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1.  Changes in central corneal thickness and refractive error after thin-flap laser in situ keratomileusis in Chinese eyes 
BMC Ophthalmology  2015;15:86.
Refractive stability is influenced by alterations in corneal curvature and corneal thickness after laser in situ keratomileusis (LASIK). The aim of this study was to analyze the changes of central corneal thickness (CCT) and refractive error following thin-flap LASIK surgery in Chinese eyes.
One hundred and fifty-eight myopic patients (302 eyes) who underwent thin-flap LASIK surgery were prospectively evaluated. CCT was measured by non-contact specular microscopy before, and 1 day, 1 week, and 1, 3, and 6 months following surgery. Age, refractive error, and optic zone diameter were also recorded.
Preoperatively, the mean CCT was 531.6 ± 24.3 μm. At 1 day, 1 week, and 1, 3, and 6 months after surgery, mean CCTs were 431.4 ± 38.4 μm, 422.6 ± 3 7.8 μm, 427.2 ± 38.0 μm, 434.4 ± 38.2 μm, and 435.6 ± 38.0 μm, respectively. Significant changes were detected in CCT values at each time point after thin-flap LASIK treatment (P < 0.05). The mean preoperative spherical equivalent (SE) was −5.73 ± 2.30 diopters (D). At 1 day, 1 week, and 1, 3, and 6 months after surgery, it was 0.26 ± 0.58 D, 0.54 ± 0.52 D, 0.49 ± 0.53 D, 0.45 ± 0.49 D, and 0.37 ± 0.42 D, respectively. The spherical equivalent refraction at 6 months postsurgery was close to the predicted value (0.34 ± 0.30 D). The changes in CCT within 6 months (4.06 ± 9.99 μm) were negatively correlated with age, preoperative refractive error, and optical zone diameter, respectively (r = −0.180, P < 0.05; r = −0.187, P < 0.001; r = −0.171, P < 0.05, respectively). No significant correlation was found between CCT changes and SE changes at different time points, postoperatively.
CCTs decreased significantly at 1 day after surgery, and continued to decline at 1 week after surgery, then increased over time. From postoperative 1 week, SE over time continually shifted to the myopic side.
PMCID: PMC4517627  PMID: 26220189
Central corneal thickness; Myopia; Non-contact specular microscope; Thin-flap laser in situ keratomileusis; Refractive error
2.  Ethynylflavones, Highly Potent, and Selective Inhibitors of Cytochrome P450 1A1 
Chemical Research in Toxicology  2014;27(8):1431-1439.
The flavone backbone is a well-known pharmacophore present in a number of substrates and inhibitors of various P450 enzymes. In order to find highly potent and novel P450 family I enzyme inhibitors, an acetylene group was incorporated into six different positions of flavone. The introduction of an acetylene group at certain locations of the flavone backbone lead to time-dependent inhibitors of P450 1A1. 3′-Ethynylflavone, 4′-ethynylflavone, 6-ethynylflavone, and 7-ethynylflavone (KI values of 0.035–0.056 μM) show strong time-dependent inhibition of P450 1A1, while 5-ethynylflavone (KI value of 0.51 μM) is a moderate time-dependent inhibitor of this enzyme. Meanwhile, 4′-ethynylflavone and 6-ethynylflavone are highly selective inhibitors toward this enzyme. Especially, 6-ethynylflavone possesses a Ki value of 0.035 μM for P450 1A1 177- and 15-fold lower than those for P450s 1A2 and 1B1, respectively. The docking postures observed in the computational simulations show that the orientation of the acetylene group determines its capability to react with P450s 1A1 and 1A2. Meanwhile, conformational analysis indicates that the shape of an inhibitor determines its inhibitory selectivity toward these enzymes.
PMCID: PMC4137986  PMID: 25033111
3.  NEXN inhibits GATA4 and leads to atrial septal defects in mice and humans 
Cardiovascular Research  2014;103(2):228-237.
Cardiac structural genes have been implicated as causative factors for congenital heart diseases (CHDs). NEXN is an F-actin binding protein and previously identified as a disease gene causing cardiomyopathies. Whether NEXN contributes to CHDs aetiologically remains unknown. Here, we explored the function of NEXN in cardiac development.
Methods and results
First, we determine the role of NEXN in cardiac differentiation using mouse P19cl6 in vitro model; we demonstrated that NEXN inhibited cardiac contractile markers, serving as a negative regulator. Interestingly, we found this effect was mediated by GATA4, a crucial transcription factor that controls cardiac development by knockdown, overexpression, and rescue experiment, respectively. We then generated transgenic mouse models and surprisingly, we discovered cardiac-selective expression of the NEXN gene caused atrial septal defects (ASDs). Next, to search for the mutations in NEXN gene in patients suffering from ASDs, we sequenced the exon and exon–intron joint regions of the NEXN gene in 150 probands with isolated ASDs and identified three mutations in the conserved region of NEXN (c.-52-78C>A, K199E, and L227S), which were not found in 500 healthy controls. Finally, we characterize the related mechanisms and found all mutations inhibited GATA4 expression.
We identify NEXN as a novel gene for ASD and its function to inhibit GATA4 established a critical regulation of an F-actin binding protein on a transcription factor in cardiac development.
PMCID: PMC4498134  PMID: 24866383
Atrial septal defect; NEXN; GATA4; Actin; Mutation
4.  Fe(III) Is Essential for Porcine Embryonic Development via Mitochondrial Function Maintenance 
PLoS ONE  2015;10(7):e0130791.
Iron is an important trace element involved in several biological processes. The role of iron in porcine early embryonic development remains unknown. In the present study, we depleted iron (III, Fe3+) with deferoxamine (DFM), a specific Fe3+ chelator, in cultured porcine parthenotes and monitored embryonic development, apoptosis, mitochondrial membrane potential, and ATP production. Results showed biphasic function of Fe3+ in porcine embryo development. 0.5 μM DFM obviously increased blastocyst formation (57.49 ± 2.18% vs. control, 43.99 ± 1.72%, P < 0.05) via reduced (P < 0.05) production of reactive oxygen species (ROS), further increased mitochondrial membrane potential and ATP production in blastocysts (P < 0.05). 0.5 μM DFM decreased mRNA expression of Caspase 3 (Casp3) and increased Bcl-xL. However, results showed a significant reduction in blastocyst formation in the presence of 5.0 μM DFM compared with the control group (DFM, 21.62 ± 3.92% vs. control, 43.99 ± 1.73%, P < 0.05). Fe3+ depletion reduced the total (DFM, 21.10 ± 8.78 vs. control, 44.09 ± 13.65, P < 0.05) and increased apoptotic cell number (DFM, 11.10 ± 5.24 vs. control, 2.64 ± 1.43, P < 0.05) in the blastocyst. An obvious reduction in mitochondrial membrane potential and ATP level after 5.0 μM DFM treatment was observed. Co-localization between mitochondria and cytochrome c was reduced after high concentration of DFM treatment. In conclusion, Fe3+ is essential for porcine embryonic development via mitochondrial function maintenance, but redundant Fe3+ impairs the function of mitochondria.
PMCID: PMC4498905  PMID: 26161974
5.  DNA methylation profiling of the X chromosome reveals an aberrant demethylation on CXCR3 promoter in primary biliary cirrhosis 
Clinical Epigenetics  2015;7(1):61.
Although the etiology of primary biliary cirrhosis (PBC) remains enigmatic, there are several pieces of data supporting the thesis that a strong genetic predisposition and environmental factors interact to produce a selective loss of tolerance. The striking female predominance of PBC has suggested that this sex predisposition may be secondary to epigenetic alterations on the X chromosome. In the present study, we rigorously defined the X chromosome methylation profile of CD4, CD8, and CD14 cells from 30 PBC patients and 30 controls. Genomic DNA from sorted CD4, CD8, and CD14 subpopulations was isolated, sonicated, and immunoprecipitated for analysis of methylation. All products were hybridized to a custom-tiled four-plex array containing 27,728 CpG islands annotated by UCSC and 22,532 well-characterized RefSeq promoter regions. Furthermore, bisulfite sequencing was then used for validation on a subsequent group of independent samples from PBC patients and controls. Thence, expression levels of selected X-linked genes were evaluated by quantitative real-time PCR with cDNA samples from all subjects.
We report herein that a total of 20, 15, and 19 distinct gene promoters reflected a significant difference in DNA methylation in CD4+ T, CD8+ T, and CD14+ cells in patients with PBC. Interestingly, there was hypermethylation of FUNDC2 in CD8+ T cells and a striking demethylation of CXCR3 in CD4+ T cells, which inversely correlated with CXCR3 expression levels in CD4+ T cells from early-stage PBC patients.
Our data provides a set of genes with epigenetic alteration likely to be indicators of autoimmunity and emphasizes the role of CXCR3 in the natural history of PBC.
Electronic supplementary material
The online version of this article (doi:10.1186/s13148-015-0098-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4491885  PMID: 26150899
X chromosome; Primary biliary cirrhosis; CXCR3
6.  Gd-EOB-DTPA-enhanced magnetic resonance imaging for bile duct intraductal papillary mucinous neoplasms 
AIM: To investigate gadolinium-ethoxybenzyl-diethylenetriamine-pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) of intraductal papillary mucinous neoplasms of the bile duct (IPMN-B).
METHODS: The imaging findings of five cases of IPMN-B which were pathologically confirmed at our hospital between March 2012 and May 2013 were retrospectively analyzed. Three of these cases were diagnosed by duodenal endoscopy and biopsy pathology, and two cases were diagnosed by surgical pathology. All five patients underwent enhanced and non-enhanced computed tomography (CT), magnetic resonance cholangiopancreatography, and Gd-EOB-DTPA-enhanced MRI; one case underwent both Gd-EOB-DTPA-enhanced MRI and positron emission tomography-CT. The clinical data and imaging results for these cases were compared and are presented.
RESULTS: Conventional imaging showed diffuse dilatation of bile ducts and multiple intraductal polypoid and papillary neoplasms or serrated changes along the bile ducts. In two cases, Gd-EOB-DTPA-enhanced MRI revealed dilated biliary ducts and intraductal tumors, as well as filling defects caused by mucin in the dilated bile ducts in the hepatobiliary phase. Gd-EOB-DTPA-enhanced MRI in one case clearly showed a low-signal tumor in the hepatobiliary phase, similar to what was seen by positron emission tomography-CT. In two patients, routine inspection was unable to discern whether the lesions were inflammation or tumors. However, Gd-EOB-DTPA-enhanced MRI revealed a pattern of gradual enhancement during the hepatobiliary phase, and the signal intensity of the lesions was lower than the surrounding liver parenchyma, suggesting tissue inflammation in both cases, which were confirmed by surgical pathology.
CONCLUSION: Gd-EOB-DTPA-enhanced MRI reveals the intraductal mucin component of IPMN-B in some cases and the extent of tumor infiltration beyond the bile ducts in invasive cases.
PMCID: PMC4491969  PMID: 26167082
Gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid; Magnetic resonance imaging; Magnetic resonance cholangiopancreatography; Multidetector computed tomography; Bile duct neoplasms
7.  Spatial–temporal FUCCI imaging of each cell in a tumor demonstrates locational dependence of cell cycle dynamics and chemoresponsiveness 
Cell Cycle  2014;13(13):2110-2119.
The phase of the cell cycle can determine whether a cancer cell can respond to a given drug. We report here on the results of monitoring of real-time cell cycle dynamics of cancer cells throughout a live tumor intravitally using a fluorescence ubiquitination cell cycle indicator (FUCCI) before, during, and after chemotherapy. In nascent tumors in nude mice, approximately 30% of the cells in the center of the tumor are in G0/G1 and 70% in S/G2/M. In contrast, approximately 90% of cancer cells in the center and 80% of total cells of an established tumor are in G0/G1 phase. Similarly, approximately 75% of cancer cells far from (>100 µm) tumor blood vessels of an established tumor are in G0/G1. Longitudinal real-time imaging demonstrated that cytotoxic agents killed only proliferating cancer cells at the surface and, in contrast, had little effect on quiescent cancer cells, which are the vast majority of an established tumor. Moreover, resistant quiescent cancer cells restarted cycling after the cessation of chemotherapy. Our results suggest why most drugs currently in clinical use, which target cancer cells in S/G2/M, are mostly ineffective on solid tumors. The results also suggest that drugs that target quiescent cancer cells are urgently needed.
PMCID: PMC4111702  PMID: 24811200
drug resistance; cell cycle; tumor; confocal laser microscopy; fluorescent proteins; FUCCI; tumor blood vessels; dormancy
8.  Stimulation of new bone formation by the proteasome inhibitor, bortezomib: implications for myeloma bone disease 
British journal of haematology  2007;139(3):434-438.
Impaired bone formation contributes to the lack of bone healing in multiple myeloma and there is a need for agents with bone anabolic properties to reverse the bone deficit in patients. Bortezomib, a proteasome inhibitor with antitumour efficacy in myeloma patients, enhanced new bone formation in mouse calvarial cultures; this effect was blocked by dickkopf 1(Dkk1), an antagonist of Wnt signalling implicated in myeloma bone disease. Bortezomib inhibited Dkk1 expression in calvariae and bone marrow-derived stromal cells, suggesting a novel mechanism by which bortezomib exerts its effects in bone. Clinical trials in patients with myeloma bone disease are needed to validate these results.
PMCID: PMC4482356  PMID: 17910634
bortezomib; osteoblast; myeloma; Dkk1; bone
9.  Soil Tillage Management Affects Maize Grain Yield by Regulating Spatial Distribution Coordination of Roots, Soil Moisture and Nitrogen Status 
PLoS ONE  2015;10(6):e0129231.
The spatial distribution of the root system through the soil profile has an impact on moisture and nutrient uptake by plants, affecting growth and productivity. The spatial distribution of the roots, soil moisture, and fertility are affected by tillage practices. The combination of high soil density and the presence of a soil plow pan typically impede the growth of maize (Zea mays L.).We investigated the spatial distribution coordination of the root system, soil moisture, and N status in response to different soil tillage treatments (NT: no-tillage, RT: rotary-tillage, SS: subsoiling) and the subsequent impact on maize yield, and identify yield-increasing mechanisms and optimal soil tillage management practices. Field experiments were conducted on the Huang-Huai-Hai plain in China during 2011 and 2012. The SS and RT treatments significantly reduced soil bulk density in the top 0–20 cm layer of the soil profile, while SS significantly decreased soil bulk density in the 20–30 cm layer. Soil moisture in the 20–50 cm profile layer was significantly higher for the SS treatment compared to the RT and NT treatment. In the 0-20 cm topsoil layer, the NT treatment had higher soil moisture than the SS and RT treatments. Root length density of the SS treatment was significantly greater than density of the RT and NT treatments, as soil depth increased. Soil moisture was reduced in the soil profile where root concentration was high. SS had greater soil moisture depletion and a more concentration root system than RT and NT in deep soil. Our results suggest that the SS treatment improved the spatial distribution of root density, soil moisture and N states, thereby promoting the absorption of soil moisture and reducing N leaching via the root system in the 20–50 cm layer of the profile. Within the context of the SS treatment, a root architecture densely distributed deep into the soil profile, played a pivotal role in plants’ ability to access nutrients and water. An optimal combination of deeper deployment of roots and resource (water and N) availability was realized where the soil was prone to leaching. The correlation between the depletion of resources and distribution of patchy roots endorsed the SS tillage practice. It resulted in significantly greater post-silking biomass and grain yield compared to the RT and NT treatments, for summer maize on the Huang-Huai-Hai plain.
PMCID: PMC4476672  PMID: 26098548
10.  Retrieval and Mapping of Soil Texture Based on Land Surface Diurnal Temperature Range Data from MODIS 
PLoS ONE  2015;10(6):e0129977.
Numerous studies have investigated the direct retrieval of soil properties, including soil texture, using remotely sensed images. However, few have considered how soil properties influence dynamic changes in remote images or how soil processes affect the characteristics of the spectrum. This study investigated a new method for mapping regional soil texture based on the hypothesis that the rate of change of land surface temperature is related to soil texture, given the assumption of similar starting soil moisture conditions. The study area was a typical flat area in the Yangtze-Huai River Plain, East China. We used the widely available land surface temperature product of MODIS as the main data source. We analyzed the relationships between the content of different particle soil size fractions at the soil surface and land surface day temperature, night temperature and diurnal temperature range (DTR) during three selected time periods. These periods occurred after rainfalls and between the previous harvest and the subsequent autumn sowing in 2004, 2007 and 2008. Then, linear regression models were developed between the land surface DTR and sand (> 0.05 mm), clay (< 0.001 mm) and physical clay (< 0.01 mm) contents. The models for each day were used to estimate soil texture. The spatial distribution of soil texture from the studied area was mapped based on the model with the minimum RMSE. A validation dataset produced error estimates for the predicted maps of sand, clay and physical clay, expressed as RMSE of 10.69%, 4.57%, and 12.99%, respectively. The absolute error of the predictions is largely influenced by variations in land cover. Additionally, the maps produced by the models illustrate the natural spatial continuity of soil texture. This study demonstrates the potential for digitally mapping regional soil texture variations in flat areas using readily available MODIS data.
PMCID: PMC4474439  PMID: 26090852
11.  Prognostic Model Based on Systemic Inflammatory Response and Clinicopathological Factors to Predict Outcome of Patients with Node-Negative Gastric Cancer 
PLoS ONE  2015;10(6):e0128540.
Prognostic models are generally used to predict gastric cancer outcomes. However, no model combining patient-, tumor- and host-related factors has been established to predict outcomes after radical gastrectomy, especially outcomes of patients without nodal involvement. The aim of this study was to develop a prognostic model based on the systemic inflammatory response and clinicopathological factors of resectable gastric cancer and determine whether the model can improve prognostic accuracy in node-negative patients. We reviewed the clinical, laboratory, histopathological and survival data of 1397 patients who underwent radical gastrectomy between 2007 and 2013. Patients were split into development and validation sets of 1123 and 274 patients, respectively. Among all 1397 patients, 545 had node-negative gastric cancer; 440 were included in the development set, 105 were included in the validation set. A prognostic model was constructed from the development set. The scoring system was based on hazard ratios in a Cox proportional hazard model. In the multivariate analysis, age, tumor size, Lauren type, depth of invasion, lymph node metastasis, and the neutrophil—lymphocyte ratio were independent prognostic indicators of overall survival. A prognostic model was then established based on the significant factors. Patients were categorized into five groups according to their scores. The 3-year survival rates for the low- to high-risk groups were 98.9%, 92.8%, 82.4%, 58.4%, and 36.9%, respectively (P < 0.001). The prognostic model clearly discriminated patients with stage pT1-4N0M0 tumor into four risk groups with significant differences in the 3-year survival rates (P < 0.001). Compared with the pathological T stage, the model improved the predictive accuracy of the 3-year survival rate by 5% for node-negative patients. The prognostic scores also stratified the patients with stage pT4aN0M0 tumor into significantly different risk groups (P = 0.004). Furthermore, the predictive value of this model was validated in an independent set of 274 patients. This model, which included the systemic inflammatory markers and clinicopathological factors, is more effective in predicting the prognosis of node-negative gastric cancer than traditional staging systems. Patients in the high-risk group might be good candidates for adjuvant chemotherapy.
PMCID: PMC4468084  PMID: 26075713
12.  Acute Interstitial Nephritis Following Multiple Asian Giant Hornet Stings 
Patient: Male, 42
Final Diagnosis: Acute interstitial nephritis
Symptoms: Difficulty breathing • headache • numbness • oliguria
Medication: Methylprednisolone
Clinical Procedure: Plasma exchange
Specialty: Nephrology
Rare disease
The Asian giant hornet is the largest wasp species in the world. Its stings can cause acute interstitial nephritis and acute renal failure. From July to October, 2013, Asian giant hornet attacks have killed 42 people and injured 1675 people with their powerful venomous stings in Hanzhong, Ankang, and Shangluo, three cities in the southern part of Shaanxi Province, China.
Case Report:
We report here a case of a 42-year-old man with acute interstitial nephritis following multiple Asian giant hornet stings. On admission, the patient had difficulty breathing, headache, and numbness in both limbs (arm and leg). He was treated in the Emergency Department and Department of Nephrology with plasma exchange and dialysis within 24 hours after being stung. A kidney biopsy revealed acute interstitial nephritis with interstitial infiltrations of eosinophils and lymphocytes. After intensive treatment, his liver function recovered within 10 days. Along with oral methylprednisolone, his renal function recovered 1 month later.
This case shows that acute interstitial nephritis happens several days after being stung. Since the number of deaths in southern Shaanxi province is much higher than other places, our report draws the attention of fellow clinicians to the acute interstitial nephritis following multiple Asian giant hornet stings.
PMCID: PMC4479185  PMID: 26076055
Acute Kidney Injury; Methylprednisolone; Wasp Venoms
13.  Relationship between insecticide resistance and kdr mutations in the dengue vector Aedes aegypti in Southern China 
Parasites & Vectors  2015;8:325.
Aedes aegypti is an important vector for dengue virus and thus has been targeted with pyrethroid insecticides in many areas of the world. As such, resistance has been detected to several of these insecticides, including in China, but the mechanisms of the resistance are not well understood in this country.
Using the World Health Organization larval mosquito bioassay, five field populations of Aedes aegypti from Southern China were characterized for their resistance to cypermethrin and cyhalothrin. RNA extraction with PCR amplification, cloning and sequencing of the sodium channel gene was followed by comparisons of susceptible and wild mosquito strains Additionally, genomic DNA was used for Allele-specific PCR (AS-PCR) genotyping of the sodium channel genes to detect S989P, V1016G and F1534C mutations and allow for correlation analysis of resistance expression for the different mutations.
All wild strains expressed resistance to cypermethrin and cyhalothrin and the resistance expression between the two insecticides was highly correlated suggesting cross-resistance between these two pyrethroids. The AS-PCR technique effectively distinguished individual genotypes for all three mutations. Among the five wild strains tested, two strains carried all three mutations. Although the S989P and V1016G mutations were positively correlated to resistance expression of both pyrethroids, the F1534C mutation was negatively correlated.
Our methodology proved highly reliable and will aid future detection of kdr mutations. The three sodium channel mutations were common in the Ae. aegypti strains sampled from Southern China. The V1016G mutation appears to be the most important kdr mutation in Ae. aegypti strains in Southern China.
PMCID: PMC4475621  PMID: 26068925
Aedes aegypti; kdr mutation; China
14.  Pyrosequencing revealed shifts of prokaryotic communities between healthy and disease-like tissues of the Red Sea sponge Crella cyathophora 
PeerJ  2015;3:e890.
Sponge diseases have been widely reported, yet the causal factors and major pathogenic microbes remain elusive. In this study, two individuals of the sponge Crella cyathophora in total that showed similar disease-like characteristics were collected from two different locations along the Red Sea coast separated by more than 30 kilometers. The disease-like parts of the two individuals were both covered by green surfaces, and the body size was much smaller compared with adjacent healthy regions. Here, using high-throughput pyrosequencing technology, we investigated the prokaryotic communities in healthy and disease-like sponge tissues as well as adjacent seawater. Microbes in healthy tissues belonged mainly to the Proteobacteria, Cyanobacteria and Bacteroidetes, and were much more diverse at the phylum level than reported previously. Interestingly, the disease-like tissues from the two sponge individuals underwent shifts of prokaryotic communities and were both enriched with a novel clade affiliated with the phylum Verrucomicrobia, implying its intimate connection with the disease-like Red Sea sponge C. cyathophora. Enrichment of the phylum Verrucomicrobia was also considered to be correlated with the presence of algae assemblages forming the green surface of the disease-like sponge tissues. This finding represents an interesting case of sponge disease and is valuable for further study.
PMCID: PMC4465955  PMID: 26082867
Low microbial abundance; Verrucomicrobia; Sponge symbiont; Disease-like sponge
15.  A Glutamate Receptor Antagonist, S-4-Carboxyphenylglycine (S-4-CPG), Inhibits Vasospasm After Subarachnoid Hemorrhage in Haptoglobin 2-2 Mice 
Neurosurgery  2013;73(4):719-729.
Vasospasm contributes to delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage (aSAH). Glutamate concentrations increase after aSAH and correlate with vasospasm in experimental SAH. The Hp2-2 genotype is associated with higher risk of vasospasm after SAH. We tested the efficacy of S-4-CPG, a metabotropic glutamate receptor inhibitor, for treatment of vasospasm after SAH in Hp2-2 and Hp1-1 mice.
To evaluate the effect on vasospasm and neurobehavioral scores after SAH of systemic S-4-CPG, as well as its toxicity, and phosphorylation of vasodilator-stimulated phosphoprotein (VASP) in Hp 2-2 mice.
Western blot was used to assess changes in VASP phosphorylation in response to glutamate with and without S-4-CPG. A pharmacokinetics study was done to evaluate S-4-CPG penetration through the blood brain barrier (BBB) in vivo. Toxicity was assessed by administering escalating S-4-CPG doses. Efficacy of S-4-CPG assessed the effect of S-4-CPG on lumen patency of the basilar artery and animal behavior after SAH in Hp 1-1 and Hp 2-2 mice. Immunohistochemistry was used to evaluate the presence of neutrophils surrounding the basilar artery after SAH.
Exposure of human brain microvascular endothelial cells to glutamate decreased phosphorylation of VASP (p-VASP), but glutamate treatment in the presence of S-4-CPG maintains p-VASP. S-4-CPG crosses the BBB and was not toxic to mice. S-4-CPG treatment significantly prevents vasospasm after SAH. S-4-CPG administered after SAH resulted in a trend towards improvement of animal behavior.
S-4-CPG prevents vasospasm after experimental SAH in Hp2-2 mice. S-4-CPG was not toxic and is a potential therapeutic agent for vasospasm after SAH.
PMCID: PMC4461079  PMID: 23842553
Glutamate; Haptoglobin; S-4-CPG, SAH; Subarachnoid; Vasospasm
16.  Tumor-Targeting Salmonella typhimurium A1-R in Combination with Trastuzumab Eradicates HER-2-Positive Cervical Cancer Cells in Patient-Derived Mouse Models 
PLoS ONE  2015;10(6):e0120358.
We have previously developed mouse models of HER-2-positive cervical cancer. Tumors in nude mice had histological structures similar to the original tumor and were stained by anti-HER-2 antibody in the same pattern as the patient’s cancer. We have also previously developed tumor-targeting Salmonella typhimurium A1-R and have demonstrated its efficacy against patient-derived tumor mouse models, both alone and in combination. In the current study, we determined the efficacy of S. typhimurium A1-R in combination with trastuzumab on a patient-cancer nude-mouse model of HER-2 positive cervical cancer. Mice were randomized to 5 groups and treated as follows: (1) no treatment; (2) carboplatinum (30 mg/kg, ip, weekly, 5 weeks); (3) trastuzumab (20 mg/kg, ip, weekly, 5 weeks); (4) S. typhimurium A1-R (5 × 107 CFU/body, ip, weekly, 5 weeks); (5) S. typhimurium A1-R (5 × 107 CFU/body, ip, weekly, 5 weeks) + trastuzumab (20 mg/kg, ip, weekly, 5 weeks). All regimens had significant efficacy compared to the untreated mice. The relative tumor volume of S. typhimurium A1-R + trastuzumab-treated mice was smaller compared to trastuzumab alone (p = 0.007) and S. typhimurium A1-R alone (p = 0.039). No significant body weight loss was found compared to the no treatment group except for carboplatinum-treated mice (p = 0.021). Upon histological examination, viable tumor cells were not detected, and replaced by stromal cells in the tumors treated with S. typhimurium A1-R + trastuzumab. The results of the present study suggest that S. typhimurium A1-R and trastuzumab in combination are highly effective against HER-2-expressing cervical cancer.
PMCID: PMC4457918  PMID: 26047477
17.  Clinical Research in a Modern Chinese Peritoneal Dialysis Center 
A prerequisite for enhancing the quality of peritoneal dialysis is the continuous review and analysis of clinical data from routine clinical care and research. Here, we describe our strategy (Peking University First Hospital, Beijing, China) to achieve that objective.
PMCID: PMC4076968  PMID: 24962963
Clinical research
18.  Plasma complement factor H is associated with disease activity of patients with ANCA-associated vasculitis 
Increasing evidences have demonstrated that activation of alternative complement pathway plays an important role in the pathogenesis of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The current study aimed to investigate the association of complement factor H (CFH), a key regulator of the alternative complement pathway, with the disease activity of AAV.
Plasma CFH levels were measured in 82 patients with myeloperoxidase (MPO)-AAV in active stage. Of the 82 patients, plasma CFH levels of 27 patients were longitudinally measured. Serum anti-CFH autoantibodies were screened in AAV patients. Circulating complement activation profiles including C4d, Bb, C3a, C5a and soluble C5b-9 of AAV patients in active stage were further detected. Associations between plasma CFH levels and clinicopathological parameters as well as the prognosis were analyzed.
Plasma CFH levels were significantly lower in active AAV patients compared with AAV patients in remission and normal controls. Correlation analysis showed that plasma CFH levels inversely correlated with initial serum creatinine, Birmingham Vasculitis Activity Score (BVAS), proportion of total crescents and cellular crescents in renal specimens, and circulating levels of C3a, C5a and Sc5b-9, meanwhile positively correlated with estimated glomerular filtration rate (eGFR), hemoglobin levels and circulating levels of C3. Moreover, multivariate survival analysis revealed that plasma CFH levels were independently associated with composite outcome of death or end stage renal disease (ESRD) in AAV patients, after adjusting for age, gender, hemoglobin level and urinary protein (P = 0.03, HR 0.85, 95 % CI 0.73–0.98) or adjusting for age, gender, total crescents (%) and urinary protein (P = 0.03, HR 0.85, 95 % CI 0.73–0.98), while not as an independent predictor after adjusting for age, gender, serum creatinine and urinary protein (P = 0.57, HR 0.96, 95 % CI 0.83–1.11).
In conclusion, plasma CFH levels are associated with disease activity, and, to some extent, associated with composite outcomes of patients with MPO-ANCA-associated vasculitis.
PMCID: PMC4489360  PMID: 25994214
19.  An Integrated Metagenomics/Metaproteomics Investigation of the Microbial Communities and Enzymes in Solid-state Fermentation of Pu-erh tea 
Scientific Reports  2015;5:10117.
Microbial enzymes during solid-state fermentation (SSF), which play important roles in the food, chemical, pharmaceutical and environmental fields, remain relatively unknown. In this work, the microbial communities and enzymes in SSF of Pu-erh tea, a well-known traditional Chinese tea, were investigated by integrated metagenomics/metaproteomics approach. The dominant bacteria and fungi were identified as Proteobacteria (48.42%) and Aspergillus (94.98%), through pyrosequencing-based analyses of the bacterial 16S and fungal 18S rRNA genes, respectively. In total, 335 proteins with at least two unique peptides were identified and classified into 28 Biological Processes and 35 Molecular Function categories using a metaproteomics analysis. The integration of metagenomics and metaproteomics data demonstrated that Aspergillus was dominant fungus and major host of identified proteins (50.45%). Enzymes involved in the degradation of the plant cell wall were identified and associated with the soft-rotting of tea leaves. Peroxiredoxins, catalase and peroxidases were associated with the oxidation of catechins. In conclusion, this work greatly advances our understanding of the SSF of Pu-erh tea and provides a powerful tool for studying SSF mechanisms, especially in relation to the microbial communities present.
PMCID: PMC4431464  PMID: 25974221
20.  The Effects of Plastic Film Mulching on Maize Growth and Water Use in Dry and Rainy Years in Northeast China 
PLoS ONE  2015;10(5):e0125781.
Plastic film mulching (PM) has been widely used to improve maize (Zea mays L.) yields and water use efficiency (WUE) in Northeast China, but the effects of PM in a changing climate characterized by highly variable precipitation are not well understood. Six site-year field experiments were conducted in the dry and rainy years to investigate the effects of PM on maize growth, grain yield, and WUE in Northeast China. Compared to crops grown without PM treatment (control, CK), PM significantly increased the grain yield by 15-26% in the dry years, but no significant yield increase was observed in the rainy years. Yield increase in the dry years was mainly due to a large increase in dry matter accumulation pre-silking compared to the CK, which resulted from a greater dry matter accumulation rate due to the higher topsoil temperature and water content. As a result, the WUE of the crops that underwent PM (3.27 kg m-3) treatment was also increased by around 16% compared to the CK, although the overall evapotranspiration was similar between the two treatments. In the rainy years, due to frequent precipitation and scant sunshine, the topsoil temperature and water content in the field that received PM treatment was improved only at some stages and failed to cause higher dry matter accumulation, except at the 8th leaf stage. Consequently, the grain yield and WUE were not improved by PM in the rainy years. In addition, we found that PM caused leaf senescence at the late growth stage in both dry and rainy years. Therefore, in practice, PM should be applied cautiously, especially when in-season precipitation is taken into account.
PMCID: PMC4430173  PMID: 25970582
21.  Oral administration of marine collagen peptides prepared from chum salmon (Oncorhynchus keta) improves wound healing following cesarean section in rats 
Food & Nutrition Research  2015;59:10.3402/fnr.v59.26411.
The goal of the present study was to investigate the wound-healing potential of marine collagen peptides (MCPs) from chum salmon skin administered to rats following cesarean section (CS).
Ninety-six pregnant Sprague-Dawley rats were randomly divided into four groups: a vehicle group and three MCP groups. After CS, rats were intragastrically given MCPs at doses of 0, 0.13, 0.38, 1.15 g/kg*bw, respectively. On postoperative days 7, 14, and 21, the uterine bursting pressure, skin tensile strength, hydroxyproline (Hyp) concentrations, and histological and immunohistochemical characteristics of the scar tissue were examined.
In the MCP groups, the skin tensile strength, uterine bursting pressure, and Hyp were significantly higher than those in the vehicle group at all three time points (p<0.05). The formation of capillary, fibroblast, and collagen fiber, the expression of platelet-endothelial cell adhesion molecule-1, basic fibroblast growth factor, and transforming growth factor beta-1 were increased in the MCP groups (p<0.05).
MCPs could accelerate the process of wounding healing in rats after CS.
PMCID: PMC4432022  PMID: 25976613
cesarean section; marine collagen peptide; wound healing; basic fibroblast growth factor; transforming growth factor beta 1; CD31
22.  Intraperitoneal administration of tumor-targeting Salmonella typhimurium A1-R inhibits disseminated human ovarian cancer and extends survival in nude mice 
Oncotarget  2015;6(13):11369-11377.
Peritoneal disseminated cancer is highly treatment resistant. We here report the efficacy of intraperitoneal (i.p.) administration of tumor-targeting Salmonella typhimurium A1-R in a nude mouse model of disseminated human ovarian cancer. The mouse model was established by intraperitoneal injection of the human ovarian cancer cell line SKOV3-GFP. Seven days after implantation, mice were treated with S. typhimurium A1-R via intravenous (i.v.) or i.p. administration at the same dose, 5×107 CFU, once per week. Both i.v. and i.p. treatments effected prolonged survival compared with the untreated control group (P=0.025 and P<0.001, respectively). However, i.p. treatment was less toxic than i.v. treatment. Tumor-specific targeting of S. typhimurium A1-R was confirmed with bacterial culture from tumors and various organs and tumor or organ colony formation after i.v. or i.p. injection. Selective tumor targeting was most effective with i.p. administration. The results of the present study show S. typhimurium A1-R has promising clinical potential for disseminated ovarian cancer, especially via i.p. administration.
PMCID: PMC4484462  PMID: 25957417
ovarian cancer; orthotopic; mouse model; bacterial therapy; Salmonella typhimurium A1-R
23.  The Real Culprit in Systemic Lupus Erythematosus: Abnormal Epigenetic Regulation 
Systemic lupus erythematosus (SLE) is an autoimmune disease involving multiple organs and the presence of anti-nuclear antibodies. The pathogenesis of SLE has been intensively studied but remains far from clear. B and T lymphocyte abnormalities, dysregulation of apoptosis, defects in the clearance of apoptotic materials, and various genetic and epigenetic factors are attributed to the development of SLE. The latest research findings point to the association between abnormal epigenetic regulation and SLE, which has attracted considerable interest worldwide. It is the purpose of this review to present and discuss the relationship between aberrant epigenetic regulation and SLE, including DNA methylation, histone modifications and microRNAs in patients with SLE, the possible mechanisms of immune dysfunction caused by epigenetic changes, and to better understand the roles of aberrant epigenetic regulation in the initiation and development of SLE and to provide an insight into the related therapeutic options in SLE.
PMCID: PMC4463688  PMID: 25988383
SLE; epigenetics; DNA methylation; histone modification; microRNA
24.  Renal myopericytoma: a clinicopathologic study of six cases and review of the literature 
To evaluate the morphologic features, immunohistochemical profiles, and biological behavior of renal myopericytoma. Six cases of renal myopericytoma are retrospectively retrieved and analyzed by H&E and immunohistochemical staining. Clinically, patient’s age ranged from 33 to 70 years (median, 56 years). Male to female ratio was 5:1. Five of the six patients were asymptomatic of the urinary tract, the remained one presented with abdomen pain. Grossly, all six tumors were solitary masses with sizes ranging from 1.8 to 7.3 cm of maximum diameter (mean, 4.4 cm). Five tumors were described as well-circumscribed, and 1 case was showed as ill-defined. Histologically, in all cases, numerous thin-walled vessels and a perivascular arrangement of ovoid, spindled or round myoid tumor cells were seen. However, a broad morphologic spectrum ranging from fibroma-like (3 cases), glomangiopericytoma-like (3 cases), angioleiomyoma-like (2 cases), glomoid- like (2 cases), and myofibroma-like (2 cases) components were observed. In addition, 1 neoplasm with immature cellular features and another infiltrating myopericytoma were found. A coexisting papillary adenoma was detected in 1 case. Nuclear atypia was seen in 2 cases. Immunohistochemically, SMA, caldesmon, and MSA were positive in all 6 cases, whereas CD34 and desmin was partial positive in 1 case, respectively. Ki67 index was aproximately 5% in 1 case but less than 2% in the others. All patients are free of disease by follow-up ranging from 14 to 66 months (mean, 38.7 months).
PMCID: PMC4502995  PMID: 26191123
Myopericytoma; perivascular myoid cell tumor; infiltrating; uncertain malignant potential; papillary adenoma; kidney
25.  Gene-gene interactions among CX3CL1, LEPR and IL-6 related to coronary artery disease in Chinese Han population 
Objective: The purpose of this study was to investigate the impact of the interactions among CX3CL1 (rs170364 and rs614230), LEPR (rs6700896), and IL-6 (rs2066992) polymorphisms on the risk of coronary artery disease (CAD) in Chinese Han population. Methods: 120 CAD patients and 109 healthy controls were enrolled in the study. Polymerase chain reaction (PCR) and direct sequencing methods were used to analyze the genotypes of CX3CL1, LEPR, and IL-6 polymorphisms. Multifactor dimensionality reduction (MDR) software was utilized to analyze gene-gene interactions. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were used for evaluating the association between gene polymorphisms or gene-gene interactions and CAD risk. Results: In the study, TT genotype of rs170364 in CX3CL1 might decrease the CAD risk (OR=0.39, 95% CI=0.16-0.98). No significant correlation was found between T allele of rs170364 and CAD risk (P>0.05). CC genotype and C allele in rs614230 (CX3CL1) were significantly related with decreased risk of CAD (OR=0.38, 95% CI=0.17-0.86; OR=0.66, 95% CI=0.45-0.97). For IL-6 rs2066992 polymorphism. GG genotype could increase the risk of CAD (OR=2.32, 95% CI=1.04-5.17). Whereas, no significant correlation was observed between LEPR rs6700896 and CAD susceptibility. MDR analysis showed that CX3CL1, LEPR and IL-6 genes might jointly promote the occurrence of CAD. Conclusions: The interactions of CX3CL1, LEPR and IL-6 genes might increase the risk of CAD.
PMCID: PMC4503200  PMID: 26191329
CX3CL1; LEPR; IL-6; interaction; coronary artery disease

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