG group mean age was younger than biliary group. The number of females was a little higher than males in both groups. There were 18 cases that were recurrent in HTG group and 11 in billiary group. The mean hospitalization times were 13.7 ± 2.6 and 11.2 ± 2.3 days in two groups. Six patients received apheresis in HTG group. The proportion of severe AP was 31.0% and 26.2%, mortality 1.6% and 1.2%, comorbidity of diabetes mellitus (DM) 20.6% and 6.5% in two groups. The number of complications of gastrointestinal (GI) bleeding, sepsis, and multiple organ dysfunction syndrome (MODS) in HTG group and biliary group was 1, 1, and 2 versus 4, 12, and 4. Conclusions. The proportion of recurrent and severe AP and comorbidity of DM of HTG group was higher than billiary group. The proportion of the complications of GI bleeding, sepsis, and MODS of HTG group was less than biliary group. Apheresis could effectively reduce serum TG levels soon. There was no significant difference of the mortality between two groups.
PMCID: PMC4736388  PMID: 26880892
18.  Association between glycemic control and birthweight with glycated albumin in Chinese women with gestational diabetes mellitus 
To assess glycated albumin (GA) as a potential glycemic index in managing gestational diabetes mellitus (GDM).
Materials and Methods
Eligible pregnant women were divided into the GDM group with abnormal result on a 75‐g oral glucose tolerance test (OGTT) and the control (normal) group. GA measurements, Pearson's correlation analysis, multiple logistic regression and receiver operating characteristic curve analysis were obtained at the follow‐up examination of participants in the two groups.
A total of 2,118 women were assigned to the GDM group (n = 639) and control group (n = 1,479). The mean level of serum GA in GDM group was significantly greater than that in the control group at both 24–28 and 36–38 weeks of gestation (P < 0.05). The area under the receiver operating characteristic curve for GA defining good glycemic control in GDM was 0.874 (95% confidence interval 0.811–0.938). The cut‐off point for the GA levels derived from the receiver operating characteristic curve was 11.60%, which had sensitivity and specificity for detecting a poor glycemic status of 75.93% and 86.36%, respectively. The risk of birthweight ≥3,500 g and macrosomia increased significantly with GA levels ≥13.00% at 24–28 weeks and ≥12.00% at 36–38 weeks of gestation.
GA might be an appropriate and conveniently measured index that can detect poor glycemic control and predict birthweights in GDM women.
PMCID: PMC4718110  PMID: 26816601
Birthweight; Gestational diabetes; Glycated albumin
19.  High throughput screening technologies for ion channels 
Acta Pharmacologica Sinica  2015;37(1):34-43.
Ion channels are involved in a variety of fundamental physiological processes, and their malfunction causes numerous human diseases. Therefore, ion channels represent a class of attractive drug targets and a class of important off-targets for in vitro pharmacological profiling. In the past decades, the rapid progress in developing functional assays and instrumentation has enabled high throughput screening (HTS) campaigns on an expanding list of channel types. Chronologically, HTS methods for ion channels include the ligand binding assay, flux-based assay, fluorescence-based assay, and automated electrophysiological assay. In this review we summarize the current HTS technologies for different ion channel classes and their applications.
PMCID: PMC4722985  PMID: 26657056
ion channels; high throughput screening; ligand binding assay; flux-based assay; fluorescence-based assay; automated electrophysiological assay; drug discovery
20.  Detection of lung adenocarcinoma with ROS1 rearrangement by IHC, FISH, and RT-PCR and analysis of its clinicopathologic features 
OncoTargets and therapy  2015;9:131-138.
To detect ROS1 rearrangement using three different assays, including immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and reverse transcription polymerase chain reaction (RT-PCR), and to analyze the clinicopathologic features of ROS1 rearrangement in patients with lung adenocarcinoma.
One hundred eighty-three consecutive patients with lung adenocarcinoma with operation and follow-up data were analyzed for ROS1 rearrangement by IHC, FISH, and RT-PCR. PCR products of the RT-PCR-positive samples were sequenced for confirmation of the specific fusion partners.
Three of the 183 (1.64%) cases were identified to be positive for ROS1 rearrangement through all three methods. The fusion patterns were CD74 e6-ROS1 e32, CD74 e6-ROS1 e34, and TPM3 e8-ROS1 e35, respectively. FISH-positive cases showed two types of signals, single 3′ signals (green) and split red and green signals. Using FISH as a standard method, the sensitivity and specificity of ROS1 IHC with 1+ staining or more were 100% and 96.67%, respectively. The sensitivity and specificity of RT-PCR were both 100%. Univariate analysis identified female sex (P=0.044), Stage I disease (P<0.001), and ROS1-negative status (P=0.022) to be significantly associated with longer overall survival.
IHC, FISH, and RT-PCR are all effective methods for the detection of ROS1 rearrangement. IHC would be a useful screening method in routine pathologic laboratories. RT-PCR can detect exact fusion patterns. ROS1 rearrangement may be a worse prognostic factor. The exact correlation of ROS1 rearrangement with prognosis and whether different fusion types are correlated with different responses to targeted therapy need to be further investigated.
PMCID: PMC4706119  PMID: 26770062
ROS1; lung adenocarcinoma; rearrangement; IHC; FISH; RT-PCR
21.  Effect of oral N-acetylcysteine on COPD patients with microsatellite polymorphism in the heme oxygenase-1 gene promoter 
Heme oxygenase-1 (HO-1) plays a protective role as an antioxidant in the lung, and HO-1 gene promoter polymorphism has been shown to be associated with the severity and prognosis of COPD patients. N-acetylcysteine (NAC), an antioxidant/mucous modifier, has shown an uncertain benefit in COPD patients. We hypothesized that this polymorphism could be associated with the effectiveness of oral NAC.
A total of 368 patients with COPD were recruited and the polymorphisms of their HO-1 gene promoter were classified into three subclasses according to the number of (GT)n repeats, as previously reported: class S (<27 (GT)n repeats), class M (27–32 (GT)n repeats), and class L (>32 (GT)n repeats). These subjects were then classified as L+ group (with the L allele: L/L, L/M, L/S) and L− group (without the L allele: M/M, M/S, S/S). All the patients were allocated to standard therapy plus NAC 600 mg bid over a 1-year period and were observed over that year.
The L− group saw improvements in forced expiratory volume in 1 second (FEV1) (from 1.44±0.37 to 1.58±0.38, P=0.04) and FEV1% predicted (from 56.6±19.2 to 59.7±17.2, P=0.03). No improvement was found in forced vital capacity of each group and the decline of forced vital capacity in both of the groups was not statistical significant. The number of yearly COPD exacerbations of the L− group was 1.5±0.66 which was lower than the 2.1±0.53 of the L+ group (P<0.01). For the changes of St George’s Respiratory Questionnaire (SGRQ) score, only the activity score of the L− group was more significant than that of the L+ group (P=0.02). The improvement of the outcome of 6-minute walking distance test in L− group (from 290.1±44.9 meters to 309.7±46.9 m) was higher than that in the L+ group (from 289.7±46.2 m to 300.3±44.2 m) (P=0.03).
A 600 mg bid oral NAC treatment for 1-year on COPD patients without the L allele can improve the FEV1, FEV1% predicted, the SGRQ activity score, and the result of 6-minute walking distance test, and the exacerbation rate of the L allele carrier in COPD patients is much higher than in the COPD patients without the L allele.
PMCID: PMC4676509  PMID: 26674585
chronic obstructive pulmonary disease; COPD prognosis; NAC treatment; gene therapy
22.  Modulation Effect of Peroxisome Proliferator-Activated Receptor Agonists on Lipid Droplet Proteins in Liver 
Journal of Diabetes Research  2015;2016:8315454.
Peroxisome proliferator-activated receptor (PPAR) agonists are used for treating hyperglycemia and type 2 diabetes. However, the mechanism of action of these agonists is still under investigation. The lipid droplet-associated proteins FSP27/CIDEC and LSDP5, regulated directly by PPARγ and PPARα, are associated with hepatic steatosis and insulin sensitivity. Here, we evaluated the expression levels of FSP27/CIDEC and LSDP5 and the regulation of these proteins by consumption of a high-fat diet (HFD) or administration of PPAR agonists. Mice with diet-induced obesity were treated with the PPARγ or PPARα agonist, pioglitazone or fenofibrate, respectively. Liver tissues from db/db diabetic mice and human were also collected. Interestingly, FSP27/CIEDC was expressed in mouse and human livers and was upregulated in obese C57BL/6J mice. Fenofibrate treatment decreased hepatic triglyceride (TG) content and FSP27/CIDEC protein expression in mice fed an HFD diet. In mice, LSDP5 was not detected, even in the context of insulin resistance or treatment with PPAR agonists. However, LSDP5 was highly expressed in humans, with elevated expression observed in the fatty liver. We concluded that fenofibrate greatly decreased hepatic TG content and FSP27/CIDEC protein expression in mice fed an HFD, suggesting a potential regulatory role for fenofibrate in the amelioration of hepatic steatosis.
PMCID: PMC4684860  PMID: 26770990
23.  Five‐year analysis from phase 2 trial of “sandwich” chemoradiotherapy in newly diagnosed, stage IE to IIE, nasal type, extranodal natural killer/T‐cell lymphoma 
Cancer Medicine  2015;5(1):33-40.
The “sandwich” protocol, was first proposed by us and comprised of l‐asparaginase, vincristine, and prednisone chemotherapy with radiotherapy, results in 2‐year overall survival and progression‐free survival rates that surpass traditional therapies for patients with newly diagnosed, stage IE‐IIE, nasal type, extranodal natural killer/T‐cell lymphoma. The results had been published by cancer. These patients were followed up over a median period of 67 months, for which updates and the results of prognostic factors analyses are presented. The 5‐year overall survival and progress‐free survival rates were both 64%. The highest rates of death occurred during the first 6 months, and between the second and third year after enrollment. The initial therapeutic response (odds ratio = 5.83; P = 0.001) and B symptoms (odds ratio = 6.13; P = 0.043) were significant prognostic factors for overall survival. However, the international prognostic index was not significant for progress‐free survival and overall survival. There were no severe long‐term side effects. These results indicate that the “sandwich” protocol may benefit the long‐term survival of patients with newly diagnosed stage IE‐IIE, nasal type, extranodal natural killer/T‐cell lymphoma. However, additional studies with larger samples are required to confirm these results. This study is registered at (ChicTR‐TNC‐09000394).
PMCID: PMC4708906  PMID: 26633585
Chemoradiotherapy; extranodal natural killer/T‐cell lymphoma; long‐term survival; l‐asparaginase prednisone; prognostic factors; vincristine
24.  High-performance probes for light and electron microscopy 
Nature methods  2015;12(6):568-576.
We describe an engineered family of highly antigenic molecules based on GFP-like fluorescent proteins. These molecules contain numerous copies of peptide epitopes and simultaneously bind IgG antibodies at each location. These “spaghetti monster” fluorescent proteins (smFPs) distribute well in neurons, notably into small dendrites, spines and axons. smFP immunolabeling localizes weakly expressed proteins not well resolved with traditional epitope tags. By varying epitope and scaffold, we generated a diverse family of mutually orthogonal antigens. In cultured neurons and mouse and fly brains, smFP probes allow robust, orthogonal multi-color visualization of proteins, cell populations and neuropil. smFP variants complement existing tracers, greatly increase the number of simultaneous imaging channels, and perform well in advanced preparations such as array tomography, super-resolution fluorescence imaging and electron microscopy. In living cells, the probes improve single-molecule image tracking and increase yield for RNA-Seq. These probes facilitate new experiments in connectomics, transcriptomics and protein localization.
PMCID: PMC4573404  PMID: 25915120
25.  Inverse relationship between serum osteocalcin levels and nonalcoholic fatty liver disease in postmenopausal Chinese women with normal blood glucose levels 
Acta Pharmacologica Sinica  2015;36(12):1497-1502.
Osteocalcin is involved in the progression of nonalcoholic fatty liver disease (NAFLD) in animal models and humans. In this study we investigated the relationship between serum osteocalcin levels and NAFLD in postmenopausal Chinese women.
A total of 733 postmenopausal women (age range: 41–78 years) with normal blood glucose levels were enrolled in this cross-sectional study. Women taking lipid-lowering or anti-hypertensive drugs were excluded. Serum osteocalcin levels were assessed using an electrochemiluminescence immunoassay. The degree of NAFLD progression for each subject was assessed through ultrasonography. The fatty liver index (FLI) of each subject was calculated to quantify the degree of liver steatosis.
The median level of serum osteocalcin for all subjects enrolled was 21.99 ng/mL (interquartile range: 17.84–26.55 ng/mL). Subjects with NAFLD had significantly lower serum osteocalcin levels (18.39 ng/mL; range: 16.03–23.64 ng/mL) compared with those without NAFLD (22.31 ng/mL; range: 18.55–27.06 ng/mL; P<0.01). Serum osteocalcin levels decreased with incre¬mental changes in the FLI value divided by the quartile (P-value for trend<0.01). The serum osteocalcin levels showed a negative correlation with the FLI values, even after adjusting for confounding factors (standardized β=−0.124; P<0.01). Binary logistic regression analysis identified an individual's serum osteocalcin level as an independent risk factor for NAFLD (odds ratio: 0.951; 95% confidence interval: 0.911–0.992; P=0.02).
Serum osteocalcin levels are inversely correlated with NAFLD in postmenopausal Chinese women with normal blood glucose levels.
PMCID: PMC4816233  PMID: 26567728
osteocalcin; nonalcoholic fatty liver disease; postmenopause; Chinese women

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